1

SREE CHITRA TIRUNAL INSTITUTE FOR MEDICAL SCIENCES AND TECHNOLOGY

THIRUVANANTHAPURAM, KERALA

Demographic, clinical and syndromic characteristics of

Frontotemporal dementia: A descriptive study.

Thesis submitted in partial fulfilment of the rules and regulations for DM

Degree Examination of Sree Chitra Tirunal Institute for Medical Sciences

and Technology

By

Dr Himanshu Soni

DM Neurology Resident

Month and Year of Submission: October 2012

Department of Neurology

Sree Chitra Tirunal Institute for Medical Sciences and Technology

Thiruvananthapuram

2

2010-2012

DECLARATION

I, Dr. Himanshu Soni, hereby declare that the projects in this book were

undertaken by me under the supervision of the faculty, Department of

Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology.

Thiruvananthapuram Dr. Himanshu Soni

Date:

Forwarded

The candidate, Dr. Himanshu Soni, has carried out the minimum required

project.

Thiruvananthapuram Prof. Dr. Muralidharan Nair

Date: Professor & Head, Dept of Neurology

3

ACKNOWLEDGEMENT

I take this opportunity to express my sincere gratitude to Dr.P S Mathuranath,

Additional Professor of Neurology and Cognitive Sciences expert, SCTIMST, my guide for

the study, for his expert guidance, constant review, kind help and keen interest at each

and every step during the completion of the study

I am thankful to Dr.M.D.Nair, Professor and Head, Department of Neurology for his

guidance, encouragement and valuable suggestions during the period of the study.

I am extremely thankful to the CBNC team comprising of Neuropsychologists, Doctoral

students, and Medical social worker for their valuable input and assistance to the study.

I express my sincere thanks to Dr.Ravi Prasad Varma, Assistant Professor, Achutha

Menon Centre for Health Science Studies for helping me with the statistical analysis of

this study.

Last but not the least, I extend my gratitudes to all my patients and their primary

caregivers who participated in this study.

Dr Himanshu Soni

Senior Resident

Department of Neurology

SCTIMST, Trivandrum, Kerala

4

INDEX

i. Introduction 1

ii. Review of Literature 3

iii. Aims of the Study 14

iv. Materials and Methods 15

v. Results 20

vi. Discussion 36

vii. Conclusions 41

viii. References 45

ix. Annexure 52

5

INTRODUCTION

FTD encompasses a group of neurodegenerative diseases characterized by focal atrophy of

frontal and anterior temporal lobes and non-Alzheimer pathology. In people under 65 years of

age, FTD is as common as Alzheimer‟s disease (AD) and its prevalence has been estimated in

15 per 100,000 patients between 45 to 64 years of age (Ratnavalli et al, 2002)

Data on Frontotemporal dementia (FTD) from India is scarce in medical literature despite the

projected rise in dementia prevalence in the subcontinent. A Pubmed/Medline search on

publications on FTD revealed only few case reports and review articles.(Mohandas E et al,

2009)

There has been extensive research about the epidemiological features of Alzheimer disease,

which has helped direct therapeutic approaches. Until recently, frontotemporal lobar

degeneration (FTLD) was considered to be rare and difficult to diagnose, (Varma et al, 1999)

and relatively little is known about the demographic features. Recent studies (Ratnavalli et al,

2002) suggest that FTLD is the second most common diagnosis of dementia in individuals

younger than 65 years. Many factors have limited research into FTLD. In particular, the size

of FTLD cohorts at any one center is modest. In addition, until recently, low diagnostic

accuracy for FTLD and related disorders has diminished enthusiasm for epidemiological

research about this neurodegenerative disease. Finally, collaborative studies have not been

possible because definitions of FTLD have varied between sites, thereby limiting the ability

to combine cohorts. Only a few reports have explored the demographic features of FTLD. It

is well accepted that FTLD is a presenile dementia with a strong genetic component, (Chow

et al, 1999) but other risk factors for FTLD remain largely unexplored.

6

The recent establishment of consensus criteria for FTLD represents an opportunity to begin

large-scale studies about the demographic features of FTLD. These criteria divide FTLD into

3 major subgroups: frontotemporal dementia (FTD), semantic dementia, and progressive

nonfluent aphasia (PNFA). Thus, this study analyzes the demographic features of a small

group of patients diagnosed as having FTLD at a tertiary dementia referral clinic.

The FrSBe (Grace J et al, 2001) is a 46-item behavior rating scale that is intended to measure

behavior associated with damage to the frontal systems of the brain. The FrSBe has been

demonstrated to have good reliability and is sensitive to behaviour change in focal frontal

lesions when compared with patients with posterior lesions (Paulsen J et al 1996). The FrSBe

has also been shown to be sensitive to behavior changes in AD, Huntington‟s disease,

Parkinson‟s disease, vascular dementia, and mild cognitive impairment. We predicted that the

FrSBe would detect the behavior changes that typify FTD, particularly the apathetic and

disinhibited behaviors commonly displayed by patients with this disorder.

7

REVIEW OF LITERATURE

Historical perspective:

“Circumscribed atrophies” were first described by the Czech-German neurologist and

psychiatrist Arnold Pick, who in 1892 reported the case of a 71-year-oldman with behavioral

symptoms and a progressive aphasia associated with focal left temporal lobe atrophy (Pick,

1892). Pick reported several other cases of circumscribed atrophies presenting with combined

behavioral and language disturbances. In one initially unpublished case with a frontal

syndrome, Alois Alzheimer observed swollen neurons and the argyrophilic “kugel”, later

known as Pick‟s body. Onari and Spatz performed extensive pathological studies on Pick‟s

case examined by Alzheimer and on similar cases. Significantly, Onari and Spatz noted that

in many cases characteristic “Pick bodies”, were entirely absent, without altering the

remainder of the clinical or pathologic picture.

Another salient observation was that cases could be divided into those with primarily frontal

or primarily temporal atrophy. Tissot and Constantinidis confirmed these data and recognized

three types of so-called “Pick disease” (clinically defined): (A) with swollen neurons and

Pick bodies, (B) with only swollen neurons and (C) without swollen neurons or Pick bodies

(Constantinidis et al., 1974).

In 1982, Marsel Mesulam coined the term “primary progressive aphasia” to describe patients

with focal left hemisphere degeneration who presented with either non-fluent or fluent

aphasia, initially without additional cognitive deficits (Mesulam, 1982). In the late 1970s,

Arne Brun and Lars Gustafson in Sweden, and later David Neary and Julie Snowden in the

UK, described the clinical, neuroimaging and pathologic features of a dementia syndrome

8

characterized by focal frontal lobe degeneration, coined “frontal lobe dementia of the non-

Alzheimer‟s type” by the Swedish group (Brun, 1987), and “dementia of the frontal type”

by the British group (Neary et al., 1988). Snowden and John Hodges described the language

disturbance in patients with focal left anterior temporal atrophy, a syndrome they called

“semantic dementia” (Snowden et al., 1989).

Pathologically, these syndromes were all characterized by a typical gross and microscopic

appearance, the absence of Alzheimer‟s pathology, and the variable presence of Pick bodies.

In 1994 the Swedish and British groups published the first consensus clinical and

neuropathological criteria for “frontotemporal dementia” (Clinical and neuropathological

criteria for frontotemporal dementia; The Lund and Manchester Groups, 1994). The clinical

criteria were refined in 1998, using the term “frontotemporal lobar degeneration” (FTLD) to

encompass three distinct clinical syndromes: frontotemporal dementia (FTD), a primary

disturbance of behavior and comportment; progressive non-fluent aphasia (PNFA), a

disturbance of expressive language; and semantic dementia (semantic dementia), a syndrome

characterized by loss of meaning of verbal and non-verbal concepts (Neary et al., 1998).

