involvement of the peripheral nervous system in

REVIEW

Involvement of the peripheral nervous systemin synucleinopathies, tauopathies and otherneurodegenerative proteinopathies of the brain

Koichi Wakabayashi • Fumiaki Mori •

Kunikazu Tanji • Satoshi Orimo • Hitoshi Takahashi

Received: 25 March 2010 / Revised: 29 May 2010 / Accepted: 29 May 2010 / Published online: 9 June 2010

� Springer-Verlag 2010

Abstract Involvement of the peripheral nervous system

(PNS) is relatively common in some neurodegenerative

proteinopathies of the brain and may be pathogenetically

and diagnostically important. In Parkinson’s disease, neu-

ronal a-synuclein aggregates are distributed throughout the

nervous system, including the central nervous system

(CNS), sympathetic ganglia, enteric nervous system, car-

diac and pelvic plexuses, submandibular gland, adrenal

medulla and skin. The pathological process may target the

PNS and CNS at the same time. In multiple system atro-

phy, numerous glial cytoplasmic inclusions composed of

filamentous a-synuclein are widely distributed in the CNS,

while a-synuclein accumulation is minimal in the sympa-

thetic ganglia and is restricted to neurons. Neurofibrillary

tangles can occur in the sympathetic and spinal ganglia in

tauopathy, although they appear to develop independently

of cerebral Alzheimer’s disease pathology. In amyotrophic

lateral sclerosis, neuronal loss with TDP-43-positive neu-

ronal cytoplasmic inclusions in the spinal ganglia is more

frequent than previously thought. Peripheral ganglia and

visceral organs are also involved in polyglutamine dis-

eases. Further elucidation and characterization of PNS

lesions will have implications for intravital biopsy

diagnosis in neurodegenerative proteinopathy, particularly

in Parkinson’s disease.

Keywords a-Synuclein � Enteric nervous system �Lewy body � Parkinson’s disease � Tauopathy � TDP-43

Introduction

Common cellular and molecular mechanisms including

protein aggregation and inclusion body formation are

involved in many neurodegenerative diseases [82, 135].

a-Synuclein is a major component of Lewy bodies (LBs) in

Parkinson’s disease (PD) and dementia with LBs (DLB)

[176] as well as in neuronal and glial cytoplasmic inclu-

sions (GCIs) in multiple system atrophy (MSA) [170]. Tau

is a principal component of neurofibrillary and glial tangles

in tauopathies [77]. Expanded polyglutamine repeats are

found in intranuclear and cytoplasmic inclusions in

hereditary neurodegeneration, including Huntington’s

disease [178]. Recently, TDP-43 was identified as a com-

ponent of ubiquitinated inclusions in amyotrophic lateral

sclerosis (ALS) and frontotemporal lobar degeneration

[8, 106].

PD is traditionally considered as a movement disorder

with hallmark lesions in the brainstem pigmented nuclei

(substantia nigra and locus ceruleus). However, accumu-

lating evidence suggests that non-motor complications

(cognitive, psychiatric, autonomic, sleep and sensory

disorders) are also common in PD [86, 91]. Pathological

changes occur in widespread regions of the central and

peripheral nervous systems (PNS) in this disease [21, 40,

41]. Furthermore, primary glial involvement (‘‘gliodegen-

eration’’) can be observed in a-synucleinopathy [29, 177]

as well as in tauopathy [31, 58].

