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Parkinson's Disease - Medical Clinical Policy Bulletins | Aetna of 99

(https://www.aetna.com/)

Parkinson's Disease

Number: 0307

Policy *Please see amendment for Pennsylvania Medicaid at the end of this CPB.

Policy History

Last Review

06/04/2020

Effective: 12/10/1998

Next

Review: 03/25/2021

Review History

Definitions

Ad d i t ion al Information

Clinical Policy Bulletin

Notes

Diagnosis

I. Aetna considers levodopa or apomorphine challenge

medically necessary when the diagnosis of Parkinson

disease (PD) is in doubt.

II. Aetna considers olfactory testing by means of the

University of Pennsylvania Smell Identification Test

(UPSIT) or “Sniffin' Sticks” medically necessary to

differentiate PD from progressive supranuclear palsy

and corticobasal degeneration.

III. Aetna considers neuropsychological testing for the

diagnosis of PD medically necessary.

IV. Aetna considers any of the following tests experimental

and investigational for differentiating PD from other

parkinsonian syndromes because their effectiveness for

this indication has not been established:

A. Electrooculography Proprietary

https://www.aetna.com


B. Growth hormone stimulation with clonidine

C. Iodine-123 meta-iodobenzylguanidine cardiac

imaging

D. Magnetic resonance imaging (MRI)

E. Tilt table testing

F. Transcranial duplex scanning

V. Aetna considers the following genetic testing of PD

experimental and investigational because its

effectiveness for this indication has not been

established:

A. PD (e.g., testing for alpha-synuclein, apolipoprotein E

(APOE),

B. DJ1,

C. fibroblast growth factor 20 rs12720208

polymorphism,

D. glutathione S-transferase M1 (GSTM1) and

glutathione S-transferase T1 (GSTT1) polymorphisms,

E. interleukin-10 polymorphisms (-1082A/G and

-592C/A),

F. LRRK2/PARK8,

G. parkin/PARK2,

H. PARK10 and its variants,

I. PINK1,

J. PITX3, and

K. sphingomyelin phosphodiesterase 1 gene (SMPD1).

VI. Aetna considers cerebrospinal fluid (CSF) α-synuclein,

heart fatty acid-binding protein, neurofilament light

chain, tau (phosphorylated or total) and ubiquitin

carboxy-terminal hydrolase L1 (UCH-L1) as diagnostic

biomarkers for PD experimental and investigational

because the effectiveness of this approach for this

indication has not been established .

Proprietary


VII. Aetna considers CSF amyloid beta 1-42 as a biomarker

for PD progression experimental and investigational

because its effectiveness for this indication has not been

established.

VIII. Aetna considers quantitative EEG (qEEG) measures as

predictive biomarkers for the development of dementia

in PD experimental and investigational because its

effectiveness for this indication has not been

established.

IX. Aetna considers SPECT scanning (e.g., DaTSCAN

(Ioflupane I-123 injection - a radiopharmaceutical

indicated for striatal dopamine transporter

visualization)) medically necessary to distinguish PD

from essential tremor. Aetna considers SPECT scanning

experimental and investigational for distinguishing PD

from other parkinsonian syndromes; and for monitoring

the progression of PD.

X. Aetna considers the use of serum α-synuclein

autoantibody as a biomarker for PD experimental and

investigational because its effectiveness for this

indication has not been established.

XI. Aetna considers submandibular gland needle biopsy for

the diagnosis of PD experimental and investigational

because its effectiveness for this indication has not been

established.

XII. Aetna considers measurement of telomere length as a

risk factor for development of PD experimental and

investigational because its effectiveness for this

indication has not been established.

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XIII. Aetna considers measurement of urinary LRRK2

phosphorylation to determine PD risk among LRRK2

mutation carriers experimental and investigational

because the effectiveness of this approach has not been

established.

XIV. Aetna considers vagotomy for the prevention and

treatment of PD experimental and investigational

because the effectiveness of this approach has not been

established.

XV. Aetna considers retinal thinning as a biomarker of PD

experimental and investigational because the

effectiveness of this approach has not been established.

XVI. Aetna considers plasma neurofilament light chain (NfL)

as a biomarker for disease severity and progression in

PD experimental and investigational because the


XVII. Aetna considers salivary biomarkers (e.g.,

acetylcholinesterase, alpha-synuclein, cortisol, heme

oxygenase-1, and nitric oxide) for diagnosis of PD

experimental and investigational because the


XVIII. Aetna considers serum fibroblast growth factor 21 (FGF

21), serum growth differentiation factor 15 (GDF-15) and

blood mitochondrial DNA (mtDNA) copy number levels

as biomarkers of PD experimental and investigational

because the effectiveness of these approaches has not

been established.

Proprietary


See

CPB 0071 - Positron Emission Tomography (PET),

also (../1_99/0071.html)

CPB 0158 - Neuropsychological and Psychological Testing

(../100_199/0158.html)

, CPB 0168 - Tumor Scintigraphy (../100_199/0168.html),

CPB 0221 - Quantitative EEG (Brain Mapping),

(../200_299/0221.html)

and

CPB 0390 - Smell and Taste Disorders: Diagnosis

(0390.html)

.

Surgical Treatment

I. Pallidotomy for the Treatment of PD

Aetna considers pallidotomy medically necessary for the

treatment of PD when all of the following selection criteria are

met:

A. Individuals with idiopathic PD who have tried and

failed medical therapy as indicated by worsening of

Parkinsonian symptoms and/or disabling medication

side effects (motor fluctuations with “wearing off”,

and unpredictable “on/off”, as well as Sinemet

induced dyskinesia); and

B. Members exhibit 2 of 4 major symptoms

(bradykinesia, tremor, rigidity, and gait disturbance);

and

C. Members have a history of positive response to

dopaminergic replacement therapy (e.g., Sinemet or

bromocriptine); and

D. Members have been screened by a neurologist who

has expertise in movement disorders to ensure all

reasonable forms of pharmacotherapies have been

tried and failed.

Proprietary


Pallidotomy for the treatment of PD is of no proven value in

persons with the following conditions:

A. Members with Parkinso n's plus or atypical

Parkinson's disorders (e.g., multi-system atrophy,

striato-nigral degeneration, progressive

supranuclear palsy, or combined Alzheimer's disease

and PD); or

B. Members with severe dementia or cerebral atrophy;

or

C. Members with Hoehn and Yahr Stage V Parkinson's

disease (see Note below).

Note: Hoehn and Yahr Stage V individuals exhibit the

following characteristics :

▪ Cachectic state

▪ Can not stand or walk (need wheelchair assistance,

or are unable to get out of bed)

▪ Invalidism

▪ Requires constant nursing care

II. Fetal Tissue/Fetal xenografts Transplantation for PD

Aetna considers transplantation of fetal mesencephalic tissue or

fetal xenografts (e.g., from pigs or other animals) experimental

and investigational for the treatment of PD because the long-term

safety and effectiveness of these procedures have not been

established.

III. Stem Cell Transplantation for PD

Aetna considers stem cell transplantation experimental and

investigational for the treatment of PD because its effectiveness

for this indication has not been established.

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IV. Adrenal Medullary Transplantation for PD

Aetna considers adrenal medullary transplantation experimental

and investigational for the treatment of PD because of a lack of

evidence of effectiveness for this indication.

V. Subthalamotomy

Aetna considers subthalamotomy experimental and

investigational for the treatment of PD because it has not been

shown to be effective for that indication.

VI. Intra-striatal Implantation of Human Retinal Pigment

Epithelial Cells

Aetna considers intra-striatal implantation of human retinal

pigment epithelial cells experimental and investigational for the

treatment of PD because its effectiveness has not been

established.

VII. Extra-dural Motor Cortex Stimulation

Aetna considers extra-dural motor cortex stimulation

experimental and investigational for the treatment of PD because

its effectiveness has not been established.

VIII. Gene Therapy

Aetna considers gene therapy for the treatment of PD

experimental and investigational because its effectiveness has not

been established.

IX. Magnetic Resonance Imaging-Guided Focused Ultrasound Neurosurgery

Proprietary


Aetna considers magnetic resonance imaging-guided focused

ultrasound neurosurgery for the treatment of PD experimental

and investigational because the effectiveness of this approach has

not been established.

See

also CPB 0208 - Deep Brain Stimulation (../200_299/ 0208.html)

for deep brain stimulation of PD,

and CPB 0153 - Thalamotomy (../100_199/ 0153.html) for

thalamotomy for PD.

Non-Surgical Treatments

Levodopa-Carbidopa Intestinal Gel

Aetna considers levodopa-carbidopa intestinal gel (Duopa)

medically necessary for the treatment of motor fluctuations in

members with advanced Parkinson's disease when all of the

following criteria are met:

▪ Member is levodopa responsive with clearly defined

“on” periods ; and

▪ The member has "off" periods greater than 3 hours per

day despite optimization efforts; and

▪ The member must have had an inadequate response or

intolerable adverse event with oral carbidopalevodopa

(IR or CR) and one of the following anti-Parkinson

agents:

• Catechol -O-m ethyl transferase (COMT) inhibitor (e.g.

entacapone)

• Monoamine oxidase B (MAO)-B inhibitor (e.g. oral

selegiline, Azilect)

• Dopamine agonists (e.g. pramipexole, ropinirole,

Neupro) .

Proprietary


Continued use of levodopa-carbidopa intestinal gel (Duopa) is

considered medically necessary for the treatment of motor

fluctuations in members with advanced Parkinson’s disease

who have demonstrated a positive clinical response to Duopa

therapy.

A pump for administering levodopa-carbidopa intestinal gel

(CADD®‐Legacy 1400 portable infusion pum p) is considered

medically n ecessary DME for persons who meet criteria for

levodopa-carbidopa intestinal gel.

Concurrent use of Duopa and nonselective monoamine

oxidase (MAO) inhibitors (e.g., phenelzine and

tranylcypromine) is considered experimental and

investigational. Duopa is considered experimental and

investigational for all other indications.

Hyperbaric Oxygen Therapy

Aetna considers hyperbaric oxygen therapy for the treatment

of PD experimental and investigational because its

effectiveness has not been established

CPB 0172 - Hyperbaric Oxygen Therapy (HBOT)

(see (../100_199/0172.html) ).

Intravenous Glutathione

Aetna considers intravenous glutathione for the treatment of

PD experimental and investigational because its effectiveness

has not been established.

Transcranial Direct Current Stimulation/Transcranial Magnetic Stimulation

Aetna considers transcranial direct current

stimulation/transcranial magnetic stimulation for the treatment

of PD experimental and investigational because their

effectiveness have not been established.

Proprietary


Bright Light Therapy

Aetna considers bright light therapy for the treatment of

depression in Parkinson disease experimental and

investigational because the effectiveness of this approach has


C u eing Module Device (Auditory Cue)

Aetna considers cueing module device (auditory cue) for the

treatment of Parkinson's freezing experimental and

investigational because the effectiveness of this approach has


Dosing Recommendations

Levodopa-Carbidopa Intestinal Gel (Duopa)

▪ Available for enteral suspension: 4.63 mg carbidopa and

20 mg levodopa per mL.

▪ The maximum recom men ded daily dose of Duopa is

2000 mg of levodopa (i.e., one cassette per day)

administered over 16 hours. Prior to initiating

Duopa, individuals should be converted from all forms

of levodopa to oral immediate-release carbidopa

levodopa tablets (1:4 ratio). The total daily dose is

titrated based on the clinical response. Duopa is

administered into the jejunum through a percutaneous

endosco pic gastrostom y with jejunal tube (PEG-J) with

the CADD-Legacy 1400 portable infusion pump.

Source: AbbVie, 2016

Background

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Parkinson disease (PD) is the most common cause of

parkinsonism, which is characterized by bradykinesia, rigidity,

resting tremor, and postural reflex impairment. The diagnosis

of PD is based on a careful taking of medical history and a

thorough physical examination. Currently, there are no

laboratory tests or imaging studies that confirm the diagnosis

(Nutt and Wooten, 2005). It is important for clinicians to

understand the clinical signs that aid to differentiate PD from

various parkinsonism syndromes (also known as Parkinson-

plus syndromes) that include progressive supranuclear palsy

(PSP), multiple system atrophy (MSA), cortico-basal

degeneration (CBD), dementia with Lewy bodies (DLB),

vascular parkinsonism, parkinsonism with no clear etiology,

and Parkinson-dementia-amyotrophic lateral sclerosis

complex.

The correct diagnosis of PD is important for prognostic as well

as therapeutic reasons. Research of the diagnostic accuracy

for the disease and other forms of parkinsonism in community-

based samples of patients taking anti-parkinsonian medication

confirmed a diagnosis of parkinsonism in only 74 % of patients

and clinically probable PD in 53 % of patients.

Clinicopathological studies based on brain bank material from

the United Kingdom and Canada have revealed that clinicians

diagnose the disease incorrectly in about 25 % of patients. In

these studies, the most common reasons for diagnostic errors

were presence of essential tremor, vascular parkinsonism, and

atypical parkinsonian syndromes. Infrequent misdiagnosis

included Alzheimer's disease (AD), DLB, and drug-induced

parkinsonism. Moreover, ancillary tests such as olfactory

testing and dopamine-transporter (DAT) single photon

emission computed tomography (SPECT) imaging may help

with clinical diagnostic decisions (Tolosa et al, 2006).

Winogrodzka et al (2005) noted that DAT scintigraphy with

SPECT has been used to evaluate the dopaminergic function

in patients with PD. Initial studies with several radioligands

show significant loss of DAT binding in PD patients as

compared to controls.

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It should be noted that the role of neuroimaging in the

differential diagnosis of PD has not been clearly established.

Piccini and Whone (2004) noted that recent improvements in

the characterization of the parkinsonian syndromes have led to

improvements in clinical diagnostic accuracy; however, clinical

criteria alone are not always sufficient to distinguish between

idiopathic PD and other parkinsonian syndromes, especially in

the early stages of disease and in atypical presentations.

Thus, in addition to the development and implementation of

diagnostic clinical assessments, there is a need for available

objective markers to aid clinicians in the differential diagnosis

of idiopathic PD (IPD). Functional neuroimaging such as

positron emission tomography (PET) and SPECT holds the

promise of improved diagnosis and allows assessment in early

disease.

Seibyl et al (2005) stated that the development of imaging

biomarkers, which target specific sites in the brain, represents

a major advance in neurodegenerative diseases and PD with

the promise of new and improved approaches for the early and

accurate diagnosis of disease as well as novel ways to monitor

patients and assess treatment. The 3 major applications that

imaging may play a role in PD are: (i) the use of

neuroimaging as a biomarker of disease in order to

improve the accuracy, timeliness, and reliability of

diagnosis; (ii) objective monitoring of the progression of

disease to provide a molecular phenotype of PD that may

illuminate some of the sources of clinical variability;and (iii)

the evaluation of disease-modifying treatments designed to

retard the progression of disease by interfering with

pathways thought to be implicated in the ongoing neuronal

loss or replace dopamine-producing cells. Each of these

areas has shown a numbers of critical clinical investigations

that have better defined the utility of neuroimaging to these

tasks. However, current unresolved issues around the clinical

role of neuroimaging in monitoring PD patients over time and

validation of quantitative imaging measures of dopaminergic

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function are immediate issues for the field and the subject of

current research efforts and the extension of the lessons

learned in PD to other neurodegenerative diseases including

AD.

In a review on conventional and advanced magnetic

resonance imaging (MRI) techniques in the differential

diagnosis of neurodegenerative parkinsonism, Seppi and

Schocke (2005) noted that research findings suggest that

novel MRI techniques such as magnetization transfer imaging,

diffusion-weighted imaging, and magnetic resonance

volumetry have superior sensitivity compared to conventional

MRI in detecting abnormal features in neurodegenerative

parkinsonian disorders. They stated that whether these

techniques will emerge as standard tools in the work-up of

patients presenting with parkinsonism requires further

prospective studies during early disease stages.

Ravina and colleagues (2005) reported that radiotracer

imaging (RTI) of the nigrostriatal dopaminergic system is a

widely used but controversial biomarker in PD. These

investigators reviewed the concepts of biomarker development

and the evidence to support the use of four radiotracers as

biomarkers in PD: (i) [18F]fluorodopa PET, (ii) (+)-[11C]

dihydrotetrabenazi ne PET, (iii) [123I]beta-CIT SPECT,and (iv)

[18F]fluorodeoxyglucose PET. According to the authors,

biomarkers used to study disease biology and facilitate drug

discovery and early human clinical trials rely on evidence that

they are measuring relevant biological processes. The 4

tracers fulfill this criterion, although they do not measure the

number or density of dopaminergic neurons. Biomarkers used

as diagnostic tests, prognostic tools, or surrogate endpoints

must not only have biological relevance but also a strong

linkage to the clinical outcome of interest. No radiotracers

fulfill these criteria, and current evidence does not support the

use of imaging as a diagnostic tool in clinical practice or as a

surrogate endpoint in clinical trials. Mechanistic information

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added by RTI to clinical trials may be difficult to interpret

because of uncertainty about the interaction between the

interventions and the tracer.