Further insight into the biology of the disease was provided by Kirk Wilhelmsen and

colleagues, who discovered the link between familial frontotemporal dementia and a locus on

chromosome 17 containing the gene for the microtubule-associated protein The subsequent

unveiling of multiple tau mutations associated with various FTLD phenotypes (Foster et al.,

1997; Clark et al., 1998; Hutton et al., 1998) has strengthened the link between FTLD and

other “tauopathies”, such as corticobasal degeneration (CBD) and progressive supranuclear

palsy (PSP) (Kertesz et al., 1999). While a link between motor-neuron disease and FTLD had

long been suspected (Hudson et al., 1993), this association was found to be much more

common than previously thought (Lomen-Hoerth et al., 2002), and to be associated with a

distinctive pathologic and genetic (Hosler et al., 2000) profile.

9

Clinical features of FTD:

Patients with FTD display a heterogeneous clinical picture, which may include behavioral,

cognitive, and motor manifestations.(Joseph KA et al, 2008) However, based on the

predominant initial symptoms, FTD can be readily separated into two groups: the behavioral

variant (bv -FTD), which is characterized by loss of insight, personality changes, and

disturbances in social cognition(Neary et al,1998) and the language variant, also referred as

primary progressive aphasia (PPA).(Mesulam 1982) The latter can be further divided into a

well-defined clinical-pathological entity, semantic dementia (SD),(Hodges JR, 2007) and

progressive nonfluent aphasia (PNFA).

Despite this classification, there is a clinical, pathological, and genetic overlap. For instance,

SD cases may develop features of bv-FTD,(Rosen HJ et al,2006) and patients with the

clinical variant often have common areas of brain atrophy and family history of another

variant. Moreover, there is increasing evidence of overlap between FTD and other

neurodegenerative disease, notably Motor Neuron disease (MND),(Bak TJ et al, 2001)

Progressive Supranuclear Palsy (PSP), and Corticobasal degeneration (CBD).(Beove BF et al

2003), For example, cases initially diagnosed as PNFA may end up showing a clinical

picture and pathology of CBD.[Kertesz et al,2003) Indeed, some argue that those entities

should all be included under the rubric of Pick‟s complex.

10

Differentiating one variant of FTD from another, as well as from other neurodegenerative and

nondegenerative diseases (particularly psychiatric conditions) remains challenging.(Rosness

TA et al, 2008) Fortunately, recent advances in molecular pathology and genetics, improved

imaging techniques, and better clinical descriptions have contributed enormously to our

understanding of these conditions and are offering new insights, which we hope will be

helpful for improved diagnosis and management of patients with these devastating disorders.

Clinical Features

Behavioral variant (bvFTD): The clinical hallmark of bvFTD is a disturbance in the

personality and behavior, with changes of mood, motivation, and inhibition, leading to

profound social disruption.(Boxer AL et al, 2005) As the initial symptoms are

neuropsychiatric, without impairment on cognitive screening tests, or overt changes on

11

structural imaging, these patients may be inappropriately diagnosed as suffering from a

psychiatric disease, usually, depression or personality disorder.(Rosness TA et al, 2008)

These changes become gradually evident to relatives, colleagues, and friends, because of

disruption in their work performance, social, and family relationships. The effect on care is

vivid with a high level of burden and stress.(Mioshi E et al,2007) Patients may perform

normally on standard neuropsychological tests of memory, language, attention, and visual

spatial ability, but more recent tests designed to assess emotion processing, social cognition,

theory of mind,(Gregory C, 2002) and complex decision making are more sensitive and may

show deficits in early cases, even if standard cognitive battery are normal.(Wittenberg et al

,2008)

In order to simplify the clinical picture, this myriad of neuropsychiatric manifestations may

be classified in three main groups

Positive symptoms: These include disinhibition with lack of concern about social norms or

embarrassment, impulsivity, outburst of violence, stereotypic and ritualistic behavior,

abnormal appetite for sweets or gluttony, and impaired emotional judgment. When they are

present, they strongly suggest the diagnosis of FTD.(Rascovsky K et al; 2007, Wittenberg et

al ,2008)

Negative symptoms: These include apathy and inertia, emotional blunting, impaired insight,

lack of interest in usual or leisure activities, decline in the amount of speech (adynamism or

laconic speech), and reduce self-care for complex instrumental activities.( Isabelle Le Ber et

al; 2006) These symptoms are less specific to FTD and also occur in depression.

Cognitive symptoms: These often appear later and include mental rigidity; loss of flexibility

and abstraction; impairment in the pragmatic level of the discourse, with disorganization and

distractibility; and poor planning and organization. At this stage, most patients fail in

executive tasks and may show frontal release sign, such as grasping.(Libon DJ et al; 2007)

12

This cluster of symptoms (positive, negative, and dysexecutive) have putative anatomical

correlate to the orbitofrontal, medial, and dorsolateral frontal cortices,

respectively.(Cummings JL;1995), Moreover, the progression of the atrophy, and

consequently the clinical manifestations, may follow a predictable fashion, beginning in

orbitofrontal and medial aspects of frontal cortex, and then involving the dorsolateral cortex

and temporal anterior structures and basal ganglia.(Kril JJ et al;2004, Perry RJ et al;2006] It

has become increasingly apparent that some patients presenting with symptoms suggestive of

bvFTD fall to progress even over many years.(Davies RR et al;2006) These “phenocopy”

cases may actually constitute an unusual presentation of other conditions, such as late onset

of bipolar disorder, personality disorder, or Asperger spectrum disorder. A number of

features set apart these nonprogressive patients; normal performance on test of executive

function and of emotion processing; better activities of daily living; and absence of brain

atrophy. The underlying pathophysiology in this group is unclear, but we assume that it

reflects function disruption of orbitomesial frontal regions in the absence of neurodegeneration

and importantly a lack of atrophy on MRI and hypometabolism on FDC-PET.

Semantic dementia

Patients typically present with “loss of memory for words” and show impairment on tests of

word comprehension, although the underlying deficit is the amodal store of semantic memory

or knowledge about words, objects, people, and sounds.(Hodges JR; 2007) Patients show a

gradual reduction of vocabulary and use high frequency terms (thing, boy), although speech

is fluent and well-articulated, without phonological or syntactic errors.(Knibb JA et al;2005)

A consistent feature is the impairment of naming objects or anomia. The performance is

influenced by the level of familiarity and specificity of items asked. In other words, if the

item is extensively encountered by the patient, it is likely to be forgotten later. Likewise, the

patient will tend to name objects that are prototypic of their category. For instance, patients

13

are able to name cat, dog, and horse, but not tiger or zebra, and use superordinate or general

labels, calling the latter also a cat and horse, and may be just animal. Impairment of single

word comprehension can be assessed by asking the patient to match the word with the

corresponding object or to define the meaning of words.(Knibb JA et al, 2005)] There is a

striking dissociation between repetition (preserved) and meaning (loss), best demonstrated by

asking patients to repeat words such as “hippopotamus” or “catastrophe” and then to say what

they mean. These patients also show surface dyslexia where all words are read according to

general rules of pronunciation, regardless of word meaning. In spite of the fact that word-

based tests show clear deficits, actually there is a deterioration of central, amodal knowledge

about objects or people which is apparent when nonverbal tests, such as “Pyramid and Palms

test ” are employed, which requires subjects to match the two pictures that go together. Some

SD patients present prominent deficits in identification of famous people. This deficit

represents a general impairment on the “knowledge of people” than merely prosopagnosia

(i.e., loss of ability to recognize faces), since patients are unable to produce any information

from their name or voice. Such patients typically show predominant right temporal atrophy

together with behavioral symptoms and poor insight.(Chan D et al; 2009)

Progressive Nonfluent Aphasia

Unlike SD, the presenting features of PNFA are more varied and may reflect breakdown at

various stages of speech production, from alterations in lexical retrieval, misarrangements of

the words according to grammatical rules, or impaired motor programming of the intended

utterance.(Ash S et al;2009) Generally speaking, there are problems with the syntactic or

motor aspects of speech, causing speech to be halting, slow, and distorted. Severe

agrammatism causes oversimplification of the language production, lack of function words

(e.g., prepositions, auxiliary verbs, or articles), or words inflections (i.e., endings of verb or

noun according to conjugation or number, respectively).(Hodges JR et al;1996). But in the

14

early stages, grammatical errors are subtle and may be difficult to distinguish from common

errors or detect in a short interview. Syntactic problems are usually best assessed by testing

sentence comprehension. Breakdown in the motor programming is referred to as apraxia of

speech, which causes distortion of output with pauses, speech errors, and loss of melody.