K. Wakabayashi (&) � F. Mori � K. Tanji

Department of Neuropathology, Institute of Brain Science,

Hirosaki University Graduate School of Medicine,

5 Zaifu-cho, Hirosaki 036-8562, Japan

e-mail: [email protected]

S. Orimo

Department of Neurology, Kanto Central Hospital,

Tokyo, Japan

H. Takahashi

Department of Pathology, Brain Research Institute,

University of Niigata, Niigata, Japan

123

Acta Neuropathol (2010) 120:1–12

DOI 10.1007/s00401-010-0706-x

Inclusion bodies are considered to be related to neuronal

degeneration, which does not imply that the inclusions are

always fatal to the neurons [10, 158]. Recent studies have

suggested that oligomers and protofibrils are cytotoxic, and

that inclusions may represent a cytoprotective mechanism

in neurodegenerative proteinopathy [43, 135, 160]. How-

ever, the number of LBs in patients with mild to moderate

loss of neurons in the substantia nigra is higher than in

those with severe neuronal depletion, thereby suggesting

that LB-containing neurons may be dying neurons [176].

The present article reviews neuropathological data

concerning the PNS involvement in neurodegenerative

disorders of the brain. Particular focus is given to abnormal

protein accumulation and inclusion body formation outside

the central nervous system (CNS).

Parkinson’s disease and dementia with Lewy bodies

The histological hallmark of PD and DLB is neuronal

a-synuclein aggregates called LBs and Lewy neurites. To

date, more than 70 molecules have been identified in LBs

[176], in which phosphorylated a-synuclein is a major

constituent [49]. It is now known that the substantia nigra is

not the only or the first brain region involved in PD [34].

Braak et al. [22] proposed a pathological staging scheme

for PD, in which early a-synuclein pathology is present in

the dorsal vagal nucleus and in the olfactory bulb. This

staging system characterizes a progression from the dorsal

vagal nucleus (stage 1), through the pontine tegmentum

(stage 2), into the midbrain and neostriatum (stage 3), and

then the basal prosencephalon and mesocortex (stage 4),

and finally through the neocortex (stages 5 and 6) [17, 22,

102]. Braak PD stages 1–3 correspond to incidental LB

disease, which is considered to represent presymptomatic

PD and/or DLB [1, 11, 35, 39, 134]. Saito et al. [136] also

proposed a pathological staging scheme for the progression

of LB disease (PD and DLB). Accumulation of a-synuclein

is also found both in astrocytes and oligodendrocytes in the

brain of patients with PD and DLB [25, 166].

LBs are widely distributed in the brain of patients with

PD [114] and DLB [80] mentioned above. a-Synuclein

abnormality is found in 10% of pigmented neurons in the

substantia nigra and more than 50% of those in the locus

ceruleus [101]. LBs are also found in the spinal cord,

including the intermediolateral nucleus, dorsal horn and

sacral autonomic nucleus [12, 14, 24, 76, 115, 125, 168].

Except for olfactory structures and spinal dorsal horn,

sensory components of the nervous system are relatively

spared. LBs are also found in the PNS even in the early

stage of PD (described below). The widespread distribution

of Lewy pathology may correspond to a variety of motor

and non-motor symptoms of PD [40, 91].

Sympathetic ganglia

LBs in the sympathetic ganglia were first observed by

Herzog [57]. In the ganglia, LBs occur mainly in the nerve

cell processes (Fig. 1a, b), and the majority of LB-con-

taining processes are unmyelinated axons [45, 171].

Although paravertebral and celiac sympathetic ganglia are

the predilection sites for LBs [37, 169], no LBs are found

in the dorsal root ganglia.

The degenerative process of the sympathetic ganglia has

been classified into three categories [117]. In the early

stage, a few LBs are observed in the ganglia but the

number of neurons and immunoreactivity for tyrosine

hydroxylase (TH), a rate-limiting enzyme of the catechol-

amine synthesizing pathway, is well preserved. In the

middle stage, many LBs are found in the ganglia but the

number of neurons appears to be normal on H&E stained

sections. Interestingly, a significant number of neuronal

somata (about 20–30% of neurons) is TH-immunonegative.

In the advanced stage, there is apparent neuronal loss in the

ganglia on H&E stained or TH immunostained sections.

The number of LBs is decreased compared with the middle

stage [117].