In the recent practice parameter on the diagnosis and

prognosis of new onset PD (an evidence-based review) by the

American Academy of Neurology (AAN), Suchowersky, et al

(2006) provided the following conclusions/recommendations:

▪ Levodopa or apomorphine challenge should be considered

for confirmation when the diagnosis of PD is in doubt.

▪ Olfactory testing by means of the University of

Pennsylvania Smell Identification Test (UPSIT) or “Sniffin'

Sticks” should be considered to differentiate PD from PSP

and CBD; but notPD from MSA.

▪ The following tests may not be useful in differentiating PD

from other parkinsonian syndromes:

• Electrooculography

• Growth hormone stimulation with clonidine

• SPECT scanning

▪ There is insufficient evidence to determine if iodine-123

meta-iodobenzylguanidine cardiac imaging is useful in

differentiating PD from MSA or PSP.

▪ In the future, there may be an increasing role for genetic

testing to diagnose PD. However, the development of any

new diagnostic test will require long-term follow-up and

autopsy confirmation to determine its accuracy.

de la Fuente-Fernández (2012) evalauted the role of

DaTSCAN in the diagnosis of PD. Using the sensitivity and

specificity values obtained in the 2 studies that recently led the

Food and Drug Administration to approve the use of

DaTSCAN for the diagnosis of PD, calculations were carried

out to estimate the accuracy of the clinical diagnosis taking

DaTSCAN findings as the standard of truth. In early PD, a

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clinical diagnosis of “possible” or “probable” PD has a

sensitivity of 98 % and a specificity of 67 %. The specificity

increases to 94 % once the clinical diagnosis becomes

established. The overall accuracy of the clinical diagnosis is

84 % in early PD and 98 % at later stages.The clinical

diagnostic accuracy is mathematically identical to the

diagnostic accuracy of DaTSCAN imaging. The authors

concluded that in the absence of neuropathologic validation,

the overall accuracy of a clinical diagnosis of PD is very high

and mathematically identical to the accuracy of DaTSCAN

imaging, which calls into question the use of radiotracer

neuroimaging as a diagnostic tool in clinical practice. They

stated that neuropathological studies are definitely needed to

evaluate the diagnostic accuracy of radiotracer neuro-imaging

compared to the clinical diagnosis. Until these assessments

are available, it may be premature to embark on a large-scale

use of DaTSCAN imaging for the diagnosis of PD.

Beyer and colleagues (2007) noted that the nosologic

relationship between DLB and PD with dementia (PDD) is

continuously being debated. These investigators conducted a

study using voxel-based morphometry (VBM) to explore the

pattern of cortical atrophy in DLB and PDD. A total of 74

patients and healthy elderly were imaged (healthy elderly, n =

20; PDD,n = 15;DLB, n = 18, and AD, n = 21). Three

dimensional T1-weighted MRI were acquired, and images

analyzed using VBM. Overall dementia severity was similar in

the dementia groups. These researchers found more

pronounced cortical atrophy in DLB than in PDD in the

temporal, parietal, and occipital lobes. Patients with AD had

reduced gray matter concentrations in the temporal lobes

bilaterally, including the amygdala, compared to PDD.

Compared to DLB, the AD group had temporal and frontal lobe

atrophy. The authors concluded that despite a similar severity

of dementia, patients with DLB had more cortical atrophy than

patients with PDD, indicating different brain substrates

underlying dementia in the 2 syndromes. Together with

previous studies reporting subtle clinical and neurobiological

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differences between DLB and PDD, the findings of this study

supported the hypothesis that PDD and DLB are not identical

entities, but rather represent 2 subtypes of a spectrum of Lewy

body disease.

While the AAN practice parameter on diagnosis and prognosis

of new onset PD (Suchowersky et al, 2006) stated that there is

insufficient evidence to support or refute the use of MRI as a

means of distinguishing PD from other parkinsonian

syndromes, Seppi and Rascol (2007), in an editorial that

accompanied the article by Beyer et al, stated that further

studies involving larger groups of patients with prospective long

term follow-up and ultimate pathologic diagnosis are needed for

verifying the findings of Beyer et al. Furthermore, while such

confirmatory data might be available in the future at the level of

groups of patients, it is unlikely that MRI will be sufficiently

sensitive and specific to allow differential diagnosis at the level

of a single patient.

Genetic causes of PD have been identified in approximately 3

% of cases with the discovery of mutations in 6 genes. The

most common of these are the gene for leucine-rich repeat

kinase 2 (LRRK2 or PARK8), which is autosomal dominant,

and parkin (PARK2), which is recessive. LRRK2 produces a

phenotype identical to classical PD, with age of onset at

approximately 50 to 70 years. The most common mutation

(G2019S) has been reported to cause 1.5 % of all cases of

PD. Penetrance is age-dependent and is estimated to be 25

% to 35 %. Despite LRRK2 being dominantly inherited,many

people who are heterozygous for LRRK2 mutations do not

develop the disease. Homozygous or compound

heterozygous mutations of parkin are the most common cause

of early-onset PD (10 % to 20 % of cases). However, because

single heterozygous mutations also are seen in many people

with PD, these mutations are thought to confer a risk for PD.

This idea is supported by studies of age of onset and by PET

imaging of the dopamine system. However, examinations of

mutation frequency in control populations have had conflicting

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results. Reduced penetrance can cause LRRK2 to act in an

apparently recessive or sporadic manner, and parkin may

appear to be dominant. Hence, the distinction between

dominant and recessive genes in PD is blurred, because the

disease is likely multi-factorial, involving causative genes,

susceptibility genes, environmental exposures that may have

protective effects such as smoking and caffeine, and

exposures that may induce neurodegeneration such as

pesticides (Factor, 2007).

Klein et al (2007) stated that the association of 6 genes with

monogenic forms of parkinsonism has unambiguously

established that the disease has a genetic component. Of

these 6 genes, LRRK2, parkin, and PINK1 (PTEN-induced

putative kinase 1, or PARK6) are the most clinically relevant

because of their mutation frequency. Insights from initial

familial studies suggested that LRRK2-associated

parkinsonism is dominantly inherited, whereas parkinsonism

linked to parkin or PINK1 is recessive. However, screening of

patient cohorts has revealed that up to 70 % of people

heterozygous for LRRK2 mutations are unaffected, and that

more than 50 % of patients with mutations in parkin or PINK1

have only a single heterozygous mutation. Deciphering the

role of heterozygosity in parkinsonism is important for the

development of guidelines for genetic testing, for the

counselling of mutation carriers, and for the understanding of

late-onset PD. However, much more remains to be

understood regarding the pathogenesis of PD before genetic

testing can be considered definitive.

Commenting on the article by Beyer et al, Factor (2007) stated

that "[b]ecause gene expression in this disease is so complex,

most results will be inconclusive. No published guidelines

currently exist regarding how to test and counsel patients

appropriately; the tests are costly; and the results, even if

conclusive,would not change treatment for individual patients,

although one hopes they soon might. For these reasons, no

good rationale yet exists for the genetic testing of PD patients".

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Williams-Gray et al (2009) noted that in addition to the well-

established association between apolipoprotein E (APOE) and

AD, this gene has also been implicated in both susceptibility

to, and dementia in, PD. However studies to date have

produced contradictory findings. These investigators

conducted a case-control study in a population of 528 PD

patients and 512 healthy controls and found no significant

difference in allele or genotype distribution of APOE between

the 2 groups. An updated meta-analysis showed a modest

increase of APOE-epsilon2 carriers among PD patients

compared to controls (p = 0.017, odds ratios [OR] = 1.16 [95 %

confidence interval (CI): 1.03 to 1.31]). A total of 107 patients

were incident cases participating in a population-based

epidemiological study. Longitudinal follow-up of this cohort

over a mean of 5.0 +/- 0.7 years from diagnosis revealed no

significant impact of APOE-epsilon4 carrier status on risk of

dementia or rate of cognitive decline. An updated meta-

analysis indicated an over-representation of APOE-epsilon4

carriers among PD dementia compared to non-dementia

cases [OR 1.74 (1.36 to 2.23), p = 1 x 10(-4)], although small

sample sizes, heterogeneity of OR and publication bias may

have confounded this finding. The authors concluded that

these findings did not support previously reported associations

between APOE genotype and susceptibility to, or cognitive

decline in, PD. An updated meta-analysis indicates any

association with PD susceptibility is at most modest, an

observation with important implications for further study of this

issue. They stated that large scale longitudinal studies would

be best placed to further evaluate any impact of APOE

genotype on cognitive decline i n PD.

The findings by Williams-Gray et al (2009) are in agreement

with those of Kurz et al (2009) who investigated the role of

APOE alleles in PD and PD dementia. These researchers

determined APOE genotypes in a group of patients with PD (n

= 95) and compared them with those of healthy control

participants (n = 73). Additionally, in 64 longitudinally followed

patients with PD, the allele types were correlated to

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development and progression of dementia and to time from

onset of PD to dementia using multi-variate and survival

analyses. The APOE e4e4 genotype was more common in

patients with PD (7.4 %) than in healthy controls (1.4 %; p =

0.03). No significant associations between the APOE

genotype and development and progression of dementia or

time to dementia were found. The authors stated that more

studies with larger PD samples are needed.

Riley and Chelimsky (2003) stated that formal laboratory

testing of autonomic function is reported to distinguish

between patients with PD and those with MSA, but such

studies segregated patients according to clinical criteria that

select those with autonomic dysfunction for the MSA category.

These researchers attempted to characterize the profiles of

autonomic disturbances in patients in whom the diagnosis of

PD or MSA used criteria other than autonomic dysfunction. A

total of 47 patients with parkinsonism and autonomic

symptoms who had undergone autonomic laboratory testing

were identified and their case records reviewed for non-

autonomic features. They were classified clinically into 3

diagnostic groups: (i) PD (n = 19), (ii) MSA (n = 14), and (iii)

uncertain (n = 14). The performance of the patients with PD

was compared with that of the MSA patients on 5 autonomic

tests: (i) R-R interval variations during deep breathing, (ii)

heart rate changes with the Valsalva maneuvre, (iii) tilt table

testing, (iv) the sudomotor axon reflex test,and (v)

thermoregulatory sweat testing.

None of the tests distinguished one group from the other with

any statistical significance, alone or in combination.

Parkinson's disease and MSA patients showed similar patterns

of autonomic dysfunction on formal testing of cardiac

sympathetic and parasympathetic, vasomotor, and central and

peripheral sudomotor functions. The authors concluded that

these findings supported the clinical observation that PD is

often indistinguishable from MSA when it involves the

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autonomic nervous system. The clinical combination of

parkinsonism and dysautonomia is as likely to be caused by

PD as by MSA. Current clinical criteria for PD and MSA that

direct patients with dysautonomia into the MSA group may be

inappropriate.

Reimann et al (2010) stated that differential diagnosis of

parkinsonian syndromes is a major challenge in movement

disorders. Dysautonomia is a common feature but may vary in

clinical severity and onset. These investigators attempted to

find a pattern of autonomic abnormalities discriminative for

patients with differentparkinsonian syndromes. The cross-

sectional study included 38 patients with MSA, 32 patients with

PSP, 26 patients with IPD, and 27 age-matched healthy

controls. Autonomic symptoms were evaluated by a

standardized questionnaire. The performance of patients and

controls was compared on 5 autonomic function tests: (i) deep

breathing, (ii) Valsalva maneuvre, (iii) tilt-table testing, (iv)

sympathetic skin response, (v) pupillography, as well as 24

hr ambulatory BP monitoring (ABPM).

Disease severity was significantly lower in IPD than PSP and

MSA. Except for pupillography, none of the laboratory

autonomic tests distinguished one patient group from the other

alone or in combination. The same was observed on the

questionnaire. Receiver operating characteristic curve

revealed discriminating performance of pupil diameter in

darkness and nocturnal BP change. The composite score of

urogenital and vasomotor domains significantly distinguished

MSA from IPD patients but not from PSP. These findings

supported the observation that even mild IPD is frequently

indistinguishable from more severe MSA and PSP. Thus,

clinical combination of motor and non-motor symptoms does

not exclusively point at MSA. Pupillography, ABPM and the

questionnaire may assist in delineating the 3 syndromes when

applied in combination.

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Although PD is primarily considered a movement disorder, the

high prevalence of psychiatric complications suggests that it is

more accurately conceptualized as a neuropsychiatric

disease. Depression, dementia, and psychosis are common

manifestations of idiopathic PD; and are associated with

excess disability, worse quality of life, poorer prognosis, as

well as caregiver burden. Rihmer and colleagues (2004)

noted that depression is one of the most disabling symptoms

of PD, with a prevalence of approximately 40 %.

Unfortunately, such depression is frequently unrecognized and

untreated in patients with PD. Papapetropoulos and Mash

(2005) stated that psychotic symptoms are common in patients

with PD, and occur in at least20 % of medication-treated

patients. Benign visual hallucinations often appear earlier,

while agitation, confusion, delirium, delusions, malignant

hallucinations, and paranoid beliefs become more frequent

with disease progression. Nearly all anti-parkinsonian

medications may produce psychotic symptoms. Moreover,

cognitive impairment, increased age, disease duration and

severity, depression, as well as sleep disorders have been

consistently identified as independent risk factors for their

development. Although the exact cause for the pathogenesis

of psychosis in PD is not fully known, there is some evidence

that links over-activity of the ventral dopaminergic pathway

with the involvement of other neurotransmitter system

imbalances as likely contributors.

Dementia occurs in up to 30 % of patients with PD. Cognitive

impairments involve attentional, executive, memory, and

visuospatial dysfunctions (Lauterbach, 2005). Furthermore,

Levin and Katzen (2005) stated that early cognitive changes in

PD patients are often subtle and influenced by factors that

interact with the disease process, including medication, motor

symptoms, and age of disease onset. These factors

notwithstanding, ample evidence exists that specific cognitive

changes occur early in the course of PD. The authors noted

that this evidence does not imply that cognitive deficits are

pervasive during the early stages. On the contrary, they are

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usually subtle and often difficult to detect without formal

neuropsychological testing. Executive-function deficits are the

most frequently reported cognitive problems and, given that

executive skills are an integral part of many tasks, it follows

that subtle difficulties may be seen on a wide range of

cognitive measures, especially in working memory as well as

visuospatial dysfunction, two areas that rely heavily on

executive skills. Whereas apraxia and language processing

deficits occur infrequently, subtle changes in olfaction and

contrast sensitivity have also been repeatedly observed.

In the recent practice parameter on the evaluation and

treatment of depression, psychosis, and dementia in PD (an

evidence-based review) by the AAN, Miyasaki et al (2006)

provided the following conclusions/recommendations:

▪ Tools such as the Beck Depression Inventory (BDI), the

Hamilton Depression R ating Scale (HDRS-17), and the

Montgomery Asberg Depression R ating Scale (MADRS)

should be considered for screening depression as sociated

with PD.

▪ Tools such as the Cambridge Cognitive Examination

(CAMCog) and the Mini-Mental State Examination (MMSE)

should be considered for screening dementia in patients

with PD.

▪ There are no widely used, validated tools for psychosis

screening in PD.

In a systematic review on transcranial duplex (TCD) scanning

in the differential diagnosis of parkinsonian syndromes, Vlaar

and colleagues (2009) concluded that before TCD scanning

can be implicated, more research is needed to standardize the

TCD technique, to investigate the TCD in non-research

settings and to determine the additional value of TCD

scanning compared with currently used clinical techniques.

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Tokuda et al (2010) stated that to-date, there is no accepted

clinical diagnostic test for PD that is based on biochemical

analysis of blood or cerebrospinal fluid (CSF). The discovery

of mutations in the SNCA gene encoding α-synuclein in

familial parkinsonism and the accumulation of α-synuclein in

the PD brain suggested a critical role for this protein in PD

etiology. These researchers investigated total and α-synuclein

oligomers levels in CSF from patients clinically diagnosed with

PD, PSP, or AD, and age-matched controls, using ELISA. The

levels of α-synuclein oligomers and oligomers/total-α-synuclein

ratio in CSF were higher in the PD group (n = 32; p < 0.0001,

Mann-Whitney U test) compared to the control group (n = 28).

The area under the receiver operating characteristic curve

(AUC) indicated a sensitivity of 75.0 % and a specificity of 87.5

%, with an AUC of 0.859 for increased CSF α-synuclein

oligomers in clinically diagnosed PD cases. However, when

the CSF oligomers/total-α-synuclein ratio was analyzed, it

provided an even greater sensitivity of 89.3 % and specificity

of 90.6 %, with an AUC of 0.948. In another cross-sectional

pilot study, these researchers confirmed that the levels of CSF

α-synuclein oligomers were higher in patients with PD (n = 25)

compared to patients with PSP (n = 18; p < 0.05) or AD (n =

35; p < 0.001) or control subjects (n = 43; p < 0.05). The

authors concluded that these findings showed that levels of

α-synuclein oligomers in CSF and the oligomers/total-α-

synuclein ratio can be useful biomarkers for diagnosis and

early detection of PD. Moreover, the authors stated that large-

scale, prospective, and well-controlled studies, especially

those that include subjects with neuroimaging-supported

definite PD and other synucleinopathies, as well as unrelated

neurologic disorders, are necessary to validate the

quantification of CSF α-synuclein oligomers as an urgently

needed surrogate biomarker. It will be critical to carry out

prospective studies to examine if individuals who do not have

PD, but have an elevated oligomer-to-total α-synuclein ratio in

their CSF will be more prone to develop the disease in the

future.