Patients may have difficulty in repeating or pronouncing polysyllabic words and strings of

syllables (such as Pa- Ta-Ka), producing distortions and aprosodic intonation. Orobuccal

apraxia may develop and some patients evolve into a picture of CBD or PSP.

A third language variant: Logopenic/phonological

Gorno-Tempini et al. described cases of language variant that fulfilled neither SD nor PFNA

criteria.(Gorno-Tempini ML, et al; 2004) These cases showed reduced speech output with

frequent pauses and impaired naming; preservation of grammar, motor speech, and semantic

knowledge. A remarkable feature was profound impairment on repetition of sentences or

string of words and difficulties in understanding complex instructions, despite of sparing

single word repetition and comprehension. This has been attributed to a reduction of working

memory resources, due to impairment of phonological loop. Interesting enough, this group

showed a distinctive pattern of brain atrophy that involved the left temporoparietal junction.

There is growing evidence that the underlying pathology is Alzheimer‟s disease, suggesting

that this variant is in fact, an atypical presentation of AD.( Rabinovici GD et al; 2008)

Imaging

The advent of high resolution MRI and of methods of automated qualification such as Voxel-

based morphometry (VBM) and cortical thickness measures has enhanced our knowledge of

the anatomical changes in the variants of FTD. Patients with bv-FTD show atrophy of the

orbitobasal and medialfrontal lobes, together with anterior temporal and insular

involvement.(Rosen HJ, et al;2002). SD is associated with atrophy of the anterior temporal

lobe involving particularly polar, anterior parahippocampal, and fusiform regions including

15

the perirhinal cortex. The atrophy is bilateral, but typically asymmetric and often more severe

on the left. In PNFA, the changes are subtler and involve the left inferior frontal lobe and

anterior insula cortex. In logopenic/phonological variant the atrophy involves the left

hemisphere, particularly the posterior temporal lobe (superior and middle temporal gyri) and

inferior parietal lobe and lesser involvement of the precuneus. These changes can also be

detected using simpler MRI-based visual rating scales, which simply use standard coronal

cuts. These scales aid diagnosis and monitoring of progression.

Pathology

Definitive diagnosis of FTD requires neuropathological examination. Unlike other dementia

syndromes, notably AD, FTD encompasses considerable pathological heterogeneity.(Cairns

NJ et al; 2007) The classification is based on the identification of intracellular protein

inclusions by means of inmunohistochemistry. Accordingly, three broad subdivisions have

been recognized:

FTD with tau-positive inclusions: This includes classic Pick‟s disease, Progressive

Supranuclear Palsy, Corticobasal degeneration, argyrophilic grain disease, and patients with

mutation of the Microtubuleassociated protein tau (MAPT) gene on chromosome 17 (FTDP-

17).

FTD with tau-negative, ubiquitin-positive inclusions: This is the commonest pathological

finding in FTD and includes these with progranulin gene mutations. The ubiquitinated protein

has been identified as the transactive response DNA-binding protein with Mr 43 (TDP-43)

which is also found in MND, (Roeber S et al; 2008) strengthening the association between

FTD and MND. Interestingly, cases with ubiquitinated lesions without TDP-43 have been

recently identified, which appear to have abnormal deposits of another protein called fused in

sarcoma protein (FUS).

16

Dementia lacking distinctive histology. Includes cases that do not show any particular or

distinctive inclusion or histology, besides neuronal loss, superficial spongiosis, and gliosis.

With the advent of newer inmunohistochemical techniques such cases are now increasingly

rare. The correspondence between clinical phenotype and underlying pathological subtype

has been a topic of considerable interest in recent years. SD has been consistently associated

with Ubiquitin (TDP-43) positive pathology. In contrast, PNFA cases show variable results in

different clinicopathology series, due probably to different diagnostic criteria employed as

well as inclusion of logopenic cases in older series. Despite that, PNFA more often associated

to tau pathology, particularly if there is motor speech disorder. In bv-FTD approximately a

half has tau-positive and the other TDP-43-positive pathology.

Genetic

Around 40% of patients report a family history of dementia, although in many instances this

is almost certainly unrelated, but 10–20% have a clear pattern of autosomal dominant

inheritance, with at least two relatives having young onset dementia or MND.(Seelaar H, et

al. 2008) The heritability, however, varies according to the variant FTD: SD showing the

least, whereas bv-FTD and FTD with MND the most inheritable. The commonest identified

mutations are MAPT and progranuline (PGRN), both in chromosome 17q21. (Baker M, et al;

2006) Although the prevalence of mutations varies among studies, the two mutations have a

similar frequency, being found in around 5–10% of patients. Other mutations involve the

Valosincontaining protein (VCP) and CHMP2B genes, but are very rare. The mutations of

MAPT lead to abnormal intracellular accumulation of hyperphosphorylated tau. While

mutation of PGRN gene results in reduced expression of progranulin and is associated with

Ubiquitin-TDP-43 pathology. MAPT mutations typically give rise to the clinical phenotype

called Frontotemporal dementia and parkinsonism linked to Chromosome 17 (FTDP-17). As

its name suggests, the clinical picture embraces isolated behavioral and personality changes,

17

initial extrapyramidal signs, suggesting of PSP or CBD, or a combination of behavioral and

extrapyramidal syndromes. In contrast, PGRN mutations appear to produce striking clinical

heterogeneity which includes CBD, PNFA, or bv-FTD. Moreover, some cases depict an

anmestic syndrome compatible with initial AD and a logopenic aphasia.

18

AIMS OF THE STUDY

1. To study and compare demographic, neurological characteristics of patients in the 3

FTD syndromes i.e. behavioural FTD, PNFA and Semantic Dementia

2. To objectively study and compare various behavioural characteristics and its

progression in FTD patients using a five point Likert rating scale (FrSBe).

19

MATERIALS AND METHODS

Study Setting and Patient selection

This study is a ambidirectional cohort study which was carried out at SCTIMST, Trivandrum,

Kerala, India. Study cases were selected from the patients visiting the Cognition and

Behavioral Neurology Center (CBNC), Department of Neurology which is a tertiary referral

speciality clinic running once a week for neurocognitive problems and it caters to patients

with amnesia, mild cognitive impairment, dementia, aphasia, neuropsychiatry syndromes and

related conditions. The study had the approval of the Institutional Ethics Committee.

We selected consecutive patients who met the criteria of Neary et al for FTD. Data was

collected from patients which were assessed between January 1, 2005, and August, 2012.

Data of patients from 2005 to 2009 was collected retrospectively from our medical records

department and the Neuropsychology testing unit. Whenever possible, their follow up data

was screened and if required next of kin/ primary caregiver were contacted on phone or mail

to know the current status of the individual. Data was collected prospectively 2010 onwards.