Parasympathetic nervous system

The largest source of preganglionic parasympathetic fibers

is the dorsal vagal nucleus, which supplies all the thoracic

and abdominal viscera except those in the pelvic region

[128]. In the cranial region, the postganglionic fibers derive

from ciliary, pterygopalatine, submandibular and otic

ganglia [128]. The occurrence of LBs has been reported in

the ciliary [7] and submandibular ganglia [153]. Recently,

Del Tredici et al. [33] have shown that Lewy pathology

occurs in the submandibular glands and in anatomically

related structures (superior cervical ganglia, cervical sym-

pathetic trunk and peripheral vagal nerve) in PD (9/9 cases)

and incidental LB disease (2/3 cases) but not in MSA or

controls. The presence of Lewy pathology in the autonomic

nerves and/or ganglia innervating the submandibular

glands might be related to the reduced salivary secretion

that accompanies PD [33].

Enteric nervous system

Gastrointestinal dysfunction is a common feature of PD

[1, 27, 97, 129], and constipation is frequent in DLB [59].

The occurrence of LBs in the enteric nervous system (ENS)

of PD patients was first reported by Qualman et al. [133]

who recognized the inclusions in the myenteric plexus of

the esophagus of 1 patient and the colon of another out of

22 patients with PD. They also found similar inclusions in

the esophagus in two out of eight patients with esophageal

2 Acta Neuropathol (2010) 120:1–12

123

achalasia. Kupsky et al. [85] reported the occurrence of

LBs in the myenteric and submucosal plexuses of the

surgically resected colon and biopsied rectum of a patient

with PD and megacolon. Wakabayashi et al. [175] dem-

onstrated that LBs were distributed widely in the myenteric

and submucosal plexuses from the upper esophagus to the

Fig. 1 Lewy pathology in the peripheral nervous system in Parkin-

son’s disease. a Intracytoplasmic (arrows) and intraneuritic Lewy

bodies (arrowheads) in the sympathetic ganglia. b a-Synuclein-

immunoreactive neuritic structures in the sympathetic ganglia.

c Lewy body in the submucosal plexus of the rectum (arrowhead).

d Lewy bodies in the myenteric plexus of the lower esophagus.

e, f Lewy bodies in the cardiac sympathetic nerves. g Lewy bodies in

the adrenal medulla (arrowheads). h a-Synuclein-immunoreactive

neuritic structures in the subcutaneous tissue (arrowheads). a, c, ghematoxylin–eosin, b, d, f, h a-synuclein immunostain, e tyrosine

hydroxylase immunostain. Bars 20 lm

Acta Neuropathol (2010) 120:1–12 3

123

rectum and were most frequent and numerous in the

myenteric plexus of the lower esophagus (Fig. 1c, d).

Recently, Beach et al. [12] have shown that there is a

rostrocaudal gradient of decreasing frequency and density

of phosphorylated a-synuclein histopathology in the gas-

trointestinal tract in LB disorders. The submandibular

gland and lower esophagus have the greatest involvement

and the colon and rectum the lowest.

A similarity has been noticed between the distribution of

LBs and that of monoaminergic neurons in the CNS [114].

In addition, intrinsic neurons immunoreactive for TH exist

in the human ENS [172]. Interestingly, these neurons are

most frequent and numerous in the myenteric plexus of the

lower esophagus, which is the site where most LBs occur in

PD [12, 175]. However, LB-containing TH-immunoreac-

tive neurons have been rarely encountered in PD. In the

gastrointestinal tract, most LBs were found in the vasoac-

tive intestinal polypeptide (VIP)-immunoreactive processes

[173]. The majority of VIP-immunoreactive processes in

the ENS are intrinsic in origin. In addition, VIP is a cho-

linergic co-transmitter in the intrinsic innervation of the

human gastrointestinal tract [6]. However, there was no

significant decrease in the number of cholinergic or VIP

neurons in PD [145] as well as in MPTP-treated mice and

monkeys [5, 28]. The number of TH-immunoreactive

neurons has been reported to be relatively preserved in PD

patients [145] and decreased in MPTP monkeys [28]. In

contrast, the number of dopaminergic neurons in the

colonic myenteric plexus was markedly reduced in patients

with advanced PD [145]. Loss of dopaminergic neurons

was also found in MPTP mice [5]. The discrepancy

between the frequency of LBs and the severity of VIP

neuron loss may imply that Lewy neurites cause dysfunc-

tional axonal transport but do not cause neuronal cell death.