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In an editorial that accompanied the afore-mentioned study,

Ballard and Jones (2010) noted that there is emerging

evidence thatmeasurementof specific forms of α-synuclein in

CSF may contribute to diagnosis and treatment development

in PD and related disorders. Moreover, they stated that further

validation is still needed; it is too preliminary to put this forward

as a diagnostic test for PD.

Siderowf et al (2010) investigated if CSF amyloid beta 1-42

(Aβ[1-42]) would predict cognitive decline i n PD. A total of 45

patients with PD were enrolled in this prospective cohort study

and had at least 1 yearly longitudinal follow-up evaluation.

Cerebrospinal fluid was collected at baseline and cognition

was assessed at baseline and follow-up v isits using the Mattis

Dementia Rating Scale (DRS-2); CSF was tested for Aβ[1-42],

p-tau(181p), and total tau levels using the Luminex xMAP

platform. Mixed linear models were used to test for

associations between baseline CSF biomarker levels and

change in cognition over time. Lower baseline CSF Aβ[1-42]

was associated with more rapid cognitive decline. Subjects

with CSF Aβ[1-42] levels less than or equal to192 pg/ml

declined an average of 5.85 (95 % CI: 2.11 to 9.58, p = 0.002)

points per year more rapidly on the DRS-2 than subjects

above that cut-off, after adjustment for age, disease duration,

and baseline cognitive status. Cerebrospinal fluid total tau and

p-tau(181p) levels were not significantly associated with

cognitive decline. The authros concluded t hat reduced CSF

Aβ[1-42] was an independent predictor of cognitive decline in

patients with PD. This observation is consistent with previous

research showing that AD pathology contributes to cognitive

impairment in PD. This biomarker may provide clinically useful

prognostic information, particularly if combined with other risk

factors for cognitive impairment in PD. Furthermore, they

noted that there are 2 main drawbacks of this study: (i) small

number of patients studied for a relatively short period of

time,and (ii) the results do not address if the association

between reduced Aβ[1-42] and cognitive decline is specific

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to PD. These findings need to be validated with well-designed

studies with larger number of subjects in longer study duration.


Aarsland and Ravina (2010) stated that there are several

limitations of this study: (i) small cohort recruited at a single

center, (ii) lack of a healthy control group,and (iii) large

variations in PD duration, severity of disease, length of follow-

up, and baseline cognitive impairment. They stated that the

potential clinical utility of these findings is not yet known.

The policy on surgical treatment of PD is based primarily on

evidence assessments by the AAN (Hallett et al, 1999), the

National Institute for Clinical Excellence (NICE, 2004), the

BlueCross BlueShield Association Technology Evaluation

Center (BCBSA, 2001), and the Agency for Healthcare

Research and Quality (AHRQ) (Levine et al, 2003).

Arle and colleagues (2008) stated that since the initial 1991

report by Tsubokawa et al, stimulation of the M1 region of the

motor cortex has been used to treat chronic pain conditions

and various movement disorders. The authors reviewed the

literature and found 459 cases in which motor cortex

stimulation (MCS) was used. Of these, 72 were related to a

movement disorder. More recently, up to 16 patients

specifically with PD were treated with MCS, and a variety of

results were reported. In this report, the authors described 4

patients who were treated with extra-dural MCS. Although

there were benefits seen within the first 6 months in Unified

Parkinson's Disease Rating Scale Part III scores (decreased

by 60 %), tremor was only modestly managed with MCS in this

group, and most benefits seen initially were lost by the end of

12 months. The authors concluded that although there have

been some positive findings using MCS for PD, a larger study

may be needed to better determine if it should be pursued as

an alternative surgical treatment to DBS.

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Martin and Teismann (2009) stated that PD is the second most

common neuro-degenerative disease, affecting over a million

people in the United States alone. Its main neuro-pathological

feature is the loss of dopaminergic neurons of the substantia

nigra pars compacta. However, the pathogenesis of this loss

is not understood fully. One of the earliest biochemical

changes seen in PD is a reduction in the levels of total

glutathione (GSH), a key cellular antioxidant. Traditionally, it

has been thought that this decrease in GSH levels is the

consequence of increased oxidative stress, a process heavily

implicated in PD pathogenesis. However, emerging evidence

suggests that GSH depletion may itself play an active role in

PD pathogenesis.

Hauser and colleagues (2009) evaluated the safety,

tolerability, and preliminary efficacy of intravenous GSH in PD

patients. This was a randomized, placebo-controlled, double-

blind, pilot trial in subjects with PD whose motor symptoms

were not adequately controlled with their current medication

regimen. Subjects were randomly assigned to receive

intravenous GSH 1,400 mg or placebo administered 3 times a

week for 4 weeks. A total of 21 subjects were randomly

assigned, 11 to GSH and 10 to placebo. One subject who was

assigned to GSH withdrew from the study for personal reasons

prior to undergoing any post-randomization efficacy

assessments. Glutathione was well-tolerated and there were

no withdrawals because of adverse events in either group.

Reported adverse events were similar in the 2 groups. There

were no significant differences in changes in Unified

Parkinson's Disease Rating Scale (UPDRS) scores. Over the

4 weeks of study medication administration, UPDRS ADL +

motor scores improved by a mean of 2.8 units more in the

GSH group (p = 0.32), and over the subsequent 8 weeks

worsened by a mean of 3.5 units more in the GSH group (p =

0.54). Glutathione was well-tolerated and no safety concerns

were identified. The authors stated that these preliminary

efficacy data suggest the possibility of a mild symptomatic

effect, but this remains to be evaluated in a larger study.

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Sedlacková and associates (2009) examined the effects of

one session of high-frequency repetitive transcranial magnetic

stimulation (rTMS) applied over the left dorsal premotor cortex

(PMd) and left dorsolateral prefrontal cortex (DLPFC) on

choice reaction time in a noise-compatibility task, and cognitive

functions in patients with PD. Clinical motor symptoms of PD

were assessed as well. A total of 10 patients with PD entered

a randomized, placebo-controlled study with a cross-over

design. Each patient received 10 Hz stimulation over the left

PMd and DLPFC (active stimulation sites) and the occipital

cortex (OCC; a control stimulation site) in the OFF motor state,

i.e., at least after 12 hrs of dopaminergic drugs withdrawal.

Frameless stereotaxy was used to target the optimal position

of the coil. For the evaluation of reaction time, a noise-

compatibility paradigm was used. A short battery of

neuropsychological tests was performed to evaluate executive

functions, working memory, and psychomotor speed. Clinical

assessment included a clinical motor evaluation using part III

of the UPDRS. Statistical analysis revealed no significant

effect of rTMS applied over the left PMd and/or DLPFC in

patients with PD in any of the measured parameters. In this

study, these researchers did not observe any effect of 1

session of high frequency rTMS applied over the left PMd

and/or DLPFC on choice reaction time in a noise-compatibility

task, cognitive functions, or motor features in patients with PD;

rTMS applied over all 3 stimulated areas was safe and well-

tolerated in terms of the cognitive and motor effects.

In a double-blind, placebo-controlled study, Arias and co-

workers (2010a) evaluated the effect of 10-day rTMS on sleep

parameters in PD patients. A total of 18 IPD patients

completed the study. Sleep parameters were evaluated

through actigraphy and the Parkinson's Disease Sleep Scale

(PDSS), along with depression (Hamilton Depression Rating

Scale, HDS), and the UPDRS. Evaluations were carried out

before treatment with rTMS (pre-evaluation, PRE), after the

rTMS treatmentprogramme (post-evaluation, POST), and 1

week after POST (POST-2). Nine PD patients received real

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rTMS and the other 9 received sham rTMS daily for 10 days,

(100 pulses at 1Hz) applied with a large circular coil over the

vertex. Stimulation had no effect over actigraphic variables.

Conversely PDSS, HDS, and UPDRS were significantly

improved by the stimulation. Notably, however, these changes

were found equally in groups receiving real or sham

stimulation. The authors concluded that rTMS, using these

researchers' protocol, has no therapeutic value on the sleep of

PD patients, when compared to appropriate sham controls.

They stated that future works assessing the possible

therapeutic role of rTMS on sleep in PD should control the

effect of placebo.

In a double-blind placebo-controlled trial, Arias et al (2010b)

evaluated the effect of low-frequency rTMS on motor signs in

PD. Patients with PD were randomly assigned to received

either real (n = 9) or sham (n = 9) rTMS for 10 days. Each

session comprises 2 trains of 50-stimuli each delivered at 1 Hz

and at 90 % of daily rest motor threshold using a large circular

coil over the vertex. The effect of the stimulation, delivered

during the ON-period, was evaluated during both ON and OFF

periods. Tests were carried out before and after the

stimulation period, and again 1 week after. The effect of the

stimulation was evaluated through several gait variables

(cadence, step amplitude, velocity, the CV(stride-time), and

the turn time), hand dexterity, and also the total and motor

sections of the UPDRS. Only the total and motor section of

the UPDRS and the turn time during gait were affected by the

stimulation, the effect appearing during either ON or OFF

evaluation, and most importantly, equally displayed in both

real and sham group. The rest of the variables were not

influenced. The authors concluded that the protocol of

stimulation used, different from most protocols that apply

larger amount of stimuli, but very similar to some previously

reported to have excellent results, has no therapeutic value

and should be abandoned. This contrasts with the positive

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reported effects using higher frequency and focal coils. These

findings also reinforced the need for sham stimulation when

evaluating the therapeutic effect of rTMS.

Filipović etal (2010) examined the effects of low-frequency

rTMS on OFF-phase motor symptoms in patients with PD. A

total of 10 patients with PD had rTMS (1,800 stimuli at just

below active motor threshold intensity) at 1Hz rate delivered

over the motor cortex for 4 consecutive days on 2 separate

occasions. On 1 of these occasions, real rTMS was used and

on the other sham rTMS (placebo) was used. Evaluations with

UPDRS Part 3 (Motor Scale) were done in practically defined

OFF-phase at the baseline and 1 day after the end of each of

the treatment series. Neither total Motor Scale scores nor

subscores for axial symptoms, rigidity, bradykinesia, and

tremor showed any significant difference. The results did not

confirm presence of residual beneficial clinical after-effects of

consecutive daily applications of low-frequency rTMS on motor

symptoms in PD, at least when 1800 stimuli at sub-threshold

intensity are applied for 4 days.

In a randomized,double-blind, sham-controlled study,

Benninger et al (2011) examined the safety and effectiveness

of intermittent theta-burst transcranial magnetic stimulation

(iTBS), a novel type of rTMS, in the treatmentof motor

symptoms in PD. These researchers investigated safety and

efficacy of iTBS of the motor and dorso-lateral prefrontal

cortices in 8 sessions over 2 weeks (evidence Class I).

Assessment of safety and clinical efficacy over a 1-month

period included timed tests of gait and bradykinesia, UPDRS,

and additional clinical, neuropsychological, and

neurophysiologic measures. A total of 26 patients with mild-to-

moderate PD were included in this study: 13 received iTBS

and 13 sham stimulation. These investigators found beneficial

effects of iTBS on mood, but no improvement of gait,

bradykinesia, UPDRS, and other measures. EEG/EMG

monitoring recorded no pathologic increase of cortical

excitability or epileptic activity. Few reported discomfort or

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pain and 1 experienced tinnitus during real stimulation. The

authors concluded that iTBS of the motor and prefrontal

cortices appears safe and improves mood, but failed to

improve motor performance and functional status in PD. This

study provided Class I evidence that iTBS was not effective for

gait, upper extremity bradykinesia, or other motor symptoms in

PD.

In a randomized,double-blind, sham-controlled study,

Benninger and colleagues (2010) examined the effectiveness

of transcranial direct current stimulation (tDCS) in the

treatment of PD. The effectiveness of anodal tDCS applied to

the motor and pre-frontal cortices was investigated in 8

sessions over 2.5 weeks. Assessment over a 3-month period

included timed tests of gait (primary outcome measure) and

bradykinesia in the upper extremities, UPDRS, Serial Reaction

Time Task, Beck Depression Inventory, Health Survey and self-

assessment of mobility. A total of 25 PD patients were studied,

13 receiving tDCS and 12 sham stimulation.

Transcranial direct current stimulation improved gait by some

measures for a short time and improved bradykinesia in both

the ON and OFF states for longer than 3 months. Changes in

UPDRS, reaction time, physical and mental well being, and self-

assessed mobility did not differ between the tDCS and sham

interventions. The authors concluded that tDCS of the motor

and prefrontal cortices may have therapeutic potential in PD;

but better stimulation parameters need to be established to

make the technique clinically viable. The findings of this

preliminary study need to be validated by well-designed

studies.

Klassen and colleagues (2011) evaluated quantitative EEG

(qEEG) measures as predictive biomarkers for the

development of dementia in PD. A cohort of subjects with PD

in the authors' brain donation program utilizes annual pre-

mortem longitudinal movement and cognitive evaluation.

These subjects also undergo biennial EEG recording. EEG

from subjects with PD without dementia with follow-up

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cognitive evaluation w as analyzed for qEEG measures of

background rhythm frequency and relative power in δ, α, and β

bands. The relationship between the time to onset of

dementia and qEEG and other possible predictors was

assessed by using Cox regression. The hazard of developing

dementia was 13 times higher for those with low background

rhythm frequency (lower than the grand median of 8.5 Hz)

than for those with high background rhythm frequency (p <

0.001). Hazard ratios (HRs) were also significant for greater

than median bandpower (HR = 3.0; p = 0.004) compared to

below, and for certain neuropsychological measures. The

HRs for δ, α, and β bandpower as well as baseline

demographic and clinical characteristics were not significant.

The authors concluded that qEEG measures of background

rhythm frequency and relative pow er in the band are potential

predictive biomarkers for dementia incidence in PD. These

qEEG biomarkers may be useful in complementing

neuropsychological testing for studying PD-D incidence.

In a randomized clinical trial, Espay and colleagues (2011)

evaluated the effectiveness of methylphenidate (MPD) for the

treatment of gait impairment in PD. A total of 27 subjects with

PD and moderate gait impairment were screened for this

6-month placebo-controlled, double-blind study. Subjects

were randomly assigned to MPD (maximum, up to 80 mg/day)

or placebo for 12 weeks and crossed-over after a 3-week

washout. The primary outcome measure was change in a gait

composite score (stride length + velocity) between groups at 4

and 12 weeks. Secondary outcome measures included

changes in motor function, as measured by the UPDRS,

Freezing of Gait Questionnaire (FOGQ), number of gait-diary

freezing episodes, and measures of depression, sleepiness,

and quality of life. Three-factor repeated-measures analysis of

variance was used to measure changes between groups.

Twenty-three eligible subjects with PD were randomized and

17 completed the trial. There was no change in the gait

composite score or treatment or time effect for any of the

variables. Treatment effect was not modified by state or study

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visit. Although there was a trend for reduced frequency of

freezing and shuffling per diary, the FOGQ and UPDRS scores

worsened in the MPD group compared to placebo. There was

a marginal improvement in some measures of depression.

The authors concluded that MPD did not improve gait and

tended to worsen measures of motor function, sleepiness, and

quality of life.

The National Institute for Health and Clinical Excellence's

clinical practice guideline on "Parkinson's disease: Diagnosis

and management in primary and secondary care" (NICE,

2006) stated that "123I-FP-CIT SPECT should be considered

for people with tremor where essential tremor can not be

clinically differentiated from parkinsonism". Furthermore, the

Scottish Intercollegiate Guidelines Network's clinical practice

guideline on "Diagnosis and pharmacological management of

Parkinson's disease" (SIGN, 2010) stated that "Single photon

emission computed tomography (SPECT) with (123I-labeled N

omega-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)

tropane (123I-FP-CIT SPECT scanning) should be considered

as an aid to clinical diagnosis in patients where there is

uncertainty between Parkinson's disease and non-

degenerative parkinsonism/tremor disorders. Routine use of

functional imaging is not recommended for the differential

diagnosis of Parkinson's disease and Parkinson's plus

disorders such as progressive supranuclear palsy and multiple

system atrophy".

Also, an UpToDate review on "Diagnosis of Parkinson

disease" (Chou, 2012) states that "Positron emission

tomography (PET) and single photon emission computed

tomography (SPECT) may be helpful for the early diagnosis of

PD. With PET, decreased tracer uptake is seen in the mid-

and posterior putamen of patients with early PD when

compared with controls. Striatal dopamine transporter imaging

using SPECT (e.g., 123I-FP-CIT SPECTscan or DaTscan)

can reliably distinguish patients with PD and other

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parkinsonian syndromes from controls or patients with

essential tremor, but it can not differentiate PD and the

parkinsonian syndromes from one another".

Fink et al (2000) stated that the observation that fetal neurons

are able to survive and function when transplanted into the

adult brain fostered the development of cellular therapy as a

promising approach to achieve neuronal replacement for

treatment of diseases of the adult central nervous system.