Diagnosis and Diagnostic criteria

The diagnosis was based on historical information, neurological examination, and

neuropsychological assessment and supported by findings on magnetic resonance imaging.

Patients in whom the clinical diagnosis was equivocal were excluded from the study. The

inclusion criteria for this study were based on the „Neary‟ criteria (Neary et al., 1998), The

criteria focussed on a predominance of a frontal or temporal lobe cognitive/behavioural

syndrome and the absence or insignificance of an anterograde amnesia and visuospatial

impairment in the initial clinical presentations (i.e. within the first 2 years of symptoms). In

20

addition, all patients were required to have imaging studies demonstrating focal cerebral

atrophy of at least one of the following: the anterior temporal lobes, frontal lobes and insula

or caudate nuclei. The criteria have been previously reported (Knopman et al., 2007).

Patients were separated on clinical grounds into those showing a predominantly behavioural

presentation (bvFTD) and those presenting with language impairment (PNFA, Semantic

dementia). The bvFTD group was further classified into those with disinhibited, distractible

picture (DbvFTD) and those showing an apathetic, inert pattern (AbvFTD).

Neuropsychological testing: The clinical diagnosis was based on the neurologic and

physical examination results, medical history, informant interview, a neuropsychological

evaluation, laboratory screening, and brain imaging. The Mini-Mental State Examination

(MMSE) was administered to all patients. The neuropsychological tests administered were a

1-hour neuropsychological battery that measures memory, language, executive function,

visuospatial skills, and praxis.

Age at onset was queried as part of the clinical interview, and is defined as the age at which

the first change in cognition or behavior is noted by the caregiver or the patient. Education

was coded as the number of years of formal education. The diagnosis was determined by

consensus, including the neurologist and/or psychiatrist and neuropsychologist.

The exclusion criteria (Knopman et al., 2007) were common to all three syndromes and

included the following:

(i) The syndrome is due to cerebrovascular disease.

(ii) The syndrome is due to traumatic brain injury.

(iii) By clinical history or neuropsychological testing, anterograde amnesia is a principal

symptom or sign.

21

(iv) By clinical history or neuropsychological testing, visuospatial deficits are principal

symptoms/signs.

(v) Rapid eye movement sleep behaviour disorder is present.

(vi) Imaging findings are diagnostic of another neurological disease, including the presence

of lacunar infarction.

(vii) Prior history dating from early adulthood of schizophrenia, bipolar disease, mental

retardation and severe personality disorder.

(viii) The clear, unequivocal presence of another neurological disease such as Parkinson‟s

disease, Huntington‟s disease, progressive supranuclear palsy, multiple sclerosis; an inherited

disorders such as metachromatic leukodystrophy, or any other defined neurological disorder

other than an FTD.

Frontal Systems Behavior Scale (FrSBe): The FrSBe (Grace J et al, 2001) is a 46-item

behavior rating scale of the Likert type that is intended to measure behavior associated with

damage to the frontal systems of the brain. 12 items/questions pertain to apathy, 15 items

assess disinhibition and 19 items deal with executive dysfunction. Minimun score is 46 and

maximum is 230 which is later converted to a T score based on normative data for age,

gender. According to the manual, the FrSBe was designed (a) to be brief, reliable, and valid;

(b) to assess adult behavior before (ie, premorbid baseline) and after frontal systems damage

occurs; and (c) to permit multiple observers to provide behavior ratings. It consists of two

rating forms: a self-rating form to be completed by the patient and a family rating form to be

completed by an informant who has regular contact with the patient, such as spouse, child,

relative, or significant other. Professionals (eg, rehabilitation staff) seeking to track patient

behavior over time also can use the family form to rate a patient‟s current behavior. Each

FrSBe form yields a Total score and scores for subscales measuring Apathy, Disinhibition,

and Executive Dysfunction. Scores are obtained on each scale for baseline behavior and

22

current behavior. Thus, behavior change can be indexed by comparing T scores based on

normative data of the ratings of prior and current patient behavior.

Reliability: High internal consistency has been demonstrated in multiple studies. The FrSBe

manual(Grace J et al, 2001) reports a coefficients of 0.92, 0.78, 0.80, and 0.87 for the Total,

Apathy, Disinhibition, and Executive scales of the family form and 0.88, 0.72, 0.75, and 0.79

for the self-form in a normative sample.

23

Biostatistics

-Data was summarized as mean, median or percentages with range or standard deviation for

dispersion. Fisher‟ exact test was performed to compare groups of small size.

-From the FrSBe main and subscores, composite Z scores were calculated and using the Z

score, T score for the main and subscores was calculated using the following formula:

T score = 10 x(Z score) + 50.

-T scores were used for further analysis for comparing between diagnostic subgroups which

was done using one way ANOVA (Analysis of Variance). A p value of < 0.05 was taken as

significant. Post hoc analysis of the subgroups was carried out using the Scheffe test.

-SPSS (15.0 for PC) was used to analyze the correlation between FrSBe subscales and

demographical and behavioral variables included in the model and to carry out statistical

comparisons between diagnostic subgroups.

24

RESULTS

Out of the 65 patients initially suspected to have FTD in the CBNC Clinic, 22 (33.8%) cases

were excluded, as on further evaluation in the form of Neuroimaging, Neuropsychological

testing, treatment response, these 22 cases had an alternate diagnosis as mentioned in Fig 1.

65 patients suspected to have FTD on

screening

43 cases included in study

35 Behavior variant

8 Language variant

22 cases excluded:

8 mixed, 4 Alzheimer's,

3 Pseudodementia, 2 MND

1 each of meningioma, Acom

artery aneurysm, NPH, CJD

Craniopharyngioma, PSP,

Amnestic MCI

Data of 20 cases collected retrospectively and 23 cases prospectively

Figure 1: Flow chart showing initial data collection and excluded cases. MND- Motor Neuron Disease, NPH- Normal Pressure Hydrocephalus, CJD- Creudzfeldt Jacob

Disease, PSP- Progressive Supranuclear Palsy, MCI- Minimal Cognitive Impairment

25

Out of the 43 cases included in the study, 35 (81%) were of the behavioural variant of FTD

(bvFTD). Of the 8 patients which were labelled as language variant of FTD, 6 patients had

PNFA and 2 had Semantic Dementia. Figure 2 depicts the patient classification.

35 (81%)

6 (14%)

2 (9%)

Number of patients(%)

bvFTD

PNFA

SD

Total FTD Patients= 43

Figure 2 : bvFTD- Behavioral variant, PNFA- Progressive Non Fluent Aphasia, SD- Semantic Dementia

26

Figure 3: AbvFTD- Apathetic variant, DbvFTD- Disinhibited variant

The behavioral variant cases of FTD were further divided into 3 clinical profiles i.e Apathetic

(AbvFTD), Disinhibited (DbvFTD) and mixed (mixed bvFTD). Out of 35 bvFTD cases, 13

(37%) were AbvFTD, 14 (40%) were DbvFTD and 8 cases (23 %) were of mixed bvFTD

type. Figure 3 above shows the subtype distribution of the bvFTD cases.