In the CNS, early sites of Lewy pathology are the

olfactory bulb and dorsal vagal nucleus [22, 34, 141].

Several investigators proposed that a neurotropic pathogen

enters the brain via two routes (1) anterogradely, via

olfactory pathway; and (2) retrogradely, via gastric nerve

plexus and preganglionic nerve fibers of the dorsal vagal

nucleus [20, 23, 55, 88]. Abbott et al. [1] have shown that

constipation could be one of the earliest markers of the

beginning of PD processes. This is supported by the find-

ings that LBs can occur in the ENS in elderly individuals

without LBs in the CNS [175] and that a-synuclein

accumulation has been seen in the gastric plexus in Braak

PD stage 2 [20]. Interestingly, a-synuclein aggregates in

the ENS precede the CNS and cardiac autonomic abnor-

malities in transgenic mice containing PD-associated

a-synuclein gene mutations [84]. It is possible that the

pathological process of PD targets the ENS even before

lower brainstem nuclei become involved. Lebouvier et al.

[87] performed routine colonic biopsies in five PD patients

complaining of constipation and five age-matched control

patients, and immunohistochemical staining revealed

phosphorylated a-synuclein-immunoreactive neurites in

the submucosal plexus in four out of five PD patients.

Colonic biopsies may be useful to detect LB-type degen-

eration in PD.

Recently, several studies have shown that PD patients

who had long-term survival of transplanted fetal nigral

tissue (11–16 years) developed LBs in grafted neurons [79,

89]. This suggests that Lewy pathology could be induced in

cells by prion-like transmissible agents [2, 23, 116]. The

mucosa of foregut receives the efferent fibers from the

dorsal vagal nucleus. Moreover, a link between Helico-

bacter pylori infection and PD has been suggested [3, 42].

If the postulated pathogen could penetrate the gastric

mucosa, it ascends retrogradely in preganglionic para-

sympathetic fibers of the vagus nerve to the medulla

oblongata [20]. This possibility deserves further

investigation.

Heart

The sympathetic neurons in the cervical and upper thoracic

ganglia are the origin of the postganglionic fibers inner-

vating the heart, namely, the cardiac sympathetic nerves.

The heart also receives parasympathetic cholinergic fibers

from the dorsal vagal nucleus. The density of sympathetic

nerves is six times higher than that of cholinergic fibers in

the anterior wall of the left ventricle [73]. In PD, LBs are

found in the ganglia located in the interatrial groove (atrial

ganglia) and in the nerve fibers around the coronary arteries

and in the myocardium (Fig. 1e, f) [169]. LBs are also

found in the heart of patients with incidental LB disease

[62].

Reduced cardiac uptake of meta-iodobenzylguanidine

(MIBG), a physiological analog of noradrenaline, on [123I]

MIBG myocardial scintigraphy has been reported in

patients with LB disorders [118]. Decreased cardiac uptake

of MIBG in LB disease reflects loss of cardiac sympathetic

nerves in the ventricular wall [4], which precedes the neu-

ronal loss in the sympathetic ganglia [117]. The depletion

of sympathetic nerves involves not only the ventricles, but

also the atria and the conduction system [51]. Accumula-

tion of a-synuclein in the distal axons of the cardiac

sympathetic nervous system precedes that in neuronal

somata or neurites in the paravertebral sympathetic ganglia

and heralds centripetal degeneration of the cardiac sym-

pathetic nerves in PD [123]. Cardiac sympathetic

denervation begins in the early disease process of PD [51,

122]. Cardiac sympathetic denervation and a-synuclein

pathology increase with disease duration and severity [48].