This approach has been demonstrated to be effective in

patients with PD after transplantation of human fetal neurons.

The use of human fetal tissue is limited by ethical, infectious,

regulatory, and practical concerns. Other mammalian fetal

neural tissue could serve as an alternative cell source. Pigs

are a reasonable source of fetal neuronal tissue because of

their brain size, large litters, and the extensive experience in

rearing them in captivity under controlled conditions. In phase

I studies, porcine fetal neural cells grafted unilaterally into PD

and Huntington's disease patients were being evaluated for

safety and effectiveness. Clinical improvement of 19 % has

been observed in the Unified Parkinson's Disease Rating

Scale "off" state scores in 10 PD patients assessed 12 months

after unilateral striatal transplantation of 12 million fetal porcine

ventral mesencephalic (VM) cells. Several patients have

improved more than 30 %. In a single autopsied PD patient

some porcine fetal VM cells were observed to survive 7

months after transplantation. Twelve Huntington's disease

patients have shown a favorable safety profile and no change

in total functional capacity score 1 year after unilateral striatal

placement of up to 24 million fetal porcine striatal cells.

Xenotransplantation of fetal porcine neurons is a promising

approach to delivery of healthy neurons to the central nervous

system. The major challenges to the successful use of

xenogeneic fetal neuronal cells in neurodegenerative diseases

appear to be minimizing immune-mediated rejection,

management of the risk of xenotic (cross-species) infections,

and the accurate assessment of clinical outcome of diseases

that are slowly progressive.

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Cederfjall et al (2012) noted that it has been suggested that

the beneficial effect of L-DOPA could be re-established by

changing the mode of administration. Indeed, continuous

delivery of L-dopa has been shown to be an effective way to

circumvent many of the side effects seen with traditional oral

administration, which results in an intermittent supply of the

dopamine precursor to the brain. However, all currently tested

continuous dopaminergic stimulation approaches rely on

peripheral administration. This is not ideal since it gives rise to

off-target effects and is difficult to maintain long-term. Thus,

there is an unmet need for an effective continuous

administration method with an acceptable side effect profile.

Viral-mediated gene therapy is a promising alternative

paradigm that can meet this demand. Encouraging pre-clinical

studies in animal models of PD showed therapeutic

effectiveness after expression of the genes encoding the

enzymes required for biosynthesis of dopamine. Although

phase I clinical trials using these approaches have been

conducted, clear positive data in placebo-controlled efficacy

studies are still lacking. The authors stated that “We are now

at a critical junction and need to carefully review the preclinical

data from the clinical translation perspective and identify the

key factors that will determine the potential for success in gene

therapy for Parkinson's disease”.

Besong-Agbo et al (2013) stated that biomarkers are needed

for the diagnosis and monitoring of disease progression in

PD. To date, most studies have concentrated on α-synuclein

(α-Syn), a protein involved in PD pathogenesis, as a potential

biomarker, with inconsistent outcomes. Recently, naturally

occurring autoantibodies againstα-Syn (α-Syn-nAbs) have

been detected in the serum of patients with PD. They

represent a putative diagnostic marker for PD. These

researchers established and validated an ELISA to quantify

α-Syn-nAbs in serum samples. They analyzed serum samples

from 62 patients with PD, 46 healthy controls (HC), and 42

patients with Alzheimer disease (AD) using this newly

established ELISA. Additionally, serum levels of endogenous

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α-Syn were measured. There was a significant difference in

α-Syn-nAbs levels between the investigated groups (p = 0.005;

Kruskal-Wallis test). Levels of α-Syn-nAbs were significantly

lower in patients with PD compared to HC (p < 0.05; Dunn

multiple comparison post-hoc test) or patients with AD (p <

0.05). Furthermore, these investigators detected no difference

between patients with AD and HC. The sensitivity and

specificity of the assay for patients with PD versus HC were 85

% and 25 %, respectively.The α-Syn-nAbs levels did not

correlate with age, Hoehn and Yahr status, or duration of

disease.Endogenous α-Syn had no influence on α-Syn-nAbs

levels in sera. The authors concluded that using a well-

validated assay, they detected reduced α-Syn-nAbs levels in

patients with PD compared to patients with AD and HC. The

assay did not achieve criteria for use as a diagnostic tool to

reliably distinguish PD from HC. They stated that

appropriately powered and independent investigations with

validated assays are needed to further evaluate the utility of

α-Syn-nAbs as a biomarker in PD.

Gan-Or et al (2013) studied the possible association of

founder mutations in the lysosomal storage disorder genes

hexosaminidase A (or HEXA), sphingomyelin

phosphodiesterase 1 gene (SMPD1), and mucolipin 1

(MCOLN1) (causing Tay-Sachs, Niemann-Pick A, and

mucolipidosis type IV diseases, respectively) with PD. Two

PD patient cohorts of Ashkenazi Jewish (AJ) ancestry, that

included a total of 938 patients, were studied: (i) a cohort of

654 patients from Tel Aviv, and (ii) a replication cohort of

284 patients from New York. Eight AJ founder mutations in

the HEXA, SMPD1, and MCOLN1 genes were analyzed. The

frequencies of these mutations were compared to AJ control

groups that included large published groups undergoing

prenatal screening and 282 individuals matched for age and

sex. Mutation frequencies were similar in the 2 groups of

patients with PD. The SMPD1 p.L302P was strongly

associated with a highly increased risk for PD (odds ratio 9.4,

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95 % CI: 3.9 to 22.8, p < 0.0001), as 9/938 patients with PD

were carriers of this mutation compared to only 11/10,709

controls. The authors concluded that the SMPD1 p.L302P

mutation is a novel risk factor for PD. Although it is rare on a

population level, the identification of this mutation as a strong

risk factor for PD may further elucidate PD pathogenesis and

the role of lysosomal pathways in disease development.

Moreover, these researchers noted that studies of SMPD1

mutations in other populations are needed to further ascertain

the role of this gene in PD.


Sharma (2013) stated that “While these data do not change

the way in which patients with PD are diagnosed or treated,

they do illustrate the utility of performing genetic studies in

relatively ethnically homogeneous cohorts that have

undergone careful clinical characterization …. The finding that

a specific mutation in the SMPD1 enzyme is associated with

an increased risk of PD gives further support to the hypothesis

that defects in the ALP [autophagy-lysosomal pathway] play a

role in the pathogenesis of PD and identifies another cellular

pathway as a target for drug development”.

Wang and Wang (2014) stated that the glutathione

S-transferase M1 (GSTM1) and glutathione S-transferase T1

(GSTT1) genes have been studied extensively as potential

candidate genes for the risk of PD; however, direct evidence

from genetic association studies remains inconclusive. These

researchers performed an updated and refined meta-analysis

to determine the effect of GSTM1 and GSTT1 polymorphisms

on PD. A fixed-effect model was utilized to calculate the

combined OR, OR of different ethnicities, and 95 % CIs.

Potential publication bias was estimated. Homogeneity of the

included studies was also evaluated. The pooled OR was

1.13 [95 % CI: 1.03 to 1.24)] and 0.96 [95 % CI: 0.82 to 1.12)]

for GSTM1 and GSTT1 polymorphisms, respectively. Analysis

according to different races found no as sociation bet ween

GSTM1/GSTT1 polymorphisms and PD risks except for

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GSTM1 variant in Caucasians, which showed a weak

correlation (OR 1.16 [95 % CI: 1.04 to 1.29), I squared = 6.2

%, p = 0.384]). Neither publication bias nor heterogeneity was

found among the included studies. The authors concluded

that the results of this meta-analysis suggested that GSTM1

polymorphism is weakly associated with the risk of PD in

Caucasians whereas GSTT1 polymorphism is not a PD risk

factor.

Jin and colleagues (2014) noted that several studies have

been conducted in recent years to evaluate the risk of PD and

polymorphisms of interleukin -10 (IL-10); however, the results

were conflicting. These researchers performed a meta-

analysis of published case-control studies to assess this

association. Systematic searches of electronic databases

PubMed Web of Science, BIOSIS Previews, Science Direct,

Chinese Biomedical Database, WANFANG Database, and

Chinese National Knowledge Infrastructure with hand-

searching of the references of identified articles were

conducted. Data were extracted using a standardized form

and pooled ORs with 95 % CIs were calculated to evaluate the

strength of the association. A total of 7 case-control studies

involving 1,912 PD cases and 1,740 controls were included,

concerning 2 polymorphisms (-1082A/G and -592C/A) of IL-10

gene. No significant associations were found in the overall

analysis for both -1082A/G and -592C/A polymorphisms with

PD risk. Similar lacking associations were observed in

subgroup analysis based on ethnicity and age of onset.The

authors concluded that there is inadequate evidence for

association between IL-10 polymorphisms (-1082A/G and

-592C/A) and risk of PD at present. Moreover, they stated that

well-designed studies with larger sample-size and multi-

ethnicity studies are needed in the future.

Mondello et al (2014) stated that α-synuclein, linked to the

pathogenesis of PD, is a promising biomarker candidate in

need of further investigation. The ubiquitin carboxy-terminal

hydrolase L1 (UCH-L1), a pivotal component of the ubiquitin

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proteasome system that seems to be disturbed in PD, may

also be involved in the pathogenesis of this disorder. These

researchers investigated CSF α-synuclein and UCH-L1 levels

from 22 healthy controls, 52 patients with PD, 34 with MSA, 32

with PSP, and 12 with CBD. Cerebrospinal fluid α-Synuclein

levels were significantly decreased in PD and in MSA

compared with controls, and in synucleinopathies compared

with tauopathies; UCH-L1 levels were significantly decreased

in PD, MSA as well as PSP compared with controls, and in PD

compared with APD (p < 0.001). Both markers discriminated

PD well from controls (p < 0.0001; AUC = 0.82 and 0.89,

respectively). Additionally, CSF α-synuclein separated

patients with synucleinopathies from those with tauopathies (p

= 0.015; AUC = 0.63), whereas CSF UCH-L1 discriminated

between PD and APD (p = 0.0003; AUC = 0.69). Interestingly,

α-synuclein and UCH-L1 levels were strongly correlated i n PD

and synucleinopathies, and weakly in tauopathies. No

correlation was found in controls. The authors concluded that

CSF levels of α-synuclein and UCH-L1 showed distinct

patterns in parkinsonian syndromes. Their combined

determination may be useful in the differential diagnosis of

parkinsonian disorders and provided k ey to understanding

their pathoetiology and clinical course. Moreover, they stated

that further large studies are needed to validate these findings.

Beach and colleagues (2013) stated that the clinical diagnosis

of PD is incorrect in 30 % or more of subjects particularly at

the time of symptom onset. Because Lewy-type

α-synucleinopathy (LTS) is present in the submandibular

glands of PD patients, these researchers assessed the

feasibility of submandibular gland biopsy for diagnosing PD.

They performed immunohistochemical staining for LTS in

sections of large segments (simulating open biopsy) and

needle cores of submandibular glands from 128 autopsied and

neuropathologically classified subjects, including 28 PD, 5

incidental Lewy body disease, 5 PSP (3 with concurrent PD), 3

CBD, 2 MSA, 22 AD with Lewy bodies,16 AD withoutLewy

bodies, and 50 normal elderly. Immunoreactive nerve fibers

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were present in large submandibular gland sections of all 28

PD subjects (including 3 that also had PSP); 3 AD with Lewy

bodies subjects were also positive, but none of the other

subjects was positive. Cores from frozen submandibular

glands taken with 18-gauge needles (total length, 15 to 38

mm; between 10 and 118 sections per subject examined) were

positive for LTS in 17 of 19 PD patients. The authors

concluded that these results suggested that biopsy of the

submandibular gland may be a feasible means of improving

PD clinical diagnostic accuracy.

Folgoas et al (2013) evaluated the diagnostic performance of

minor salivary gland biopsy for PD. Minor salivary glands were

examined f or Lewy pathology using phosphorylated alpha-

synuclein antibody in 16 patients with clinically diagnosed PD

and 11 control subjects with other neurological disorders.

Abnormal accumulation of alpha-synuclein was found in 3 out

of 16 PD patients. Two control subjects exhibited weak

phosphorylated alpha-synuclein immunoreactivity. The

authors concluded that these results did not support the use

of minor salivary glands biopsy for the detection of Lewy

pathology in living subjects.

Adler et al (2014) examined salivary gland biopsies in living

patients with PD. Patients with PD for greater than or equal to

5 years underwent outpatient transcutaneous needle core

biopsies (18-gauge or 16-gauge) of 1 submandibular gland.

Minor salivary glands were removed via a small incision in the

lower lip. Tissue was fixed in formalin and serial 6-µm paraffin

sections were immunohistochemically stained for

phosphorylated α-synuclein and reviewed for evidence of

LTS. A total of 15 patients with PD were biopsied: 9 females/6

males, mean age of 68.7 years, mean PD duration of 11.8

years. Twelve of the needle core biopsies had microscopically

evident submandibular gland tissue to assess and 9/12 (75 %)

had LTS. Only 1/15 (6.7 %) minor salivary gland biopsies

were positive for LTS; 5 patients had an adverse event; all

were minor and transient. The authors concluded that this

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study demonstrated the feasibility of performing needle core

biopsies of the submandibular gland in living patients with PD

to assess LTS. Moreover, they stated that although this was a

small study, this tissue biopsy method may be important for

tissue confirmation of PD in patients being considered for

invasive procedures and in research studies of other PD

biomarkers. One major drawback of this study was the lack of

control subjects. Also, this study did not include patients with

other parkinsonian disorders, so determination of the

specificity for LTS in submandibular gland biopsies for PD will

require further study. The authors stated that future studies

should include patients with early-stage PD, control subjects,

subjects with other parkinsonian disorders, and when possible,

longitudinal studies extended to autopsy with neuropathologic

confirmation of PD.

Du opa (Levodopa-Carbidopa Intestinal Gel)

Parkinson’s disease (PD) is a common and complex

movement disorder characterized by progressive

neurodegeneration, loss of nigrostriatal dopaminergic and

extra‐nigral neurons, and functional disability because of motor

and nonmotor symptoms.

The goal of PD management is to improve motor and

nonmotor symptoms so that patients obtain the best function

for their stage of disease.

Levodopa is an endogenous chemical that is a precursor to

several neurotransmitters including norepinephrine,

epinephrine, and dopamine. In individuals with Parkinson’s

disease, a loss of dopaminergic cells in the midbrain results in

abnormal nerve functioning, which in turn leads to a reduced

ability or loss of ability to control body movements.

The combination product of carbidopa and levodopa is the

most effective agent for controlling the symptoms of

Parkinson’s disease. Levodopa, the precursor to dopamine,

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crosses the blood brain barrier while dopamine itself cannot.

Levodopa is given concomitantly with carbidopa, as carpidopa

inhibits the peripheral metabolism of levodopa, thus allowing a

higher percentage of levodopa to cross the blood brain barrier

for central nervous system effect, this also limits adverse

effects. Oral carbidopa and levodopa becomes progressively

less effective as the disease progresses. Motor complications

occur in 80% of young patients and 44% of older patients after

5 years of oral levodopa therapy.

Motor complications in Parkinson's disease (PD) are

associated with long-term oral levodopa treatment and linked

to pulsatile dopaminergic stimulation. l-dopa-carbidopa

intestinal gel (LCIG) is delivered continuously by percutaneous

endoscopic gastrojejunostomy tube (PEG-J), which reduces

l-dopa-plasma-level fluctuations and can translate to reduced

motor complications.

Duopa is a combination of carbidopa (an aromatic amino acid

decarboxylation inhibitor) and levodopa (an aromatic amino

acid) which has been approved by the U.S. Food and Drug

Administration (FDA) for the treatment of motor fluctuations in

patients with advanced Parkinson's disease. Duopa (levodopa‐

carbidopa enteral suspension) provides continuous daily 16‐

hour delivery of levodopa directly into the jejunum through a

percutaneous endoscopic gastrostomy with jejunal tube (PEG‐

J) with the CADD‐Legacy 1400 portable i nfusion pum p i n order

to reduce the amount of motor fluctuations that patients with

advanced Parkinson’ disease c urrently taking oral

carbidopa/levodopa are experiencing.

Duopa is administered over a 16‐hour infusion period through

either a naso‐jejunal tube for short‐term administration (i.e.

temporary administration of Duopa prior to PEG‐J tube

placement to observe patient’ clinical response) or through a

PEG‐J for long‐term administration. Each cassette is for single

‐use only and should not be used for longer than 16 hours,

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even if some drug remains. The daily dose is determined by

individualized patient titration and composed of a morning

dose, a continuous dose and an extra dose.

Duopa (carbidopa and levodopa enteral suspension) has been

shown to be an effective and safe therapy compared with oral

immediate release of carbidopa and levodopa tablet, but it

would likely be reserved for patients with persistent, severe, on

‐off fluctuations who are not candidates for deep brain

stimulation (DBS).

Most common adverse reactions (at least 7% greater than oral

carbidopa-levodopa incidence) were complication of device

insertion, nausea, depression, peripheral edema,

hypertension, upper respiratory tract infection, oropharyngeal

pain, atelectasis, and incision site erythema (AbbVie, 2016).