1314

8

0

2

4

6

8

10

12

14

16

AbvFTD DbvFTD Mixed bvFTD

bvFTD subtypes

No. of patients

27

Figure 4 : Number of FTD cases diagnosed per year along with total no. of new

dementia/MCI patients seen in the CBNC Clinic. The Annualized hospital incidence rate

was 4.83 new cases/year

Table 1: Annualized hospital incidence rate = 4.83 per 100

As mentioned previously, the cases included in the study were taken over a time period from

2005 to 2012. An average of 111 new patients attended the CBNC Clinic per year from 2005

to 2012 apart from the follow up cases and the number of FTD cases diagnosed per year

ranged from 3 to 10 cases per annum. The annualized hospital incidence rate was 4.83 per

100 dementia/MCI cases i.e approximately 5 cases of FTD were diagnosed per year which is

shown in Figure 4 and Table 1

9098

115110

99

125130

126

6 5 4 4 4 3 7 100

20

40

60

80

100

120

140

2005 2006 2007 2008 2009 2010 2011 2012

No

. of

pat

ien

ts

Year

new dementia/MCI

FTD

2005 2006 2007 2008 2009 2010 2011 2012

Total New patients 90 98 115 110 99 125 130 126

FTD patients 6 5 4 4 4 3 7 10

Hospital incidence

rate 6.67 5.10 3.48 3.64 4.04 2.40 5.38 7.94

28

Gender:

Of the 43 cases, 28 (65%) were male and 15 (35%) were female. Similar distribution of

gender was seen in the bvFTD and PNFA subtype. There was one each patient in the

semantic dementia subtype. (Table 2)

Diagnosis No. of cases Male (%) Female (%)

bvFTD 35 23 (65%) 12 (35%)

PNFA 6 4 (66%) 2 (34%)

Semantic dementia 2 1 (50 %) 1 (50%)

Total 43 28 (65%) 15 (35%)

Table 2: Gender distribution of the study population.

Age at Onset:

Age of onset ranged from 29 to 79 years. The youngest case was of a 29 yr old male

diagnosed with apathetic variant of FTD who had initial presentation as impairment of

attention without any family history and neuroimaging (MRI Brain) showed characteristic

bifrontal and temporal atrophy. In this study 11 of 43 (25%) had onset of disease symptoms

beyond 65 yrs age. Among the variants of FTD, the behavioral variant showed a similar

proportion of early vs late onset {77 % (27 of 35) patients had early onset, 23 % ( 8 of 35)

had late onset dementia}.

Figure 5 shows the proportion of early Vs late onset FTD in the total study population as

well as in the behavioral and the language variant.

29

Figure 5: 25 % (11 out of 43) of total cases had onset of illness at > 65 yrs age.

FTD type

N Mean Std. Deviation Minimum Maximum

ANOVA p

value

bvFTD 35 55.94 10.541 29 79

0.334 PNFA 6 57.33 12.291 41 76

SD 2 67.50 .707 67 68

Total 43 56.67 10.679 29 79

Table 3: Analysis of each FTD subtype on the basis of age of onset

Table 3 shows the age of onset data of the study population, the mean age of onset for the

entire study population was 56.67 years with a standard deviation of 10.5 years. Mean age of

onset for bvFTD, PNFA & SD was 55.94, 57.33 and 67.5 respectively. On applying one way

32

27

5

0

11

8

1 2

0

5

10

15

20

25

30

35

total bvFTD PNFA SD

Presenile Vs Senile onset

< 65 yrs

> 65 yrs

30

ANOVA, there was no statistical significance between the age of onset of the three main

types of FTD although mean age of onset of Semantic dementia was later as compared to that

of bvFTD. Even on subgroup analysis among patients of bvFTD (apathetic vs disinhibited vs

mixed bvFTD) statistical significance was not reached (Table 4)

FTD Subtype N Mean

Std. Deviation

(Std D) Minimum Maximum

ANOVA p

value

A-bvFTD 13 53.23 11.973 29 75 0.476

D-bvFTD 13 56.77 9.139 47 69

Mixed 9 58.67 10.512 50 79

Total 35 55.94 10.541 29 79

Table 4: Subgroup analysis of bvFTD patients according to age of onset

Onset to Diagnosis:

The range of duration of onset of symptoms to diagnosis of the syndrome was 1 to 7 years

with mean time interval from onset of symptoms to diagnosis was 3.14 years (Std D of 1.65).

Among the broad type ( bvFTD, PNFA, SD), largest time interval was for the SD group pf

patients i.e 4 years. Among the bvFTD subtype, mean interval to diagnosis ranged from 2.62

yrs (for DbvFTD) and 3.67 yrs (for mixed bvFTD). There was no statistically significant

difference in the time interval to diagnosis either between the broad syndrome or the subtypes

of bvFTD. Table 5 & 6.

31

FTD N Mean Std. Deviation Minimum Maximum

ANOVA p

value

bvFTD 35 3.14 1.734 1 7

0.699

(NS)

PNFA 6 2.83 1.472 1 5

SD 2 4.00 .000 4 4

Total 43 3.14 1.656 1 7

Table 5: mean interval from onset to diagnosis of FTD type. ( NS- not significant)

N Mean

Std.

Deviation Minimum Maximum

ANOVA

p value Subtype

AbvFTD 13 3.31 1.653 1 6

0.353

(NS)

DbvFTD 13 2.62 1.938 1 7

Mixed

bvFTD

9 3.67 1.500 1 5

Total 35 3.14 1.734 1 7

Table 6: mean interval from onset to diagnosis of bvFTD subtype

Education, Handedness, Family History:

Mean education years of the study population was 10.8 years with range from 2 to 18 years.

Mean years of education for the bvFTD and the language FTD group was 10.02 and 14.12

years respectively. Since the number of SD & PNFA cases were not high, this difference was

not statistically significant. Handedness information was available in 40/43 patients and all of

them were right handed. Family history was available in 37 of 43 patients (86%). Three

patients of 37 (8.1%) had a positive family history of which 2 had bvFTD and one had

PNFA.

32

Neurological signs:

At the time of inclusion, a parkinsonian syndrome was present in 18% of the patients. An

akinetorigid form (60%) was more frequent than rest tremor (40%). Other movement

disorders were less common (8%). The most frequent was postural tremor, present in 3% of

the patients. Oculomotor disturbances were noted in 5% of the patients and consisted mainly

in slow saccades (4%) and up-gaze limitation (1%), after verification that none of these

patients had parkinsonian syndrome or fulfilled the international consensus diagnosis criteria

for progressive supranuclear palsy (Litvan et al., 1996).

Motor Neuron Disease was seen in two patients of the 43 cases (4.65%), spinal form was

seen in one patient which was of the disinhibited bvFTD subtype presenting with loss of

social conduct, addiction and sexual disinhibition at 48 years of age and diagnosed at our

institute 3 years into the illness in 2012 at the age of 51 years. The patient did not have any

family history suggestive of amyotrophic lateral sclerosis. The other patient was a 42 year old

female presenting with progressive language dysfunction in the form of reduced word output,

grammatical mistakes. Two years into the illness she developed progressive bulbar palsy

requiring PercutaneousEnteroGastrostomy for severe swallowing disability.

Table 7 lists the neurological signs seen in the study population and its frequency.

33

Neurological signs Frequency

Primary reflexes

Grasping

Sucking

36%

10%

Parkinsonian syndrome 18%

Pyramidal signs 13%

Postural tremor 3%

Oculomotor disorders 5%

Eyelid apraxia 2%

Table 7: Clinical characteristics of 43 patients with FTD

Survival time/ onset to death:

Survival( alive/dead) data was available for 40 patients on follow up or on telephonic enquiry

with 3 patients being lost to follow up. 10/40 patients (25%) had died during the course of the

study with mean time in years of disease onset to death being 4.3 years. All the 10 deaths

occurred in the bvFTD variant.

Alive Dead Total

Fishers exact p

FTD type

bvFTD

22(68%) 10 (31%) 32 0.16 NS

PNFA +

SD 8 0 8

Total 30(75%) 10(25%) 40(100%)

Only 44.51% power to detect a difference

Table 8 : number and proportion of deaths and comparison within FTD subtypes

None of the patient was institutionalized prior to death and at follow up none of the alive

patients are being managed in a hospice or an institution. Cause of death was aspiration

pneumonia in 2 patients and cause in rest of the patients could be recorded in others.