Similar degeneration occurs in PARK4 (familial PD linked

to SNCA duplication) [51, 124], but not in PARK2 (familial


123

PD linked to parkin mutations without LBs) [119].

Reduced cardiac uptake of MIBG is a potential biomarker

for the presence of LBs [118]. Interestingly, reduced car-

diac uptake of MIBG is also reported in idiopathic REM

sleep behavior disorder [99]. However, it is uncertain

whether idiopathic REM sleep behavior disorder is a forme

fruste of LB disease or not.

Recently, Miki et al. [95] reported the presence of LBs

and Lewy neurites solely in the cardiac sympathetic nerves

and stellate ganglia of a non-parkinsonian young adult at

autopsy. This singular finding is not consistent with the

‘‘dual-hit’’ hypothesis mentioned above [55].

Pelvic organs

In the pelvic plexus, LBs are found in the ganglia near the

urinary bladder and accessory male genital organs [169] as

well as in the ovary [12]. Wakabayashi et al. [169] have

reported that LBs were found in the pelvic plexus in 11 out

of 30 patients with PD. Minguez-Castellanos et al. [98]

examined surgical specimens from 100 patients without

known neurodegenerative disorders, who ranged in age

from 44 to 84 years and reported that a-synuclein aggre-

gates were found in the abdominopelvic autonomic

plexuses in 9% of the whole sample but were more com-

mon in vesicoprostatic (26.1%) than in digestive tract

specimens (3.9%). Although the most widely accepted

mechanisms of urinary and sexual dysfunctions in PD are

thought to be related to nerve cell loss in the CNS [13, 94],

Lewy pathology in the pelvic plexus may also play a role in

these conditions.

Adrenal gland

LBs occur in the nerve plexuses around the adrenal gland

and in the ganglion cells in the adrenal medulla (Fig. 1g)

[169, 174]. These ganglion cells are observed singly or in

small groups and are sympathetic in nature. Fumimura et al.

[50] reported that the accumulation of a-synuclein was

found in the adrenal gland in 207 (26.4%) of 783 cases

ranging in age from 48 to 104 years, with 1 case solely in the

adrenal gland. LBs in the adrenal medulla are easily dif-

ferentiated from adrenal bodies [36] observed in the

noradrenaline-containing chromaffin cells because the latter

are positive for periodic acid-Schiff but immunonegative for

ubiquitin and a-synuclein [149]. Interestingly, the number

of adrenal bodies in LB disease is significantly higher than

that in controls, and correlated with disease duration [149].

Other visceral organs

Recently, Beach et al. [12] have shown that Lewy pathol-

ogy occurs in multiple visceral organs including the

respiratory tract (larynx and bronchus), endocrine system

(pancreas and parathyroid gland) and genitourinary tract in

Lewy body disorders.

Skin

Ikemura et al. [61] prospectively examined skin samples

from the abdominal wall and upper limb in 279 consecu-

tively autopsied patients ranging in age from 52 to

104 years (mean 80.8 years) and showed that a-synuclein

immunoreactivity was present in the dermis in 20 (23.5%)

of 85 patients with Lewy pathology in the CNS. The latter

authors also retrospectively examined the abdominal skin

in 142 patients with Lewy pathology in the CNS and

demonstrated that the sensitivity of Lewy pathology in the

skin was 70% in PD and 40% in DLB. Dabby et al. [30]

performed 4-mm punch biopsies from the lower limb in 22

patients with PD and 19 controls using anti-PGP 9.5 anti-

body as a panneuronal marker. They reported that

cutaneous autonomic innervation was decreased in PD

compared to controls and that the denervation scores were

significantly correlated with disease duration in PD.