Orthostatic systolic hypotension (≥30 mm Hg decrease)

occurred in 73% of Duopa treated patients compared to 68%

of patients treated with oral immediate‐release carbidopa

levodopa in the controlled clinical study.

There is an increased risk for hallucinations and psychosis

while taking Duopa. In addition, patients may experience

intense urges to gamble, increased sexual urges, intense

urges to spend money, binge or compulsive eating, and/or

other intense urges, and the inability to control these urges

while taking one or more of the medications.

Monitoring for the development of depression and concomitant

suicidal tendencies os recommended.

Duopa may cause or exacerbate dyskinesia. In addition,

patients should have clinical assessments for the signs and

symptoms of peripheral neuropathy before starting Duopa.

Monitoring patients periodically for signs of neuropathy is

recommended.

Because Duopa is administered using a PEG‐J,

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gastrointestinal complications can occur. These complications

include bezoar, ileus, implant site erosion/ulcer, intestinal

hemorrhage, intestinal ischemia, intestinal obstruction,

intestinal perforation, pancreatitis, peritonitis, pneumo‐

peritoneum, and post‐operative wound infection. These

complications may result in serious outcomes, such as the

need for surgery or death. Gastrointestinal hemorrhage may

occur in patients with a history of peptic ulcer.

Melanoma has been reported with a higher risk in patients with

Parkinson’ disease, thus, close monitoring is recommended.

In clinical trials, Duopa significantly reduced daily mean off

time at 12 weeks by 4 hours, which resulted in an average of

1.9 fewer hours of off time compared with carbidopa‐levodopa

IR tablets. Treatment with Duopa was also associated with an

improved mean on time without dyskinesia by 4 hours at 12

weeks, which resulted in an average of 1.9 more hours of on

time compared with carbidopa‐levodopa IR tablets.

Additionally, the mean score increase i n “n”time by 1.9 hours

without dyskinesia from baseline to Week 12 was statistically

significant greater (p=0.0059) for Duopa t han for oral

immediate‐release carbidopa and levodopa. In a long‐term

follow‐up study, initiation of Duopa required an average of 11‐

day of hospitalization stay. The first 3 days involved placement

of a nasogastric tube and dose adjustments to reach maximal

motor performance w ithout relevant dyskinesia. Then the J‐

tube was placed and Duopa was converted to the J‐tube

infusion. The study results showed reduction of motor

fluctuations and dyskinesias along w ith improved quality of life.

Adverse reactions are similar to oral carbidopa and levodopa

(i.e. hallucinations and dyskinesias). There are few

complications associated with the J‐tube such as surgical

placement complications, infections, perforation, tube kinking,

dislocating as well as pump programming malfunction.

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Olanow et al (2014) assessed the efficacy and safety of

levodopa-carbidopa i ntestinal gel delivered continuously

through an intrajejunal percutaneous tube. In a 12-week,

randomized, double-blind, double-dummy, double-titration trial,

investigators enrolled adu lts (aged ≥ 30 years) with advanced

Parkinson's disease and motor complications at 26 centers in

Germany, New Zealand, and the United States. Eligible

participants had jejunal placement of a percutaneous

gastrojejunostomy tube and were then randomly allocated

(1:1) to treatment with immediate-release oral levodopa-

carbidopa plus placebo intestinal gel infusion or levodopa-

carbidopa intestinal gel infusion plus oral placebo.

Randomization was stratified by site, with a mixed block size of

2 or 4. The primary endpoint was change from baseline to final

visit in motor off-time. Investigators assessed change in motor

on-time without troublesome dyskinesia as a prespecified key

secondary outcome. They assessed efficacy in a full-analysis

set of participants with data for baseline and at least one post-

baseline assessment, and imputed missing dat a with the last

observation carried forward approach. They assessed safety

in randomly allocated patients who underwent the

percutaneous gastrojejunostomy procedure. From baseline to

12 weeks in the full-analysis set, mean off-time decreased by

4.04 h (SE 0.65) for 35 patients allocated to the levodopa-

carbidopa intestinal gel group compared w ith a decrease of

2.14 h (0.66) for 31 patients allocated to immediate-release

oral levodopa-carbidopa (difference -1.91 h [95% CI -3.05 to

-0.76]; p=0.0015). Mean on-time without troublesome

dyskinesia increased by 4.11 h (SE 0.75) in the intestinal gel

group and 2.24 h (0.76) in the immediate-release oral group

(difference 1.86 [95% CI 0.56 to 3.17]; p=0.0059). In the safety

analyses 35 (95%) of 37 patients allocated to the levodopa-

carbidopa intestinal gel group had adverse events (five [14%]

serious), as did 34 (100%) of 34 patients allocated to the

immediate-release oral levodopa-carbidopa group (seven

[21%] serious), mainly associated with the percutaneous

gastrojejunostomy tube. The investigators concluded that

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continuous delivery of levodopa-carbidopa with an intestinal

gel offers a promising option for control of advanced

Parkinson's disease with motor complications.

An accompanying editorial (Rascol, 2014) noted some of the

limitations of the randomized controlled trial (RCT) by Olanow

et al. The editorialist noted that the trial by Olanow et al was

small (71 patients) and short (3 months). This design

prevented long-term conclusions and provided insufficient

power to assess rare adverse events such as polyneuropathy

and Guillain-Barré syndrome, or even more common ones

such as impulse-control disorders. The editorialist noted that

unmasking factors because of efficacy (as with any strongly

efficacious intervention) or black coloration of the tube caused

by levodopa oxidation might have enhanced placebo response

on the active infusion. The editorialist noted that, unfortunately

no formal assessment of masking was done. The editorialist

noted that patients on sustained-release levodopa-carbidopa

formulations had to be converted to immediate-release

levodopa-carbidopa to allow double-blind adjustments during

the trial. This design deprived the trial participants of the

benefit of the long-term oral formulation, thus favoring the

active infusion. Moreover, forbidding changes in oral dosing

frequency during the titration phase might have induced similar

consequences. Finally, head-to-head comparisons have not

been done to assess the respective advantages and

disadvantages of levodopa jejunal infusion versus the two

main alternatives for management of severe problems with

refractory off -time complications: continuous subcutaneous

apomorphine infusion and functional surgery.

Fernandez et al (2015) reported on the results of a

prospective, 54-week, open-label LCIG study. PD patients with

severe motor fluctuations (>3 h/day "off" time) despite

optimized therapy received LCIG monotherapy. Additional PD

medications were allowed >28 days post-LCIG initiation.

Safety was the primary endpoint measured through adverse

events (AEs), device complications, and number of

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completers. Secondary endpoints included diary-assessed off

time, "on" time with/without troublesome dyskinesia, UPDRS,

and health-related quality-of-life ( HRQoL) outcomes. Of 354

enrolled patients, 324 (91.5%) received PEG-J and 272

(76.8%) completed the study. The investigators reported that

most AEs were mild/moderate and transient; complication of

device insertion (34.9%) was the most common. Twenty-seven

(7.6%) patients withdrew because of AEs. Serious AEs

occurred in 105 (32.4%), most commonly complication of

device insertion (6.5%). Mean daily off time decreased by 4.4

h/65.6% (P < 0.001). On time without troublesome dyskinesia

increased by 4.8h/62.9% (P < 0.001); on time with troublesome

dyskinesia decreased by 0.4 h/22.5% (P = 0.023).

Improvements persisted from week 4 through study

completion. UPDRS and HRQoL outcomes were also

improved throughout. In the advanced PD population, LCIG's

safety profile consisted primarily of AEs associated with the

device/procedure, l-dopa/carbidopa, and advanced P D. The

investigators stated that LCIG was generally well tolerated and

demonstrated clinically significant improvements in motor

function daily activities, and HRQoL sustained over 54 weeks.

Caceres-Redondo et al (2014) reported on the motor and

cognitive outcome of LCIG treatment in advanced PD after a

follow-up period of at least 24 months. The investigators

assessed 29 patients with advanced PD who started LCIG

infusion at one center between 2007 and 2013. Motor

fluctuations, parkinsonian symptoms, activities of daily living

and impact on quality of life were evaluated. They also

evaluated the cognitive outcome us ing a battery of

neuropsychological tests. All adverse events were recorded.

Of the 29 PD patients who initiated LCIG, 16 patients reached

the follow-up evaluation (24 months), after a mean time period

of 32.2 ± 12.4 months. Six patients did not fulfil the 24-month

follow-up visit and were evaluated after a mean time period of

8.6 ± 5.4 months. Seven patients discontinued the treatment

before the scheduled visit. The authors reported that "Off" time

and "On" dyskinesia duration w ere s ignificantly reduced. LCIG

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improved quality of life and non-motor symptoms, despite

overall unchanged total levodopa doses prior to LCIG

beginning. Motor and cognitive decline were detected. The

authors noted that a relatively high number of adverse events

occurred during the follow-up, above all, technical problems

with the infusion device and mild problems related with

gastrostomy. There were four cases of peripheral neuropathy

(PN), 2 of which were considered serious. The authors stated

that their data confirm that LCIG is beneficial in the long-term

treatment of advanced PD patients despite a decline in

cognitive functions in a subgroup of patients, probably due to

disease progression. PN in patients with LCIG may be more

frequent than the published data suggest.

Zibetti et al (2014) analyzed all PD patients treated with LCIG

at their center over a 7-year period to determine the duration

of treatment, retention rate, reasons for discontinuation, LCIG

efficacy in motor complications, modifications of concomitant

therapy and adverse events. Of the 59 patients, seven

subjects (12%) died of causes unrelated to LCIG infusion and

11 patients (19%) discontinued therapy prior to the cut-off

date. The authors reported that Duodopa improved motor

complications and over 90% of patients reported an

improvement in their quality of life, autonomy and clinical

global status. The most common adverse events were

dislocation and kinking of the intestinal tube.

Cerebro-Spinal Fluid (CSF) Biomarkers

Leaver and Poston (2015) stated that cross-sectional studies

have shown that certain protein levels are altered in the CSF

of PD patients with dementia and are thought to represent

potential biomarkers of underlying pathogenesis. Recent

studies suggested that CSF biomarker levels may be

predictive of future risk of cognitive decline in non-demented

PD patients. However, the strength of this evidence and

difference between specific CSF biomarkers is not well-

delineated. These investigators performed a systematic

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review to examine if levels of specific CSF protein biomarkers

are predictive of progression to cognitive impairment. A total

of 9 articles were identified that met inclusion criteria for the

review. Findings from the review suggested a convergence of

evidence thata low baseline Aβ42 in the CSF of non-

demented PD patients predicts development of cognitive

impairment over time. Conversely, there is limited evidence

that CSF levels of tau, either total tau or phosphorylated tau, is

a useful predictive biomarker. There are mixed results for

other CSF biomarkers such as α-synuclein, neurofilament light

chain, and heart fatty acid-binding protein. Overall the results

of this review showed that certain CSF biomarkers have better

predictive ability to identify PD patients who are at risk for

developing cognitive impairment. The authors concluded that

given the interest in developing disease-modifying therapies,

identifying this group will be important for clinical trials as

initiation of therapy prior to the onset of cognitive decline is

likely to be more effective.

In a longitudinal, single-center, cohort study, Mollenhauer and

associates (2016) examined multi-modal progression markers

for PD in patients with recently diagnosed PD (n = 123) and

age-matched, neurologically healthy controls (HC; n = 106). A

total of 30 tests at baseline and after 24 months covered non-

motor symptoms (NMS), cognitive function, and REM sleep

behavior disorder (RBD) by polysomnography (PSG), voxel-

based morphometry (VBM) of the brain by MRI, and CSF

markers. Linear mixed-effect models were used to estimate

differences of rates of change and to provide standardized

effect sizes (d) with 95 % CI. A composite panel of 10

informative markers was identified. Significant relative

worsening (PD versus HC) was seen with the following

markers: the UPDRS I (d 0.39;95 % CI: 0.09 to 0.70), the

Autonomic Scale for Outcomes in Parkinson's Disease (d 0.25;

95 % CI: 0.06 to 0.46), the Epworth Sleepiness Scale (ESS) (d

0.47; 95 % CI: 0.24 to 0.71), the RBD Screening

Questionnaire (d 0.44; 95 % CI: 0.25 to 0.64), and RBD by

PSG (d 0.37; 95 % CI: 0.19 to 0.55) as well as VBM units of

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cortical gray matter (d -0.2; 95 % CI: -0.3 to -0.09) and

hippocampus (d -0.15; 95 % CI -0.27 to -0.03). Markers with a

relative improvement included the Non-motor Symptom

(Severity) Scale (d -0.19; 95 % CI: -0.36 to -0.02) and 2

depression scales (BDI; d -0.18:95 % CI: -0.36 to 0; MADRS;

d -0.26; 95 % CI: -0.47 to -0.04). Unexpectedly, cognitive

measures and select laboratory markers were not significantly

changed in PD versus HC participants. The authors

concluded that current CSF biomarkers and cognitive scales

do not represent useful progression markers. However, sleep

and imaging measures, and to some extent NMS, assessed

using adequate scales, may be more informative markers to

quantify progression. Moreover, they stated that future studies

need to examine the validity of these proposed markers,

standardize the assessment of non-motor features, and

identify more sensitive and disease-specific marker candidates

that reflect underlying biological processes (such as

propagation of α-synuclein pathology, inflammation and

neuronal death).

Hu and colleagues (2017) stated that as a biomarker of axonal

injury, neurofilament light chain (NFL) in MSA patients and PD

patients has been investigated by numerous studies.

However, CSF NFL changes are conflicting in MSA patients

relative to PD patients to date. In a meta-analysis, these

researchers attempted to find out possible heterogeneity

sources. Furthermore, "neurofilament", "neurofilament light

chain" and "multiple system atrophy" were employed to search

"PubMed", "Springer" and "Medline" databases until August

2016 with standard mean difference (Std.MD) being

calculated. In addition, subgroup analysis and meta-

regression were performed to assess possible heterogeneity

sources. A total of 9 studies were pooled, in which 212 MSA

patients and 373 PD patients were involved. Moreover, CSF

NFL in MSA patients was higher than that in PD patients

[pooled Std.MD = 1.56, 95 % CI: 1.12 to 2.00, p < 0.00001]

with significant heterogeneity (I 2 = 76 %). Besides,

population variations, sample size, the difference in CSF

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phosphorylated tau (p-tau) levels between MSA patients and

PD patients, and Hoehn-Yahr staging of PD patients were the

main heterogeneity sources. As shown by meta-regression,

Hedges's g of CSF NFL was correlated with CSF Std.MD of

α-synuclein between MSA patients and healthy controls (r =

-1.34824, p = 0.00025). Therefore, CSF NFL increased in

MSA patients relative to PD patients. Meta-regression showed

that NFL was associated with α-synuclein in CSF of MSA

patients relative to healthy controls. The authors concluded

that due to the influence of heterogeneity sources, more

prospective large sample studies are still needed to assess

CSF NFL changes in MSA patients relative to PD patients.

Genetic Testing of PARK10 and Variants

Beecham et al (2015) noted that to minimize pathologic

heterogeneity in genetic studies of PD, the Autopsy-Confirmed

Parkinson Disease Genetics Consortium conducted a

genome-wide association study using both patients with

neuropathologically confirmed PD and controls. A total of 484

cases and 1,145 controls met neuropathologic diagnostic

criteria, were genotyped, and then imputed to 3,922,209

variants for genome-wide association study analysis. A small

region on chromosome 1 was strongly associated with PD

(rs10788972; p = 6.2 × 10(-8)). The association peak lied

within and very close to the maximum linkage peaks of 2 prior

positive linkage studies defining the PARK10 locus. These

researchers demonstrated that rs10788972 is in strong linkage

disequilibrium with rs914722, the SNP defining the PARK10

haplotype previously shown to be significantly associated with

age at onset in PD. The region containing the PARK10 locus

was significantly reduced from 10.6 mega-bases to 100 kilo-

bases and contains 4 known genes: TCEANC2, TMEM59, miR

4781, and LDLRAD1. The authors concluded that they

confirmed the association of a PARK10 haplotype with the risk

of developing idiopathic PD. Furthermore, they significantly

reduced the size of the PARK10 region. None of the

candidate genes in the new PARK10 region have been

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previously implicated in the biology of PD, suggesting new

areas of potential research. They stated that the findings of

this study strongly suggested that reducing pathologic

heterogeneity may enhance the application of genetic

association studies to PD.


Simon-Sanchez and Gasser (2015) stated that “although

spurious associations driven by undetected population

stratification remains a possibility until this findings has been

replicated in other studies, another possible explanation for

this discrepancy is that the PARK10 locus is only associated

with a special subgroup of PD and that its effect size is strong

enough to yield statistical association when a selection of LB

[Lewy body] PD class is made, but not when larger series of

clinical PD cases are studied …. Another limitation of this

study 9and GWAS in general) is the relatively small effect size

associated with the identified loci. This precludes useful

individual disease prediction, and is a problem for risk

stratification and personalized medicine …. Further

applications of the data derived from this and other GWAS

include the possibility to build genetic risk profiles for a disease

of interest. These profiles have the potential to identify at-risk

individuals and apply different therapeutic strategies

depending on the specific genetic underpinnings of the

disease in a given individual”.