34

Neuropsychological evaluation:

MMSE was available in 24 of 43 patients, 17 patients (39.5%) were untestable and MMSE

was not available in 2 patients studied retrospectively. Mean MMSE of the study population

was 15.91 with a range of 2 to 27. Mean MMSE of the bvFTD group was 14.38 whereas that

of the language variant was 20.5. Detailed neuropsychological testing in the testable patients

revealed significant fronto-temporal function impairment with preservation of visuospatial

function. As compared to published western literature (Isabelle Le Ber et al, Brain 2006)

which report a mean MMSE of 21.5 (± 5.1), our study patients had a much lower MMSE

score, more so for the bvFTD subtype. The lower MMSE score cannot be explained by the

years of education parameter as the mean years of education was 10.8 years in the study

group (Kerala has the highest Literacy rate among all Indian states approaching 100 %).

Other factors probably responsible for this observation may be the delay in diagnosis and

relatively advanced state in which the patient first reaches the neurologist, especially because

the patients are prone to be treated as psychiatric/mood disorder patients in view of the

typical neuropsychiatric profile and relatively younger age of onset.

Behavioral symptoms at the onset of disease:

Among the study population of 43 cases, the most common initial presenting symptom at the

onset of disease as reported by the patient‟s primary care giver or next of kin was apathy (9 of

43 patients, 21%). Frequency of other symptoms at the onset of disease is as follows:

language disturbance 18.6 %, executive dysfunction 16.2 %, aggression 9.3%, addiction 7 %,

food faddism, attention loss, excessive talk- each 4.6 % and 2.3 % each of obsessive

compulsive behaviour, selfish behaviour, hoarding and mental rigidity. Figure 6 gives the

absolute values of the symptoms at disease onset.

35

Frequency of Various Behavioral symptoms:

The study evaluated 15 symptoms characteristically described in FTD, more so in the bvFTD

category. Figure 8 enumerates the frequency of these individual symptoms present during the

course of the illness of the 43 patients of the study. More than 50 % cases had loss of insight,

apathy and social bladder incontinence which are characteristic symptoms described in

frontal lobe dysfunction. Other commonly noted symptoms (> 25 % incidence) were

restlessness, anger outbursts/agitation, food faddism, hallucinations/delusions and

hyperorality/utilization behaviour. Other less common ( ~ 10 to 20 %) features were seen in

emotional incontinence, sexual disinhibition, stereotypy, addictions, perseveration, hoarding

and sign board reading. Figure 9 shows the absolute numbers of various behavioural

symptoms seen in the study population.

9

8

7

4

3

2

2

2

1

1

1

1

0 2 4 6 8 10

Apathy

Language

Executive dysfunction

Aggression

Addiction

Food fadism

Attention

Excessive talk

OCD

Selfish Behavior

Hoarding

Mental rigidity

no.of patients

Initial presenting symptom

Figure 6: Presenting symptom at disease onset as reported by caregiver.

36

81

67

51

39.5 39.534.9

30.225.6 23.3

18.6 18.6 16.3 16.39.3 7

0

10

20

30

40

50

60

70

80

90

Frequency of behavioral symptoms in %

35

29

17

17

7

15

8

22

4

11

7

8

3

13

10

8

14

26

26

36

28

35

21

39

32

36

35

40

30

33

0 10 20 30 40 50

Loss of insight

Apathy

Restlessness

Anger outbursts/agitation

Addiction

Food fadism

Sexual disinhibition

Social incontinence

Hoarding

Utilization/Hyperorality

Perseveration

Stereotypy

Sign board

Hallucination/Delusions

Emotional incontinence

Frequency of Behavior symptoms in 43 patients

present

absent

Figure 8 : Frequency of characteristic symptoms described in FTD

Figure 9 (below): Relative proportion of FTD symptoms

37

Figure 10 depicts the frequency of these 15 symptoms in the subtypes of bvFTD.

Comparison of diagnostic groups on FrSBe (Frontal system behavioural

scale):

Table 9 presents the average T scores of the total and each of the three FrSBe subscale for

the 3 diagnostic groups namely bvFTD, PNFA and SD. FrSBe score estimation was done in

25 of the 43 patients. These 25 patients were included and prospectively followed up year

2010 onwards and hence FrSBe data was not available on the remaining 18 patients.

Table 10 presents the comparison of the total and the subscale FrSBe score among the three

subtypes of bvFTD i.e. AbvFTD, DbvFTD and mixed bvFTD. The post hoc analysis of the

bvFTD subtype data is given below table 10.

13

13

3

4

2

3

2

7

1

2

1

1

0

4

4

14

6

10

8

3

7

5

10

1

4

5

5

0

7

2

8

8

4

5

2

5

1

5

2

3

1

2

3

2

2

0 5 10 15 20 25 30 35 40

Loss of Insight

Apathy

Restlessness

Anger …

Addiction

food fadism

Sexual disinhibition

Social incontinence

Hoarding

Utilization/Hyperorality

Perseveration

Stereotypy

Sign board

Hallucination/Delusions

Emotional incontinence

AbvFTD DbvFTD mixed bvFTD

38

FTD type N Mean Std.

Deviation Minimum Maximum

ANOVA p

value

FrSBe total

score

bvFTD 20 52.84 7.67 39.57 70.22

0.008 PNFA 3 41.18 14.36 28.28 56.67

SD 2 34.73 2.73 32.80 36.67

Total 25 50.00 10.00 28.28 70.22

FrSBe Apathy

score

bvFTD 20 51.86 9.27 35.08 71.56

0.120 PNFA 3 45.71 13.09 35.99 60.62

SD 2 37.81 .00 37.82 37.82

Total 25 50.00 10.00 35.08 71.56

FrSBe

Disinhibition

score

bvFTD 20 52.41 9.16 34.92 69.72

0.034 PNFA 3 42.97 9.18 33.95 52.32

SD 2 36.36 .68 35.89 36.85

Total 25 50.00 10.00 33.95 69.72

FrSBe Executive

dysfunction

score

bvFTD 20 52.96 7.44 42.83 70.51

0.006 PNFA 3 39.37 14.58 25.53 54.59

SD 2 36.25 5.38 32.45 40.06

Total 25 50.00 10.00 25.53 70.51

Table 9: Total and subscale FrSBe score for the 3 FTD types Mean differences are not significant in post-hoc Scheffe tests at 0.017 levels

39

FTD subtype N Mean Std. Deviation Minimum Maximum ANOVA p

value

FrSBe total

score

AbvFTD 8 53.44 6.68 45.70 63.77

0.491

DbvFTD 6 49.78 6.20 41.51 59.58

Mixed

bvFTD 6 55.11 10.22 39.57 70.22

Total 20 52.84 7.67 39.57 70.22

FrSBe Apathy

score

AbvFTD 8 57.99 7.23 47.85 71.56

0.004

DbvFTD 6 42.83 6.44 35.08 50.58

Mixed

bvFTD 6 52.71 7.31 42.38 64.26

Total 20 51.86 9.27 35.08 71.56

FrSBe

Disinhibition

score

AbvFTD 8 47.60 5.15 39.75 53.29

0.122

DbvFTD 6 57.47 8.55 47.49 69.72

Mixed

bvFTD 6 53.77 11.77 34.92 66.82

Total 20 52.41 9.16 34.92 69.72

FrSBe Executive

dysfunction

score

AbvFTD 8 53.03 7.91 42.83 64.28

0.327

DbvFTD 6 49.63 4.09 44.91 55.98

Mixed

bvFTD 6 56.20 8.95 44.21 70.51

Total 20 52.96 7.44 42.83 70.51

Mean differences are significant in post-hoc Scheffe tests at 0.017 levels.