Nolano et al. [113] also performed 3-mm punch skin

biopsies from the fingertip, thigh and distal leg in 18

patients with PD and 30 controls and demonstrated

significant loss of epidermal nerve fibers in PD patients.

Recently, Miki et al. [96] immunohistochemically exam-

ined cutaneous tissue obtained from 6-mm punch biopsies

in 20 clinically diagnosed PD patients using phosphory-

lated a-synuclein immunohistochemistry. Abnormal

a-synuclein accumulation was found in the dermis of the

thoracic wall but not in the lower limb in 2 (10%) of 20

patients with PD (Fig. 1h). This suggests that skin biopsy

may not be suitable for the diagnosis of PD.

Pure autonomic failure and Lewy body dysphagia

From clinical and neuropathological viewpoints, primary

autonomic failure is divided into three types: pure auto-

nomic failure (PAF) without other neurological conditions,

autonomic failure with PD and autonomic failure with

MSA. In PAF, the main pathological findings are neuronal

loss in the intermediolateral column of the spinal cord and

sympathetic ganglia and the occurrence of LBs in the

brainstem pigmented nuclei, sympathetic ganglia, myen-

teric plexus, epicardium, adrenal medulla and urinary

bladder [7, 52, 71, 162]. Pigmented neurons in the sub-

stantia nigra and locus ceruleus are well preserved in PAF.

Cardiac sympathetic denervation has been observed in PAF

[121]. Skin biopsy revealed a-synuclein accumulation in

the skin nerve fibers in a patient with PAF [144]. Kauf-

mann et al. [72] reported two cases present with PAF; one


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developed PD 20 years after onset of the disease and the

other developed DLB 4 years later. Similar cases have

been reported by several investigators [67, 182]. PAF is an

extreme variant of LB disorders, in which LB-type

degeneration may begin outside the CNS. Given the dis-

tribution and severity of Lewy pathology, PAF and a

significant proportion of PD may represent a ‘‘bottom-up’’

variant of LB disease, whereas cerebral type LB disease

[81] represents a ‘‘top-down’’ variant of LB disease.

The presence of LBs in autonomic structures could

explain isolated progressive dysphagia without extrapyra-

midal symptoms, i.e., LB dysphagia [66, 83]. Postmortem

examination has shown that neuronal loss with LBs was

chiefly restricted to the dorsal vagal nucleus in patients

with LB dysphagia [66, 83].

It is important to note that PAF and LB dysphagia are not

incompatible with early stages (or an early phase) of PD.

Multiple system atrophy

Multiple system atrophy is a sporadic adult-onset neuro-

degenerative disease, which is characterized by

striatonigral degeneration, olivopontocerebellar atrophy

and preganglionic autonomic lesions in any combination.

The histological hallmark is the presence of GCIs [105,

127] that contain many substances, including ubiquitin,

a-synuclein and p25a [170, 177]. The incidence of GCIs is

correlated with the severity of neuronal loss in the olivo-

pontocerebellar system as well as in the striatonigral

system [126]. Fibrillary inclusions are also found in the

neuronal somata, axons and nucleus [9, 107, 108, 164].

Severe atrophy of the frontal or temporal lobes has also

been reported in some cases of MSA [78, 131, 143]. The

primary motor cortex and spinal anterior horn are also

involved in MSA [148, 155, 161]. Thus, the neuropathol-

ogy of MSA is more extensive than previously thought.

The PNS is also affected in MSA. Filamentous aggre-

gates of a-synuclein are found in neurons in the

sympathetic ganglia [107]. Sone et al. [146] reported that

a-synuclein-immunoreactive neuronal inclusions were

found in the sympathetic ganglia in 11 out of 26 cases with

MSA and that the mean disease duration in cases with

a-synuclein inclusions was significantly longer than those

without. Although a-synuclein immunoreactivity is present

in the cytoplasm of Schwann cells [100], abnormal accu-

mulation of a-synuclein has not been reported in the PNS

glial cells. Sural nerve biopsy from patients with MSA

shows a reduction of unmyelinated fibers (sensory afferent

fibers and postganglionic sympathetic fibers) by 23% [68].