Simon-Sanchez et al (2015) stated that a recent study in

autopsy-confirmed PD patients and controls revived the

debate about the role of PARK10 in this disorder. In an

attempt to replicate these results and further understand the

role of this locus in the risk and age at onset of PD, these

researchers explored NeuroX genotyping and whole exome

sequencing data from 2 large independent cohorts of clinical

patients and controls from the International Parkinson's

Disease Genomic Consortium. A series of single-variant and

gene-based aggregation (sequence kernel association test

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and combined multi-variate and collapsing test) statistica l tests

suggested that common and rare genetic variation in this locus

do not influence the risk or age at onset of clinical PD.

Guo et al (2015) noted that PD is the second most common

chronic neuronal degeneration di sorder with motor and non-

motor clinical features. The rs10788972 variant of the

transcription elongation factor A (SII) N-terminal and central

domain containing 2 ( TCEANC2) gene in the PARK10 region

was recently identified to be strongly related to sporadic PD in

the American population. These researchers examined if the

same variant is associated with sporadic PD in Chinese Han

population. They researched 513 sporadic PD patients and

512 normal controls of Chinese Han ethnicity in Mainland

China. No significant difference i n genotypic and allelic

distributions between patients and control groups for either

rs10788972 (for genotypic distribution, χ(2) = 0.412, p = 0.814,

and for allelic distribution, χ(2) = 0.280, p = 0.597) or its

neighbor marker rs12046178 (for genotypic distribution, χ(2) =

1.500, p = 0.472, and for allelic distribution, χ(2) = 1.339, p =

0.247) was found. The authors concluded that these findings

suggested that neither variant is related to sporadic PD in

Chinese Han population.

Genetic Testing of PITX3

Jimenez-Jimenez et al (2014) noted that several single

nucleotide polymorphisms (SNPs) in the PITX3 gene have

been associated with the risk for PD. These investigators

performed a systematic review and a meta-analysis including

all the studies published on the risk of PD related with these

polymorphisms. The systematic review was carried out using

several databases. Eligible studies were included in the meta-

analysis that was carried out using Meta-DiSc 1.1.1 software.

Heterogeneity between studies was tested using the

Q-statistic. The meta-analysis included 8 association studies

for the PITX3 rs3758549 SNP (4,052 PD patients, 3,949

controls), 8 studies for the PITX3 rs2281983 SNP (4,309 PD

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patients, 4,287 controls), and 6 studies for the rs4919621 SNP

(2,724 PD patients, 2,285 controls), and the risk for PD, global

diagnostic ORs (95 % CIs) for rs3758549, rs2281983, and

rs4919621 were, respectively, 1.00 (0.89-1.12) (p = 0.979),

0.99 (0.91-1.09) (p = 0.896), and 0.98 (0.83-1.16) (p = 0.844)

for the total group. The separate analysis in Caucasian and

Chinese subjects on the frequency of the minor allele of the 3

SNPs analyzed did not show significant differences between

PD patients and controls in both subgroups; rs2281983 and

rs4919621 SNPs were related with early-onset PD risk in

Caucasians. The authors concluded t hat the findings of this

meta-analysis suggested t hat rs3758549, rs2281983, and

rs4919621 SNPs are not major determinants of the risk for PD.

Measurement of Telomere Length

Forero et al (2016) stated that differences in telomere length

(TL) have been reported as possible risk factors for several

neuropsychiatric disorders, including PD. Results from

published studies for TL in PD are inconsistent, highlighting

the need for a meta-analysis. In the current work, a meta-

analysis of published studies for TL in PD was carried out.

PubMed, Web of Science and Google Scholar databases

were used to identify relevant articles that reported TL in

groups of PD patients and controls. A random-effects model

was used for meta-analytical procedures. The meta-analysis

included 8 primary studies, derived from populations of

European and Asian descent, and did not show a significant

difference in TL between 956 PD patients and 1,284 controls

(p value: 0.246). The authors concluded that the findings of

this meta-analysis showed that there is no consistent evidence

of shorter telomeres in PD patients and suggested the

importance of future studies on TL and PD that analyze other

populations and also include assessment of TL from different

brain regions.

Partial Body Weight-Supported Treadmill Training

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Ganesan and colleagues (2015) evaluated the effect of

conventional gait training ( CGT) and partial weight-supported

treadmill training (PWSTT) on gait and clinical manifestation in

patients with PD. Patients with idiopathic PD (n = 60; mean

age of 58.15 ± 8.7y) on stable dosage of dopaminomimetic

drugs were randomly assigned into the 3 following groups (20

patients in each group): (i) non-exercising PD group, (ii) CGT

group, and (iii) PWSTT group. The interventions included i n

the study were CGT and PWSTT. The sessions of the CGT

and PWSTT groups were given in patient's self-reported best

on status after regular medications. The interventions were

given for 30 mins/day, 4 day/week, for 4 weeks (16 sessions).

Clinical severity was measured by UPDRS and its sub-scores.

Gait was measured by 2 minutes of treadmill walking and the

10-m walk test. Outcome measures were evaluated in their

best on status at bas eline and after the 2nd and 4th weeks.

Four weeks of CGT and PWSTT gait training showed

significant improvements of UPDRS scores, its sub-scores,

and gait performance m easures. Moreover, the Brabenec and

associates (2017) revieweffects of PWSTT were significantly

better than CGT on most measures. The authors concluded

that PWSTT is a promising intervention tool to improve the

clinical and gait outcome measures in patients with PD.

Progressive Resistance Training

In a systematic review and meta-analysis, Saltychev and

colleagues (2016) examined if there is evidence on

effectiveness of progressive resistance training in rehabilitation

of PD. Data sources included Central, Medline, Embase,

Cinahl, Web of Science, Pedro until May 2014. Randomized

controlled or controlled clinical trials were selected for

analysis. The methodological quality of studies was assessed

according to the Cochrane Collaboration's domain-based

evaluation framework. Adults with primary/idiopathic PD of

any severity, excluding other concurrent neurological condition

were included in this analysis. Progressive resistance training

defined as training consisting of a small number of repetitions

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until fatigue, allowing sufficient rest between exercises for

recovery, and increasing the resistance as the ability to

generate force improves. Of 516 records, 12 were considered

relevant; 9 of them had low risk of bias. All studies were RCTs

conducted on small samples with none or 1 month follow-up

after the end of intervention. Of them, 6 were included in

quantitative analysis. Pooled effect sizes of meta-analyses on

fast and comfortable walking speed, the 6-min walking test,

Timed Up and Go test and maximal oxygen consumption were

below the level of minimal clinical significance. The authors

concluded that there is so far no evidence on the superiority of

progressive resistance training compared with other physical

training to support the use of this technique in rehabilitation of

PD.

Non-Invasive Brain Stimulation (e.g., Transcranial Direct C u rrent Stimulation/Transcranial Magnetic Stimulation)

Dinkelbach and co-workers (2017) noted that cognitive

impairments and depression are common non-motor

manifestations in PD, and recent evidence suggested that both

partially arise via the same fronto-striatal network, opening the

opportunity for concomitant treatment with non-invasive brain

stimulation (NIBS) techniques (e.g., rTMS and tDCS). In this

systematic review, these investigators evaluated the effects of

NIBS on cognition and/or mood in 19 placebo-controlled

studies involving 561 PD patients. Outcomes depended on

the area stimulated and the technique used; rTMS over the

dorsolateral-prefrontal cortex (DLPFC) resulted in significant

reductions in scores of depressive symptoms with moderate- to-

large effect sizes along with increased performance in several

tests of cognitive functions; tDCS over the DLPFC improved

performance in several cognitive measures, including

executive functions with large effect sizes. Additional effects of

tDCS on mood were not detectable; however, only non-

depressed patients were assessed. The authors

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concluded that further confirmatory research is needed to

clarify the contribution that NIBS could make in the care of PD

patients.

Brabenec and associates (2017) review papers on hypokinetic

dysarthria (HD) in PD with a special focus on (i) early PD

diagnosis and monitoring of the disease progression using

acoustic voice and speech analysis, and (ii) functional

imaging studies exploring neural correlates of HD in PD,

and (iii) clinical studies using acoustic analysis to evaluate

effects of dopaminergic medication and brain stimulation.

A systematic literature search of articles written in English

before March 2016 was conducted in the Web of Science,

PubMed, SpringerLink, and IEEE Xplore databases using and

combining specific relevant keywords. Articles were

categorized into 3 groups: (i) articles focused on neural

correlates of HD in PD using functional imaging (n = 13); (ii)

articles dealing with the acoustic analysis of HD in PD (n =

52); and (iii) articles concerning specifically dopaminergic and

brain stimulation-related effects as assessed by acoustic

analysis (n = 31); the groups were then reviewed. These

researchers identified 14 combinations of speech tasks and

acoustic features that can be recommended for use in

describing the main features of HD in PD. While only a few

acoustic parameters correlate with limb motor symptoms and

can be partially relieved by dopaminergic medication, HD in

PD appeared to be mainly related to non-dopaminergic deficits

and associated particularly with non-motor symptoms. The

authors concluded that future studies should combine NIBS

with voice behavior approaches to achieve the best treatment

effects by enhancing auditory-motor integration.

Measurement of Urinary LRRK2 Phosphorylation

Fraser and colleagues (2016) examined if phosphorylated Ser-

1292 LRRK2 levels in urine exosomes predicts LRRK2

mutation carriers (LRRK2+) and non-carriers (LRRK2-) with

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Parkinson disease (PD+) and without Parkinson disease (PD-

). LRRK2 protein was purified from urinary exosomes

collected from participants in 2 independent cohorts. The 1st

cohort included 14 men (LRRK2+/PD+, n = 7; LRRK2-/PD+, n

= 4; LRRK2-/PD-, n = 3). The 2nd cohort included 62 men

(LRRK2-/PD-, n = 16; LRRK2+/PD-, n = 16; LRRK2+/PD+, n =

14; LRRK2-/PD+, n = 16).The ratio of Ser(P)-1292 LRRK2 to

total LRRK2 was compared between LRRK2+/PD+ and

LRRK2- in the 1st cohort and between LRRK2 G2019S

carriers with and without PD in the 2nd cohort. LRRK2+/PD+

had higher ratios of Ser(P)-1292 LRRK2 to total LRRK2 than

LRRK2-/PD- (4.8-fold, p < 0.001) and LRRK2-/PD+ (4.6-fold, p

< 0.001). Among mutation carriers, those with PD had higher

Ser(P)-1292 LRRK2 to total LRRK2 than those withoutPD (2.2

fold, p < 0.001). Ser(P)-1292 LRRK2 levels predicted

symptomatic from asymptomatic carriers with an area under

the receiver operating characteristic curve of 0.844. The

authors concluded that elevated ratio of phosphorylated Ser-

1292 LRRK2 to total LRRK2 in urine exosomes predicted

LRRK2 mutation status and PD risk among LRRK2 mutation

carriers. Moreover, they stated that future studies may explore

whether interventions that reduce this ratio may also reduce

PD risk. In particular, they stated that larger studies that

measure Ser(P)-1292 LRRK2 levels over time in asymptomatic

carriers will be needed to understand the prognostic potential

of this new biomarker.


Grunewald and Klein (2016) stated that “The findings by

Fraser et al are exciting and promising. However, they remain

subject to independent confirmation and have been only

obtained in a relatively small sample of 18 probands per

group”.

CSF Biomarkers

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Mollenhauer and colleagues (2017) analyzed longitudinal

levels of CSF biomarkers in drug-naive patients with PD and

HC, examined the extent to which these biomarker changes

relate to clinical measures of PD, and identified what may

influence them.CSFα-synuclein (α-syn), total and

phosphorylated tau (t- and p-tau), and β-amyloid 1-42 (Aβ42)

were measured at baseline and 6 and 12 months in 173

patients with PD and 112 matched HC in the international

multi-center Parkinson's Progression Marker Initiative.

Baseline clinical and demographic variables, PD medications,

neuroimaging, and genetic variables were evaluated as

potential predictors of CSF biomarker changes. CSF

biomarkers were stable over 6 and 12 months, and there was

a small but significant increase in CSFAβ42 in both patients

with patients with PD and HC from baseline to 12 months. The t-

tau remained stable. The p-tau increased marginally more in

patients with PD than in HC; α-syn remained relatively stable

in patients with PD and HC. Ratios of p-tau/t-tau increased,

while t-tau/Aβ42 decreased over 12 months in patients with

PD. CSF biomarker changes did not correlate with changes in

Movement Disorder Society-sponsored revision of the UPDRS

motor scores or dopamine imaging.CSFα-syn levels at 12

months were lower in patients with PD treated with dopamine

replacement therapy, especially dopamine agonists. The

authors concluded that these core CSF biomarkers remained

stable over 6 and 12 months in patients with early PD and HC;

PD medication use may influence CSFα-syn. Moreover, they

stated that novel biomarkers are needed to better profile

progressive neurodegeneration in PD.

Genetic Testing of Fibroblast Growth Factor 20 rs12720208 Polymorphism

Wang and colleagues (2017) noted that many studies had

examined the association between fibroblast growth factor 20

(FGF20) rs12720208 polymorphism and the susceptibility of

PD. However, published data are still controversial. These

researchers performed a meta-analysis to evaluate the

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association of rs12720208 polymorphism with the risk of PD.

Up to April 2016, PubMed, Embase, Web of science, the

Chinese National Knowledge Infrastructure, and Wanfang

Medicine were reviewed to identify appropriate documents. A

total of 7 articles involving 11 studies with 3,360 PD cases and

3,681 controls were included based on the strict inclusion and

exclusion standards. And STATA 12.0 statistics software was

used to calculate available data from each study. The pooled

OR and 95 % CI were calculated to assess the association

between FGF20 rs12720208 polymorphism and PD risk.

When all studies were pooled into this meta-analysis, neither

the minor T allele frequencies nor the genotypic distributions

were different between PD cases and controls. But the

subgroup analysis stratified by ethnicity showed FGF20

rs12720208 polymorphism was associated with increased risk

in the allele model (T versus C: OR = 1.167, 95 % CI: 1.020 to

1.335) and dominant model (TT + TC versus CC: OR = 1.156,

95 % CI: 1.001 to 1.335) in Caucasians but not in Asians. The

authors concluded that the findings of this meta-analysis

indicated that rs12720208 C/T variant might be associated

with PD susceptibility in Caucasians.

Vagotomy for the Prevention and Treatment of PD

Liu and colleagues (2017) examined if vagotomy decreases

the risk of PD. Using data from nationwide Swedish registers,

these researchers conducted a matched-cohort study of 9,430

vagotomized patients (3,445 truncal and 5,978 selective)

identified between 1970 and 2010 and 377,200 reference

individuals from the general population individually matched to

vagotomized patients by sex and year of birth with a 40:1 ratio.

Participants were followed-up from the date of vagotomy until

PD diagnosis, death, emigration out of Sweden, or December

31, 2010, whichever occurred first. Vagotomy and PD were

identified from the Swedish Patient Register. These

researchers estimated HRs with 95 % CIs using Cox models

stratified by matching variables, adjusting for country of birth,

chronic obstructive pulmonary disease, diabetes mellitus,

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vascular diseases, rheumatologic disease, osteoarthritis, and

co-morbidity index. A total of 4,930 cases of incident PD were

identified during 7.3 million person-years of follow-up. PD

incidence (per 100,000 person-years) was 61.8 among

vagotomized pat ients (80.4 for truncal and 55.1 for selective)

and 67.5 among reference individuals. Overall, vagotomy was

not associated with PD risk (HR 0.96, 95% CI 0.78-1.17).

However, there was a suggestion of lower risk among patients

with truncal vagotomy (HR 0.78, 95 % CI: 0.55 to 1.09), which

may be driven by truncal vagotomy at least 5 years before PD

diagnosis (HR 0.59, 95 % CI: 0.37 to 0.93). Selective

vagotomy was not related to PD risk in any analyses. The

authors stated that although overall vagotomy was not

associated the risk of PD; they found suggestive evidence for

a potential protective effect of truncal, but not selective,

vagotomy against PD development.


Borghammer and Hamani (2017) stated that “At this stage, we

have insufficient knowledge to propose vagotomy as a putative

treatment for PD”.

Brain SPECT for Monitoring the Progression of Parkinson’s Disease

Jeong and colleagues (2018) stated that levodopa-induced

dyskinesia (LID) is a major complication of dopamine

replacement drug usage in PD patients. Since the mechanism

of LID is yet unclear, these researchers analyzed serial [I-123]

N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)

nortropane (I-123 FP-CIT) SPECT images. They examined

the changes of dopaminergic innervation during the

progression of PD in relation to the development of LID. Data

were obtained from the Parkinson's Progression Markers

Initiative (PPMI) database. A total of 290 PD dopamine

replacement drug-naïve patients (age of 61.0 ± 9.7 years, M: F

= 195: 95) were enrolled. I-123 FP-CIT SPECT images from

baseline, 12, 24, and 48 months were analyzed among with

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clinical factors. Specific binding ratios (SBRs) of the striatal

regions from I-123 FP-CIT SPECT images were analyzed.