Table 10: FrSBe total and subscale score comparison among bvFTD sybtypes and below- Post hoc

analysis.

Dependent Variable bvFTD

subtype

bvFTD

subtype Sig.

FrSBe Apathy score

AbvFTD DbvFTD .004

mixed .400

DbvFTD Mixed .079

40

DISCUSSION

The present study describes the demographic, clinical characteristics of a study population of

43 FTD patients seen at a single centre. This study, to our knowledge, is the first study

devoted to clinical, neuropsychiatric characteristics of FTD from an Indian population and it

provides valuable insight regarding the demographic data of FTD in this part of the world.

FTD type distribution:

81 % of cases in this study were of the behavioural presentation (bvFTD) whereas the

proportion of PNFA & Semantic dementia(SD) was very low ( 14 & 9 % respectively).

Previous studies have reported that around quarter of the patients are of PNFA and SD type.

Whether this observation is true or as a result of a selection bias, it has to be seen in

subsequent studies in the similar population or any other part of the country.

Gender distribution:

In terms of gender, overall there was a predominance of men diagnosed as having FTD ( 65

% men vs 35 % women) and similar representation was seen in the subtypes of Behavioral

FTD and PNFA. In semantic dementia, equal prevalence was found.

A few studies (Diehl et al, 2002) document a predominance of men in patients with FTD.

However, others report a predominance of women,(Gustafson et al, 2001) and yet others find

an equal sex distribution.( Hodges JR et al, Neurology 2003, Rosso SM et al, 2003) Fewer

studies have evaluated the sex distribution in those with semantic dementia and PNFA.

Snowden et al, 1996 demonstrated a 2:1 ratio of women to men with semantic dementia,

while Hodges et al, 2003 found a predominance of women in 8 PNFA patients and a

41

predominance of men in 9 patients with semantic dementia. The confusing pattern of sex

differences may be due to the small samples previously described. Johnson et al 2005 studied

the demographic characteristics of 353 patients and reported male predominance for bvFTD

and semantic dementia and the female predominance for PNFA which they hypothesize that

it may reflect differences in biological vulnerability to the 3 anatomically distinct syndromes.

This cortical asymmetry may reflect different vulnerabilities to neurodegeneration between

women (left frontal) and men (right frontal and/or bilateral temporal).

Age of onset of FTD:

Frontotemporal lobar degeneration comprises 5–6% of all dementias, but 8–17% of early-

onset (under 70) dementias in autopsy series (Barker et al.,2002). The disease most

commonly presents in the sixth decade, though presentation may occur as early as the third

and as late as the ninth decade of life (Knopman et al., 1990; Barker et al.,2002; Ratnavalli et

al., 2002; Hodges et al., 2003; Johnson et al., 2005). FTLD is generally considered an early-

onset dementia, but up to one-quarter of cases can present after age 65 (Rosso et al., 2003;

Johnson et al., 2005). Progressive non-fluent aphasia presents later than other clinical

syndromes in some series (Hodges et al., 2003; Johnson et al., 2005).

In this study too 75 % patients presented with illness starting in the 6th

decade (

42

FTD, suggesting that this disorder also occurs in older patients. The age at onset for FTLD is

an important issue to resolve because several studies have used an age of 65 or 70 years as

the cutoff to estimate the prevalence of FTD. By using these definitions, there is an inherent

diagnostic bias against the diagnosis of FTLD in the very old.

A positive family history is present in 20–56% of the patients with FTLD (Ratnavalli et al.,

2002; Hodges et al., 2003). The mode of inheritance is autosomal dominant in the majority of

cases. Interest in FTLD has increased during the past decade, since hereditary bvFTD was

found in some cases to be associated with mutations in the microtubule associated protein tau

(MAPT) gene (Hutton et al., 1998). Two other genes, VCP (Watts et al., 2004) and CHMP2B

(Skibinski et al., 2005) are responsible for a minority of familial cases. Recently, mutations in

the PGRN gene, coding for progranulin were found in FTLD-U families (Baker et al., 2006).

Our study showed a positive family history in 3 of 37 patients (8.1 %). Family history was

not available in 6 patients. Out of the three patients who had a positive family history, 2 had

bvFTD and one had PNFA. Genetic studies would have thrown more light on the inheritance

of these cases, which however could not be done.

Survival time/ symptom onset to death:

Various studies have described median survival from symptom onset and diagnosis as 6 and 3

years respectively, with the clinical syndrome of FTD-MND associated with a more rapidly

progressive course (2 and 1 years respectively) (Hodges et al., 2003; Johnson et al., 2005;

Roberson et al., 2005). Significantly, mean time from diagnosis to institutionalization can be

as short as 1 year, probably due to the high prevalence of behavioral symptoms. Survival is

shorter and cognitive and functional decline are much more rapid than in AD (Roberson et

43

al., 2005). In our study, 10/40 patients (25%) had died during the course of the study with

mean time in years of disease onset to death being 4.3 years. This figure is less as compared

to the median survival from symptom onset as described by Hodges et al, 2003 was 6 ± 1.1

years (95% CI) for bvFTD. Probable explanation to this finding could be lack of

institutionalization facilities for care of FTD patients of the Indian population, increasing

prevalence of smaller, nuclear families, poor support infrastructure for neurological

rehabilitation. Further studies probing into this specific aspect of patient survival in and out

of dedicated patient care setting may throw further light on the issue.

Behavioral symptoms at the onset and in the course of the disease:

Among the study population of 43 cases, the most common initial presenting symptom at the

onset of disease as reported by the patient‟s primary care giver or next of kin was apathy (9 of

43 patients, 21%). Frequency of other symptoms at the onset of disease is as follows:

language disturbance 18.6 %, executive dysfunction 16.2 %, aggression 9.3%, addiction 7 %,

food faddism, attention loss, excessive talk- each 4.6 % and 2.3 % each of obsessive

compulsive behaviour, selfish behaviour, hoarding and mental rigidity. Figure 6 gives the

absolute values of the symptoms at disease onset.

More than 50 % cases had loss of insight, apathy and social bladder incontinence which are

characteristic symptoms described in frontal lobe dysfunction. Other commonly noted

symptoms (> 25 % incidence) were restlessness, anger outbursts/agitation, food faddism,

hallucinations/delusions and hyperorality/utilization behaviour. Other less common ( ~ 10 to

20 %) features were seen in emotional incontinence, sexual disinhibition, stereotypy,

addictions, perseveration, hoarding and sign board reading.

44

Comparison of FrSBe scores among FTD patients:

FrSBe T scores (total and subscale scores of Apathy, Disinhibition and Executive

dysfunction) were compared across the three syndromes of FTD i.e. bvFTD, PNFA, Semantic

dementia as well as subtypes of bvFTD namely Apathetic(AbvFTD), Disinhibited(DbvFTD)

and MixedbvFTD. FrSBe scores were available in 25 out of 43 study cases. Among the 25

cases in which FrSBe scores were available, 20 were of bvFTD type( 8 AbvFTD, 7 DbvFTD,

5 mixed bvFTD) and 5 were of the language variant ( 3 PNFA, 2 SD).

The mean FrSBe total as well as the three subscale scores for the bvFTD group were higher

than the PNFA and SD group. On applying ANOVA, significant difference was noted among

the three FTD syndromes in the total, Disinhibition and Executive dysfunction scores,

whereas the apathy score difference was not statistically significant. This suggests that the

language variant of FTD differs from the behavioural variant more in terms of disinhibition

and executive dysfunction but is similar to the latter in terms of presence of apathy. As the

number of PNFA and SD patients in the current study was low, post hoc analysis using

Scheffe test failed to show any statistical significance.