Mild degeneration of cardiac sympathetic nerves can occur

in MSA [120]. Thus, no portion of the nervous system

appears to be spared in MSA.

Tauopathy

Tauopathies comprise a group of neurodegenerative dis-

orders that share accumulation of phosphorylated tau in

selected vulnerable neurons and glial cells in the brain,

including Alzheimer’s disease (AD) [16, 19, 60, 104],

progressive supranuclear palsy (PSP) [64, 147], cortico-

basal degeneration (CBD) [38, 54], argyrophilic grain

disease [18, 44, 138] and Pick disease [77]. The spinal cord

is also involved in the disease process of AD [137], PSP

[63, 70, 75], CBD [65] and Guam parkinsonism-dementia

complex [93].

The occurrence of neurofibrillary tangles (NFTs) in the

PNS was first reported in the upper cervical ganglia in a

76-year-old man by Kawasaki et al. [74], who also dem-

onstrated that the NFTs are ultrastructurally composed of

paired helical filaments. To date, 10 autopsy cases with

NFTs in the paravertebral and prevertebral (celiac) sym-

pathetic ganglia have been reported [15, 74, 154, 163, 165].

All of these patients were over the age of 60 (age range

61–96 years; mean 78.8 years) and concomitant AD

lesions (many NFTs and senile plaques in the brain) were

found in only three cases. In addition, no NFTs were found

in the sympathetic ganglia of 27 patients with AD [140]

and in 20 patients with AD [165]. Shankle et al. [142]

examined the myenteric plexuses of 18 patients with AD

using an anti-tau antibody (Alz-50) and found no NFTs in

the plexuses. These findings suggest that NFTs in the

sympathetic ganglia develop independently of AD.

Nishimura et al. [112] reported that NFTs were found in

the spinal ganglia in two out of five patients with PSP. The

two patients’ ages were 76 and 71 years at death. Although

NFTs present in the CNS in PSP patients are ultrastructur-

ally composed of 15-nm-wide straight tubules [152, 157],

the NFTs observed in the spinal ganglia were composed of

paired helical filaments. However, immunohistochemical

study using antibodies against phosphorylation-dependent

and -independent tau has shown that no NFTs were detected

in the spinal ganglia of 8 patients with PSP and of 20

patients with AD [165]. The occurrence of NFTs in the

spinal ganglia may be unrelated to the occurrence of NFTs

in the CNS.

NFTs have not been reported in the visceral autonomic

nervous system in human subjects. Interestingly, however,

phosphorylated tau is deposited in the myenteric plexus in

aged Fischer 344 rats [130].

TDP-43 proteinopathy

TDP-43 is a major component of ubiquitinated inclusions

in ALS and frontotemporal lobar degeneration with or

without motor neuron disease [8, 106]. Thus, these


123

neurodegenerative disorders comprise a new disease con-

cept, namely that of ‘‘TDP-43 proteinopathy.’’ TDP-43

immunohistochemistry has revealed overt inclusions of

filamentous structures (skein-like inclusions) or compact,

round morphology (round inclusions) in motor and non-

motor neurons in TDP-43 proteinopathy [32, 103]. In

addition, TDP-43-positive inclusions occur both in oligo-

dendrocytes and astrocytes in a considerably wider area in

the CNS [109–111]. TDP-43 deposited in TDP-43 pro-

teinopathy lesions is phosphorylated [53].

Although an absence of sensory disturbances is a

negative neurological sign in sporadic ALS, occasional

reports describing sensory signs and symptoms have been

published [92, 156]. Brownell et al. [26] have reported

that posterior column lesions were observed in 5 out of 45

cases of sporadic ALS. In addition, rare instances of

sporadic ALS with severe involvement of the posterior

column and spinal sensory ganglia have been reported

[167]. However, some of these lesions have been con-

sidered an incidental complication due to spondylotic

myelopathy or circulatory disturbance. Recent studies

have revealed that abnormal accumulation of TDP-43

occurs in the dorsal root ganglia but not in the peripheral

sympathetic ganglia in patients with sporadic ALS [110].