These investigators used independent tests and logistic

regression for analysis of LID risk association. Among 290

patients, 36 patients developed LID after 48 months follow-up.

Baseline MDS-UPDRS Part II and III scores were significantly

higher in the PD patients with LID, compared with the PD

patients without LID. Striatal SBRs were significantly lower in

the PD patients with LID at baseline, 24 and 48 months (p <

0.001). Multi-variate analysis revealed MDS-UPDRS Part II

and putaminal SBRs at baseline and 24 months to be

significantly associated with the development of LID (p <

0.001). Furthermore, patients who developed LID at 48

months had a higher decrease rate of putaminal SBR at the 24

months (p < 0.05), and 48 months (p < 0.01) period. The

authors concluded that in this study, they demonstrated the

serial changes of the nigrostriatal dopaminergic innervation in

relationship to LID development for the first time. The

deterioration rate of dopaminergic innervation was significantly

higher in the PD patients who developed LID, compared with

the PD patients who did not develop LID. These researchers

stated that serial follow-up I-123 FP-CIT SPECT acquisition

during the course of PD could be helpful in predicting the

development of LID.

The authors stated that this study had several drawbacks.

First, this study did not include the FP-CIT SPECT images of

healthy controls, since the PPMI data did not provide follow-up

FP-CIT SPECT images nor clinical data of healthy controls. It

remains to be seen whether the striatal neuronal loss in PD

patients progress in a higher rate compared with those of age-

and sex-matched healthy controls, and whether these

researchers could exclude the effect of normal aging process.

Second, the PPMI data were collected from multiple

institutions, and could have variations in the FP-CIT SPECT

image acquisition. In order to maintain a uniformly acquired

imaging dataset, quality assurance procedures were

performed. Third, all 3 follow-up FP-CIT SPECT images were

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acquired in 215 patients out of 290 patients. In 75 patients,

only 2 follow-up FP-CIT SPECT images were acquired.

Finally, although these investigators have focused on the pre-

synaptic hypothesis for LID development, this does not

undermine the post-synaptic hypothesis. They stated that

further studies focusing on the post-synaptic striatal signal

transduction are needed.

Djaldetti and co-workers (2018) stated that the role of nuclear

imaging in predicting PD progression is unclear. These

investigators examined if the degree of reduced striatal DAT

binding at diagnosis of PD predicts later motor complications

and time to disease progression. They retrospectively studied

41 patients with early PD who underwent 123I-FP-CIT SPECT

and were followed thereafter with a mean disease dur ation of

9.51 ± 3.18 years. The association of quantitatively analyzed

123I-FP-CIT binding in striatal sub-regions with the

development of motor fluctuations, dyskinesia, freezing of gait

(FOG), and falls as well as the time to Hoehn and Yahr (H&Y)

stage 3 was evaluated. Logistic regression models controlling

for age at diagnosis, sex, disease duration, and L-dopa dose

revealed that 123I-FP-CIT binding in the putamen and striatum

significantly predicted FOG (OR = 0.02, p = 0.03; OR = 0.01,

p = 0.04; respectively); but not falls. Cox proportional hazard

analysis did not reveal significant relationship between 123I-

FP-CIT binding and motor fluctuations, dyskinesia, or H&Y

stage 3. The authors concluded that these findings suggested

that a more severe depletion of pre-synaptic dopamine in early

PD is a bad prognostic sign in terms of FOG development.

They stated that these findings, if replicated, may point to

dopaminergic transmission as part of the mechanism

underlying FOG in PD.

In a retrospective, cohort study, Kim and colleagues (2018)

examined if the degree of pre-synaptic striatal dopamine

depletion could predict the later development of FOG in PD.

This trial included 390 de-novo patients with PD without FOG

at baseline. Subjects were divided into tertiles according to

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the baseline DAT uptake of each striatal sub-region, and the

cumulative risk of FOG was compared using the Kaplan-Meier

method. Cox proportional hazard models were used to assess

the predictive power of DAT uptake of striatal sub-regions for

the development of FOG. During a median follow-up period of

4.0 years, 143 patients with PD (36.7 %) developed FOG. The

severe reduction group of DAT uptake in the caudate nucleus

and putamen had a significantly higher incidence of FOG than

that of the mild and moderate reduction groups. Multi-variate

Cox regression analyses showed t hat DAT uptakes in the

caudate nucleus (HR 0.551; 95 % CI: 0.392 to 0.773;

p = 0.001) and putamen (HR 0.441; 95 % CI: 0.214 to 0.911;

p = 0.027) predicted the development of FOG. In addition,

male sex, higher postural instability and gait difficulty score,

and a lower Montreal Cognitive Assessment score were also

significant predictors of FOG. The authors concluded that

these findings suggested t hat pre-synaptic striatal

dopaminergic denervation predicted the later development of

FOG in de-novo patients with PD, which may provide reliable

insight into the mechanism of FOG in terms of nigrostriatal

involvement.

Kuo and associates (2019) noted that quantitative assessment

of DAT imaging can aid in diagnosing PD and assessing

disease progression i n the context of therapeutic trials.

Previously, the software program SBRquant was applied to

123I-ioflupane SPECT images acquired on healthy controls

and subjects with PD. Earlier work on optimization of the

parameters for differentiating between controls and subjects

with dopaminergic deficits was extended for maximizing

change measurements associated with disease progression

on longitudinally acquired scans. Serial 123I-ioflupane SPECT

imaging for 51 subjects with PD (conducted approximately 1

year apart) were down-loaded from the PPMI database. The

software program SBRquant calculated the SBR separately for

the left and right caudate and putamen regions of interest

(ROI). Parameters were varied to evaluate the number of

summed transverse slices and the positioning of the striatal

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ROIs for determining signal-to-noise associated with their

annual rate of change in SBR. The parameters yielding the

largest change of the lowest putamen's SBR from scan 1 to

scan 2 were determined. For the change from scan 1 to scan

2 in the 51 subjects, the largest annual change was observed

when the putamen ROI was placed 3 pixels away from the

caudate and by summing 5 central striatal slices. This resulted

in an 11.2 ± 4.3 % annual decrease in the lowest putamen's

SBR for the group. The authors concluded that quantitative

assessment of DAT imaging for assessing progression of PD

requires specific, optimal parameters different than those for

diagnostic accuracy.

Furthermore, UpToDate reviews on “Clinical manifestations of

Parkinson disease” (Chou, 2018) and “Cognitive impairment

and dementia in Parkinson disease” (Rodnitzky, 2018) do not

mention SPECT scanning as a management tool.

Retinal Thinning as a Biomarker of Parkinson Disease

Ahn and colleagues (2018) analyzed the relationship between

retinal thinning and nigral dopaminergic loss in de-novo PD. A

total of 49 patients with PD and 54 age-matched controls were

analyzed. Ophthalmologic examination and macula optical

coherence tomography (OCT) scans were performed with

additional micro-perimetry, N-(3-[18F]fluoropropyl)-2-

carbomethoxy-3-(4-iodophenyl) nortropane PET, and 3T MRI

scans were done in patients with PD only. Retinal layer

thickness and volume were measured in sub-fields of the 1-,

2.22-, and 3.45-mm Early Treatment of Diabetic Retinopathy

Study circle and compared in patients with PD and controls.

Correlation of inner retinal layer thinning with micro-perimetric

response was examined in patients with PD, and the

relationships between retinal layer thickness and dopamine

transporter densities in the ipsilateral caudate, anterior and

posterior putamen, and substantia nigra were analyzed.

Retinal layer thinning was observed in the temporal and

inferior 2.22-mm sectors (false discovery rate-adjusted p <

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0.05) of drug-naive patients with PD, particularly the inner

plexiform and ganglion c ell layers. The thickness of these

layers in the inferior 2.22-mm sector showed a negative

correlation with the Hoehn and Yahr stage (p = 0.032 and

0.014, respectively). There was positive correlation between

macular sensitivity and retinal layer thickness in all 3.45-mm

sectors, the superior 2.22-mm sector, and 1-mm circle (p <

0.05 for all). There was an association between r etinal

thinning and dopaminergic loss in the left substantia nigra

(false discovery rate-adjusted p < 0.001). The authors

concluded that retinal thinning was present in the early stages

of PD, correlated with disease severity, and may be linked to

nigral dopaminergic degeneration. These researchers stated

that retinal imaging may be useful for detection of pathologic

changes occurring in early PD.

Bright Light Therapy for the Treatment of Depression in Parkinson Disease

In a double-blind RCT, Rutten and colleagues (2019)

examined the efficacy of bright light therapy (BLT) in reducing

depressive symptoms in patients with PD and major

depressive disorder (MDD) compared to a control light.

Patients with PD and MDD were randomized to receive

treatment with BLT (± 10,000 lux) or a control light (± 200 lux);

they were treated for 3 months, followed by a 6-month

naturalistic follow-up. The primary outcome of the study was

the HDRS score. Secondary outcomes were objective and

subjective sleep measures and salivary melatonin and cortisol

concentrations. Assessments were repeated halfway, at the

end of treatment, and 1, 3, and 6 months after treatment. Data

were analyzed with a linear mixed-model analysis. These

researchers enrolled 83 subjects; HDRS scores decreased in

both groups without a significant between-group difference at

the end of treatment. Subjective sleep quality improved in

both groups, with a larger improvement in the BLT group (B

[SE] = 0.32 [0.16], p = 0.04). Total salivary cortisol secretion

decreased in the BLT group, while it increased in the control

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group (B [SE] = -8.11 [3.93], p = 0.04). The authors concluded

that BLT was not more effective in reducing depressive

symptoms than a control light. Mood and subjective sleep

improved in both groups; BLT was more effective in improving

subjective sleep quality than control light, possibly through a

BLT-induced decrease in cortisol levels. This study provided

Class I evidence that BLT was not superior to a control light

device in reducing depressive symptoms in patients with PD

with MDD.


Videnovic and Messinis (2019) stated that “This trial

represents an important contribution to a growing body of

literature centered on chrono-therapeutics of PD. While

reported effects of LT on depressive symptoms in PD are

encouraging, further studies are needed to better define the

role of LT in the management of PD”.

Cueing Module Device (Auditory Cue) for the Treatment of Parkinson's Freezing

Lopez et al (2014) noted that evidence supports the use of

rhythmic external auditory signals to improve gait in

Parkinson’s disease (PD) patients. However, few prototypes

are available for daily use, and to the authors’ knowledge,

none utilize a smartphone application allowing individualized

sounds and cadence. These researchers analyzed the effects

on gait of Listenmee, an intelligent glasses system with a

portable auditory device, and presented its smartphone

application, the Listenmee app, offering over 100 different

sounds and an adjustable metronome to individualize the

cueing rate as well as its smartwatch with accelerometer to

detect magnitude and direction of the proper acceleration,

track calorie count, sleep patterns, steps count and daily

distances. The present study included patients with idiopathic

PD presented gait disturbances including freezing. Auditory

rhythmic cues were delivered through Listenmee.

Performance was analyzed in a motion and gait analysis

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laboratory. The results revealed significant improvements in

gait performance over 3 major dependent variables: walking

speed in 38.1 %, cadence in 28.1 % and stride length in 44.5

%. The authors concluded that these findings suggested that

auditory cueing through Listenmee may significantly enhance

gait performance. Moreover, these investigators stated that

further studies are needed to elucidate the potential role and

maximize the benefits of these portable devices.

Zhao et al (2016) stated that new mobile technologies like

smart-glasses could deliver external cues that may improve

gait in people with PD in their natural environment. However,

the potential of these devices must first be assessed in

controlled experiments. These researchers evaluated

rhythmic visual and auditory cueing in a laboratory setting with

a custom-made application for the Google Glass. A total of 12

participants (mean age of 66.8 years; mean disease duration

of 13.6 years) were tested at end of dose. These investigators

compared several key gait parameters (walking speed,

cadence, stride length, and stride length variability) and

freezing of gait for 3 types of external cues (metronome,

flashing light, and optic flow) and a control condition (no-cue).

For all cueing conditions, the subjects completed several

walking tasks of varying complexity; 7 inertial sensors attached

to the feet, legs and pelvis captured motion data for gait

analysis. Two experienced raters scored the presence and

severity of freezing of gait using video recordings. User

experience was evaluated through a semi-open interview.

During cueing, a more stable gait pattern emerged, particularly

on complicated walking courses; however, freezing of gait

(FOG) did not significantly decrease. The metronome was

more effective than rhythmic visual cues and most preferred by

the participants. Subjects were overall positive about the

usability of the Google Glass and willing to use it at home.

The authors concluded that smart-glasses like the Google

Glass could be used to provide personalized mobile cueing to

support gait; however, in its current form, auditory cues

appeared more effective than rhythmic visual cues. These

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researchers stated that smart-glasses have the potential to

become mobile assistive devices for on-demand cueing in

daily life, but further development is needed to better

accommodate the individual needs of patients with PD.


First, out of the 12 participants, only 6 experienced FOG more

than once, 4 exhibited no FOG, and 2 had a single FOG

episode. Due to this small sample size of freezers, the effect

of cueing on FOG was inconclusive. Second, a potential

confound was that many of the participants have already used

cues in their daily life and may be more efficient during the

cued walking trials. As the effects of cueing did not generalize

well and none of the participants had prior experience using

the Google Glass, these researchers did not expect that those

with cueing experience would out-perform those with no

previous experience during this study. Visual inspection of

individual performances also did not show consistent

differences between these 2 groups. Third, as the study was

conducted at end of dose, the findings may be less applicable

to daily life when people are mostly in the on state. However,

as FOG is known to be resistant to medication and deep brain

stimulation and motor fluctuations -- alterations between on

and off states -- are the most common complications of long-

term levodopa use, cueing during the on state is still a useful

strategy. Lastly, the version of the Google Glass used in this

study is no longer available for purchase, with Google

pursuing a new Enterprise edition of the Glass tailored for

working environments. As numerous other augmented reality

smart-glasses are appearing on the market, mobile cueing will

continue to advance.

Furthermore, an UpToDate review on “Motor fluctuations and

dyskinesia in Parkinson disease” (Tarsy, 2020) does not

mention auditory cue as a management option.

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Plasma Neurofilament Light Chain (NfL) as a Biomarker for Disease Severity and Progression in Parkinson Disease

In a prospective, follow-up study, Lin and colleagues (2019)

examined if plasma neurofilament light chain (NfL) levels were

associated with motor and cognitive progression i n PD. This

trial enrolled 178 subjects, including 116 with PD, 22 with

multiple system atrophy (MSA), and 40 healthy controls.

These researchers measured plasma NfL l evels with electro-

chemiluminescence i mmunoassay. Patients with PD received

evaluations of motor and cognition at baseline and at a mean

follow-up interval of 3 years. Changes in the UPDRS part III

motor score and MMSE score were used to assess motor and

cognition progression. Plasma NfL levels were significantly

higher in the MSA group than in the PD and healthy groups

(35.8 ± 6.2, 17.6 ± 2.8, and 10.6 ± 2.3 pg/ml, respectively, p <

0.001). In the PD group, NfL levels were significantly elevated

in patients with advanced Hoehn-Yahr stage and patients with

dementia (p < 0.001). NfL levels were modestly correlated

with UPDRS part III scores (r = 0.42, 95 % CI: 0.46 to 0.56, p <

0.001). After a mean follow-up of 3.4 ± 1.2 years, a Cox

regression analysis adjusted for age, sex, disease duration,

and baseline motor or cognitive status showed that higher

baseline NfL levels were associated with higher risks for either

motor or cognition progression ( p = 0.029 and p = 0.015,

respectively). The authors concluded that these findings

suggested that the plasma NfL level could serve as a non-

invasive, easily accessible biomarker to evaluate disease

severity and to monitor disease progression in PD. They

stated that future, large longitudinal follow-up s tudies that

incorporate other biomarkers such as neuroimages are

needed to strengthen the possible prognostic role of blood NfL

levels in PD progression. Level of Evidence = Class III.


First, these researchers evaluated cognitive function only with

MMSE, a simple measurement of global cognitive function.

Detailed neuropsychological tests for evaluating individual

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cognitive domains are needed for further assessments of

correlations between plasma NfL levels and individual

cognitive domain declines in patients with PD. Second, the

clinical diagnosis of PD and MSA was not confirmed by post-

mortem pathological confirmation and may be susceptible to

mis-classification. However, these researchers based the final

diagnosis on thorough clinical and laboratory examinations

such as autonomic function tests and nuclear imaging studies,

with close clinical follow-up, using the international consensus

criteria in a movement disorder specialist's clinic. Third, the

plasma level of NfL was checked only when the subjects were

enrolled in the study. Future studies that serially follow-up

plasma levels of NfL accompanied by motor and cognitive

function evaluations would further delineate the changes of

NfL in the disease course of PD and MSA. Finally, although

the plasma NfL level was significantly increased in patients

with PD compared to controls and was correlated with disease

severity (both motor and cognition) in the cross-sectional

design of comparison, the Cox progression analysis revealed

a modest significance of higher HRs for either motor or

cognition progression in the follow-up study. The possible

reason may come from the relatively short follow-up time

period for neurodegenerative disorders. A future cohort with a

larger sample size of subjects and longer follow-up is needed

to confirm these findings and to validate the role of plasma NfL

in predicting disease progression.