Nishihira et al. [110] found mild neuronal loss in the

dorsal root ganglia in 10 out of 35 patients with sporadic

ALS, two of whom showed TDP-43-positive neuronal

cytoplasmic inclusions in the ganglia. TDP-43-immuno-

reactive LB-like inclusions have also been described in

the dorsal root ganglia in a patient with ALS after long-

term survival on a respirator [111]. Sensory involvement

may occur with greater frequency in sporadic ALS than

previously thought.

TDP-43 is a nuclear transcription factor and TDP-43

immunohistochemistry shows diffuse nuclear staining in

unaffected neurons. However, in neurons with well-formed

inclusions, such as skein-like and round inclusions, nuclear

TDP-43 immunoreactivity is absent. Recently, Suzuki et al.

[150] performed a quantitative immunohistochemical study

of TDP-43 in the skin from patients with ALS (n = 15) and

control subjects (n = 15). The proportion and optical den-

sity of TDP-43-positive nuclei in the epidermis were

significantly higher in ALS than in controls. In addition,

there was a significant positive relationship between the

nuclear staining and disease duration in ALS patients. TDP-

43 protein in the plasma [46, 47] and cerebrospinal fluid

[69] may be a potential biomarker of TDP-43 proteinopa-

thy, and skin biopsy may be useful for the diagnosis of ALS.

Bunina bodies are small round eosinophilic inclusions

observable in the lower motor neurons in ALS. They are

thought to originate from the endoplasmic reticulum [151,

159]. Piao et al. [132] have reported the presence of Bunina

bodies in 88 out of 102 patients with ALS (86.3%).

However, such inclusions have not hitherto been reported

in the PNS.

Polyglutamine disease

The expansion of a CAG repeat that codes for polyglutamine

is a common gene mutation in hereditary neurodegenerative

disorders [178]. Recent immunohistochemical studies of

human and animal models of polyglutamine diseases have

shown that neuronal and glial nuclear abnormalities extend

to multiple central and peripheral areas of the nervous sys-

tem, far beyond the affected regions that have been reported

in conventional pathological studies [56, 180]. Immuno-

histochemistry for expanded polyglutamine stretches have

demonstrated that neuronal intranuclear inclusions are

present in the dorsal root ganglia and paravertebral and

celiac sympathetic ganglia in spinocerebellar ataxia type 3

(Machado-Joseph disease) [179], but not in dentatorubral-

pallidoluysian atrophy [181] or spinal and bulbar muscular

atrophy [90]. Moreover, formation of polyglutamine inclu-

sions have been reported in non-CNS tissue in a mouse

model of Huntington’s disease [139] and patients with spinal

and bulbar muscular atrophy [90].

Conclusions

Neurodegenerative proteinopathies are multisystem disor-

ders including the PNS. Further elucidation and

characterization of the PNS lesions will provide implica-

tions for intravital biopsy diagnosis in neurodegenerative

proteinopathy, particularly in LB disease. Future studies

are necessary to identify novel biomarkers and proteins for

the diagnosis and for assessing disease progression of

neurodegenerative disorders.

Acknowledgments This work has been supported by Grants-in-Aid

20300123 (K.W.), 20591361 (F.M.) and 20590335 (K.T.) for Scien-

tific Research from the Ministry of Education, Culture, Sports,

Science, and Technology, Japan, a Grant for Hirosaki University

Institutional Research (K.W.), and a Grant-in-Aid for Studies on the

Development of Diagnostic Technique and Therapies for Lewy Body

Disease, the Ministry of Health, Labour and Welfare, Japan (K.W.).

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