Magnetic Resonance Imaging-Guided Focused Ultrasound Neurosurgery

Xu and colleagues (2019) stated that magnetic resonance

imaging-guided focused ultrasound (MRgFUS) neurosurgery is

a new option for medication-resistant PD, but its safety and

efficacy remain elusive. These investigators examined the

safety and efficacy of MRgFUS for PD by systematically

reviewing related literature. PubMed and Embase were

searched to identify related studies. Inclusion criteria were

reported the efficacy or safety of MRgFUS for PD and

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published in English. Exclusion criteria were non-human

study, review or meta-analysis or other literature types without

original data, and conference abstract without full text. Data

on study characteristics, treatment parameters, efficacy, and

As were collected. Descriptive synthesis of data was

performed. A total of 11 studies containing 80 patients were

included; 9 studies were observational studies with no

controls; 2 studies included a randomized and controlled

phase. Most studies included tremor-dominant PD; 10 studies

reported decline of UPDRS-III scores after MRgFUS, and 5

reported a statistically significant decline; 9 studies evaluated

the quality of life (QOL). Significant improvement of QOL was

reported by 4 studies using the 39-item PD questionnaire; 4

studies examined the impact of MRgFUS on non-motor

symptoms. Most tests indicated that MRgFUS had no

significant effect on neuropsychological outcomes; most AEs

were mild and transient. The authors concluded that MRgFUS

is a potential treatment for PD with satisfying efficacy and

safety. Studies in this field are still limited. These researchers

stated that more studies with strict design, larger sample size,

and longer follow-up are needed to further examine its safety

and efficacy for PD.

Respiratory Muscle Training

In a systematic review, Rodríguez and colleagues (2019)

examined the effectiveness of respiratory muscle training in

persons with PD. PubMed/Medline, Embase, Web of Science,

Scopus and PEDro electronic databases were searched unt il

November 15, 2019. Reference lists of included studies were

hand-searched; RCTs assessing the effects of respiratory

muscle training programs (both inspiratory and expiratory) in

patients with PD were included. Two reviewers independently

identified eligible studies and extracted data; method quality

was appraised with the PEDro scale. A total of 5 papers

including 3 RCTs with a total of 111 patients were identified.

Method appraisal showed a mean score of 5 in the PEDro

scale. One study analyzed inspiratory muscle training, 1

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expiratory muscle training and 2 es tablished a comparison

between both of them. Statistically positive results were found

in maximal inspiratory pressure (p < 0.05 and d = 0.76),

maximal expiratory pressure (p < 0.01 and d = 1.40),

perception of dyspnea (p < 0.01), swallowing function (d = 0. 55)

and phonatory measures, without significant differences

in spirometric indices. The authors concluded that respiratory

muscle training may be an effective alternative f or improving

respiratory muscle strength, swallowing function and

phonatory parameters in subjects with PD. Moreover, these

researchers stated that the lack of primary studies regarding

this type of training prevents obtaining robust evidence.

Salivary Biomarkers of Parkinson's Disease

Bougea and colleagues (2019) noted that the search for a

reliable, early-disease biomarker for PD that reflects

underlying pathology is a high priority in PD research. Salivary

alpha-synuclein (α-Syn) is an easily accessible biomarker for

PD with promising results. These researchers examined the

performance of salivary α-Syn as a diagnostic biomarker of

PD. They identified 476 studies through a systematic literature

review according to PRISMA guidelines. A total of 8 studies

reporting data on salivary α-Syn were included in the review

(1,240 participants). The quality of studies was assessed by

Newcastle-Ottawa scale: 3 studies showed that the total α-Syn

levels were significantly lower in PD patients compared to

healthy controls, while in another 5 there was no significant

association. In some studies, total salivary α-Syn was

associated with demographic and clinical features; however,

no consistent pattern emerged. In 1 study, total α-Syn levels

were associated with poor cognitive performance i n PD

patients. Four studies showed a higher salivary oligomeric

α-Syn and oligomeric α-Syn/total α-Syn ratio in PD compared

to healthy controls, while in another 4 there was no

association. One study concluded that genetic polymorphisms

may influence total salivary α-Syn in PD patients. The authors

concluded that the potential of salivary total α-Syn as a PD

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biomarker is still uncertain,whereas salivary oligomeric α-Syn

appeared quite promising. Pre-analytical and analytical

factors of included studies were important limitations to justify

the introduction of salivary α-Syn into clinical practice.

Vivacqua and associates (2019) stated thatα-Syn aggregation

is the pathological hallmark of PD. These investigators

measured α-Syn total (α-Syntotal), oligomeric α-Syn

(α-Synolig) and α-Synolig/α-Syntotal ratio in the saliva of

patients affected by PD and in age and sex-matched healthy

subjects.They also compared salivary α-Sntotal measured in

PD with those detected in progressive supranuclear palsy

(PSP), in order to examine if salivary α-Syn could be used as a

biomarker for PD and for the differential diagnosis between PD

and PSP. These researchers studied 100 PD patients, 20

patients affected by PSP and 80 age- and sex-matched

healthy subjects; ELISA analysis was performed using 2

commercial ELISA platforms and a specific ELISA assay for

α-Syn aggregates.They detected lower α-Syntotal and higher α-

Synolig in PD than in healthy subjects. Conversely in PSP

salivary α-Syntotal concentration was comparable to that

measured in healthy subjects. Receiver operating

characteristic (ROC) analyses revealed specific cut-off values

able to differentiate PD patients from healthy subjects and

PSP patients with high sensitivity and specificity. However,

there was no significant correlation between clinical and

molecular data.The authors concluded that salivary α-Syn

detection could be a promising and easily accessible

biomarker for PD and for the differential diagnosis between PD

and PSP.

Figura and Friedman (2020) stated that the identification of

reliable biomarkers of PD is a pivotal step in the introduction of

causal therapies. Saliva is a biofluid that may be involved in

synuclein pathology in PD. These researchers have reviewed

current studies on salivary proteins and compounds in PD

patients and healthy controls, and their potential application as

biomarkers. They carried out a systematic literature search of

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the PubMed and Scopus databases. A total of 198 studies

were screened, of which 20 were included in this qualitative

analysis. The authors concluded that the oligomeric form of

salivary α-Syn was higher in PD patients, and that this may

serve as a potential biomarker of PD. Salivary DJ-1

concentrations failed to differentiate PD patients from controls.

Other enzymes and substances (heme oxygenase-1, nitric

oxide, acetylcholinesterase) have been assessed in single

studies. Salivary cortisol levels were higher in PD than in

healthy subjects. These researchers stated that saliva may be

a promising source of biomarkers in PD; moreover, further

validation of these findings is needed.

Serum FGF-21, GDF-15, and Blood mtDNA Copy Number as Biomarkers of Parkinson Disease

Davis and colleagues (2019) noted that strong evidence of

mitochondrial dysfunction exists for both familial and sporadic

PD. A simple test, reliably identifying mitochondrial

dysfunction, could be important for future stratified medicine

trials in PD. These researchers previously undertook a

comparison of serum biomarkers in classic mitochondrial

diseases and established that serum growth differentiation

factor 15 (GDF-15) out-performed fibroblast growth factor 21

(FGF-21) when distinguishing patients with mitochondrial

diseases from healthy controls. These investigators evaluated

serum FGF-21 and GDF-15, together with mitochondrial DNA

(mtDNA) copy number levels in peripheral blood cells from

patients with PD and healthy controls, to examine if these

measures could act as a biomarker of PD. A total of 121

patients with PD and 103 age-matched healthy controls were

recruited from a single center. Serum FGF-21 and GDF-15,

along with blood mtDNA copy number, were quantified using

established assays. There were no meaningful differences

identified for any of the measures when comparing patients

with PD with healthy controls. This highlighted a lack of

diagnostic sensitivity that is incompatible with these measures

being used as biomarkers for PD. The authors concluded that

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in this study, serum FGF-21, serum GDF-15, and blood

mtDNA levels were similar in patients with PD and healthy

controls and thus unlikely to be satisfactory indicators of

mitochondrial dysfunction in patients with PD.

CPT Codes / HCPCS Codes / ICD-10 Codes

Information in the [brackets] below has been added for clarification purposes. Codes requiring a 7th character are represented by "+":

Code Code Description

Diagnostic Tests:

CPT codes covered if selection criteria are met:

96132 -

96133

Neuropsychological testing evaluation s ervices

by physician or other qualified health care

professional, including integration of patient

data, interpretation of standardized test results

and clinical data, clinical decision m aking,

treatment planning and r eport, and interactive

feedback to the patient, family member(s) or

caregiver(s), when performed

96146 Psychological or neuropsychological test

administration, with single automated,

standardized instrument via electronic platform,

with automated result only

CPT codes not covered for indications listed in the CPB: Genetic testing of fibroblast growth factor 20

rs12720208 polymorphism, plasma neurofilament light

chain (NfL) as a biomarker , salivary biomarker s, serum

fibroblast growth factor 21 (FGF-21), serum growth

differentiat ion factor 15 (GDF-15) and blood

mitochondrial DNA (mtDNA) copy number levels as

biomarkers of PD - no specific code


Proprietary


70551 -

70553

Magnetic resonance (eg, proton) imaging, brain

(including brain stem) [for differentiating PD

from other parkinsonian syndromes]

78607 Brain imaging, tomographic (SPECT) [to

distinguish PD from other parkinsonian

syndromes]

80428 Growth hormone stimulation panel (e.g.,

arginine infusion, l-dopa administration)

81330 SMPD1 (sphingomyelin phosphodiesterase 1,

acid lysosomal)(eg, Niemann-Pick disease,

Type A) gene analysis, common variants (eg,

R496L, L302P, fsP330)

81401 Molecular pathology procedure level 2 [Not

covered for urinary LRRK2 phosphorylation for

parkinson’s disease risk]

82013 Acetylcholinesterase [salivary biomarker]

82172 Apolipoprotein, each [not covered for

apolipoprotein E (APOE)]

82530 Cortisol; free [salivary biomarker]

82533 total [salivary biomarker]

88184 Flow cytometry, cell surface, cytoplasmic, or

nuclear marker, technical component only; first

marker [measurement of telomere length]

88185 Flow cytometry, cell surface, cytoplasmic, or

nuclear marker, technical component only;

each additional marker (List separately in

addition to code for first marker) [measurement

of telomere length]


Proprietary


88341 -

88344

Immunohistochemistry or

immunocytochemistry, per specimen [ICSF

alpha-synuclein test as a biomarker for PD]

[cerebrospinal fluid ubiquitin c arboxy-terminal

hydrolase L1 (UCH-L1] ], [not covered for CSF

levels of heart fatty acid-binding protein,

neurofilament light chain, and tau

(phosphorylated or total) as biomarkers of PD]

Surgical Procedures:


61720 Creation of lesion by stereotactic method,

including burr hole(s) and localizing and

recording techniques, single or multiple stages;

globus pallidus or thalamus

61735 subcortical structure(s) other than global

pallidus of thalamus

61863 Twist drill, burr hole, craniotomy, or craniectomy

with stereotactic implantation of neurostimulator

electrode array in subcortical site (e.g.,

thalamus, globus pallidus, subthalamic nucleus,

periventricular, periaqueductal gray), without

use of intraoperative microelectrode recording;

first array

+ 61864 each additional array (List separately in

addition to primary procedure)

61867 Twist drill, burr hole, craniotomy, or craniectomy

with stereotactic implantation of neurostimulator

electrode array in subcortical site (e.g.,

thalamus, globus pallidus, subthalamic nucleus,

periventricular, periaqueductal gray), with use

of intraoperative microelectrode recording, first

array


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+ 61868 each additional array (List separately in

addition to primary procedure)

CPT codes not covered for indications listed in the CPB:

0398T Magnetic resonance image guided high

intensity focused ultrasound (MRgFUS),

stereotactic ablation lesion, intracranial for

movement disorder including stereotactic

navigation and frame placement when

performed

38232 Bone marrow harvesting for transplantation;

autologous

38240 Hematopoietic progenitor cell (HPC); allogeneic

transplantation per donor

38241 autologous transplantation

42400 Biopsy of salivary gland; needle

[submandibular]

61850 Twist drill or burr hole(s) for implantation of

neurostimulator electrodes, cortical

61860 Craniectomy or craniotomy for implantation of

neurostimulator electrodes, cerebral, cortical

64760 Transection or avulsion of; vagus nerve

(vagotomy), abdominal

90867 Therapeutic repetitive transcranial [direct

current] magnetic stimulation treatment;

planning [for the treatment of PD]

90868 Delivery and management, per session [for the

treatment of PD]

90869 subsequent delivery and management, per

session [for the treatment of PD]


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92270 Electro-oculography with interpretation and

report

93660 Evaluation of cardiovascular function w ith tilt

table evaluation, with continuous ECG

monitoring, with or without pharmacological

intervention [for differentiating P D from other

parkinsonian syndromes]

93890 Transcranial Doppler study of the intracranial

arteries; vasoreactivity study

95961 Functional cortical and subcortical mapping by

stimulation and/or recording of electrodes on

brain surface, or of depth electrodes, to

provoke seizures or identify vital brain

structures; initial hour of attendance by a

physician or other qualified hea lth care

professional

95962 each additional hour of attendance by a

physician or other qualified hea lth care

professional (List separately in addition t o code

for primary procedure)

99183 Physician attendance and supervision of

hyperbaric oxygen therapy, per session

HCPCS codes covered if selection criteris are met:

A9584 Iodine 1-123 ioflupane, diagnostic, per study

dose, up to 5 millicuries [to distinguish PD from

essential tremor]

J7340 Carbidopa 5 mg/levodopa 20 mg enteral

suspension

HCPCS codes not covered for indications listed in the CPB:


Cueing module device (auditory cue) - no specific code

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A4575 Topical hyperbaric oxygen chamber, disposable

C9734 Focused ultrasound ablation/therapeutic

intervention, other than uterine leiomyomata,

with magnetic resonance ( MR) guidance

E0446 Topical oxygen delivery system, not otherwise

specified, includes all supplies and accessories

G0277 Hyperbaric oxygen under pressure, full body

chamber, per 30 minute interval

G0461 Immunohistochemistry or

immunocytochemistry, per specimen; first

single or multiplex antibody stain

G0462 each additional single or multiplex antibody

stain (list separately in addition to code for

primary procedure)

S8042 Magnetic resonance imaging (MRI), low-field

[for differentiating PD from other parkinsonian

syndromes]

Other HCPCS codes related to the CPB:

J0364 Injection, apomorphine hydrochloride, 1 mg

J0735 Injection, clonidine HCl, 1 mg

J1265 Injection, dopamine HCl, 40 mg

ICD-10 codes covered if selection criteria are met:

F06.8 Other specified mental disorders due to known

physiological condition [development of

dementia in parkinsonism]

G20 Parkinson's disease

G21.0 -

G21.9

Secondary parkinsonism


Proprietary


G23.1 Progressive supranuclear ophthalmoplegia

[Steele-Richardson-Olszewski] [supranuclear

palsy associated with parkinsonism] [covered

for levodopa or apomorphine challenge,

olfactory testing by UPSIT or Sniffin' Sticks, and

neuropsychological testing]

G31.85 Corticobasal degeneration [covered f or

levodopa or apomorphine challenge, olfactory

testing by UPSIT or Sniffin' Sticks, and

neuropsychological testing]

ICD-10 codes not covered for indications listed in the CPB:

F02.80 -

F02.81

Dementia in other diseases classified

elsewhere [not covered for continued use of

levodopa-carbidopa intestinal gel]

F03.90 -

F03.91

Unspecified dementia [not covered for

continued use of levodopa-carbidopa intestinal

gel]

F06.0 -

F06.4

Other mental disorders due to known

physiological condition

G30.0 -

G30.9

Alzheimer's disease

R64 Cachexia

Z74.01 Bed confinement status

SPECT Scanni ng:


78607 Brain imaging, tomographic (SPECT) [to

distinguish PD from essential tremor]

HCPCS codes covered if selection criteria are met:


Proprietary


A9584 Iodine 1-123 ioflupane, diagnostic, per study

dose, up to 5 millicuries [to distinguish PD from

essential tremor]

ICD-10 codes covered if selection criteria are met:

G20


Parkinson's Disease

G21.11 -

G21.19

Other drug-induced secondary parkinsonism

G25.0

-G25.2

Essential, drug-induced and other specified

forms of tremor

ICD-10 codes not covered for indications listed in the CPB:

H35.89 Other specified retinal disorders brackets

thinning brackets [retinal thinning as a

biomarker of PD]

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AETNA BETTER HEALTH® OF PENNSYLVANIA

Amendment to Aetna Clinical Policy Bulletin Number: 0307 Parkinson's

Disease

For the Pennsylvania Medical Assistance Plan, effective 1/1/20 medication coverage requests for medications on the statewide preferred drug list will be reviewed using the guidelines for determination of medical necessity developed by the Pennsylvania Department of Human Services.

www.aetnabetterhealth.com/pennsylvania revised 06/04/2020

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