When comparison using the FrSBe scale was done among the bvFTD subtypes (AbvFTD,

DbvFTD, Mixed bvFTD), it was evident that the mean total and subscale FrSBe scores were

similar in the three subtypes but statistically significant difference was noted on the Apathy

score (p value = 0.004, ANOVA) among the three subtypes, on post hoc analysis this

difference was sustained only when comparing the apathetic and disinhibited group which

can be explained by the fact the mixed bvFTD patients also had high Apathy scores in view

of presence of symptoms of both the groups. Although the mean disinhibition score was more

in the DbvFTD subtype (T score- 69.72) as compared to that of AbvFTD ( T score- 53.29), it

failed to reach a level of statistical significance.

45

Apathy was the most common behavioral problem in AbvFTD, and dysexecutive problems

was found in both AbvFTD and DbvFTD, particularly as the severity of the disorders

increases . Both of our groups displayed increases in apathy and dysexecutive behaviors after

the onset of dementia, but the DbvFTD group showed more dramatic change in disinhibition.

The FrSBe Disinhibition scale contains items assessing behaviors commonly observed in

FTD, such as swearing, silly or childlike behavior, impulsivity, inappropriate sexual

behavior, and labile emotionality.

Similar findings have been reported when the FrSBe has been used with other disorders

involving disinhibition as a prominent feature. (Spinella et al, 2004) have conducted a series

of studies showing that high FrSBe scores were associated with polysubstance abuse, binge

eating, and difficulty delaying gratification in simulated gambling tasks.

In addition to its utility in differential diagnosis, the FrSBe correlates with real-world

outcomes in dementia patients. FrSBe Apathy scores predict performance on activities of

daily living (Norton LE et al, 2001), whereas higher FrSBe Disinhibition and Executive

scores are associated with caregiver burden (Davis J et al, 2007). The present study extends

these findings to FTD and bolsters the notion that quantified measurement of behavioural

change provides useful information in dementia diagnosis. The FrSBe might be a useful

addition to the armamentarium of clinicians by allowing objective evaluation of behaviour

change over time. The FrSBe is not meant to replace a comprehensive, multidisciplinary

evaluation. Rather, it can provide a standardized method for evaluating behavior change,

complementing cognitive assessment, neuroimaging, and the neurologic examination. It is

low in cost and in burden on the patient, requiring only about 15 minutes of caregiver time to

complete.

46

FTLD is a relatively rare disorder, and our sample was therefore small, despite recruitment

from 2005 to 2012. Consensus diagnosis by expert clinicians with research diagnostic criteria

was chosen as the gold standard for accurate diagnosis for this study. The only more accurate

method of diagnosis of which we are aware is autopsy. These data were unfortunately not

available in this cohort. We hope to investigate the FrSBe further with a larger sample of

FTLD patients and to correlate scores with pathology and/or neuroimaging changes in future

studies.

Divisions between clinical syndromes are not absolute. Clinical overlap would inevitably

have the effect of reducing behavioural differences between groups. The fact that strong

behavioural differences can nevertheless be identified, which accords with previous clinical

experience, suggests that such differences are real and robust. The study draws attention to

behavioural distinctions between the clinical syndromes of bvFTD, PNFA and semantic

dementia in the domains of emotion and insight, social behaviour, response to sensory

stimuli, eating, addictions and oral behaviour, and repetitive behaviours and compulsions.

Further correlative studies of behavioural change and structural and functional change on

brain imaging would provide further understanding of the anatomical substrate of the

behavioural disorders of frontotemporal lobar degeneration.

47

CONCLUSIONS

1. The proportion of patients with onset after 65 was high in our study (25%)which was

consistent with earlier observations, The diagnosis of FTD should therefore be considered

even in elderly patients.

2. Incidence of PNFA and Semantic dementia was low in our study as compared to western

data.

3. Time to death from symptom onset was low (4.3 years) as compared to published literature

(6.1 years) which may suggest lack of neurorehabilitation and institutionalization facilities.

4. Patients enrolled in the study presented in a relatively advanced state at the time of

enrolment and diagnosis

5. The language variant of FTD (PNFA and SD) differs from the behavioural variant more in

terms of disinhibition and executive dysfunction but is similar to the latter in terms of

presence of apathy.

6. At an early state in the disease, clinical/neuropsychological differentiation into an apathetic

vs disinhibited bvFTD is possible, however this distinguishability cannot be maintained as

the disease advances.

7. The FrSBe Scale might be a useful addition to the armamentarium of clinicians by

allowing objective evaluation of behaviour change over time and it can provide a

standardized method for evaluating behavior change, complementing cognitive assessment,

neuroimaging, and the neurologic examination. It is low in cost and in burden on the patient,

requiring only about 15 minutes of caregiver time to complete.

48

Limitations of the study

1. In view of lesser numbers of language variant of FTD, comparative analysis was not

significant regarding few parameters due to lack of power of study.

2. Pathological confirmation of the FTD diagnosis could not be made due to

unavailability of consent from the patients.

3. Genetic studies could not be possible due to resource and infrastructure limitations.

4. Although on follow up, few patients had development of new signs like parkinsonism,

bulbar palsy, definite documentation of evolving into a 2nd

or 3rd

syndrome could not

be made as reported in few previous studies (Kertesz A et al., Alzheimer Dis Assoc Disord 2007).

5. Although VBM correlation was contemplated as a part of this study, sufficient

number of cases with follow up neuroimaging was not possible in the stipulated time

period in view of advanced disease state of patients, uncooperativeness for imaging

and hazards of imaging under sedation/anesthesia. This arm of the study is being

continued.

49

REFERENCES

1. Ash S, Moore P, Vesely L, Gunawardena D, McMillan C, Aderson C, Avants B,

Grossman M. Nonfluent speech in frontotemporal lobar degeneration. J

Neurolinguistics. 2009;22:370–83.

2. Bak TH, Hodges JR. Motor neurone disease, dementia and aphasia: Coincidence, co-

occurrence or continuum? J Neurol. 2001;248:260–70.

3. Baker M, et al. Mutations in progranulin cause tau-negative frontotemporal dementia

linked to chromosome 17. Nature 2006; 442: 916–9.

4. Barker WW, Luis CA, Kashuba A, et al. (2002). Relative frequencies of Alzheimer

disease, Lewy body, vascular and frontotemporal dementia, and hippocampal

sclerosis in the State of Florida Brain Bank. Alzheimer Dis Assoc Disord 16: 203–

212.

5. Boeve BF, Lang AE, Litvan I. Corticobasal degeneration and its relationship to

progressive supranuclear palsy and frontotemporal dementia. Ann Neurol.

2003;54:S15–9.

6. Boxer AL, Miller BL. Clinical features of frontotemporal dementia. Alzheimer Dis

Assoc Disord.2005;19:S3–6.

7. Brun A (1987). Frontal Lobe Degeneration of the Non-Alzheimer Type. I.

Neuropathology Arch Gerontol Geriatrics 6: 193–208.

8. Cairns NJ, et al. Neuropathologic diagnostic and nosologic criteria for frontotemporal

lobar degeneration: Consensus of the Consortium for Frontotemporal Lobar

Degeneration. Acta Neuropathol. 2007;114:5–22.

9. Chan D, Anderson V, Pijnenburg Y , Whitwell J, Barnes J, Scahill R, et al. The

clinical profile of right temporal lobe atrophy. Brain. 2009;132:1287–98.

50

10. Chow TW, Miller BL, Hayashi VN, Geschwind DH. Inheritance of frontotemporal

dementia. Arch Neurol. 1999;56:817-822.

11. Clark LN, Poorkaj P, et al. (1998). Pathogenic implications of mutations in the tau

gene in pallido-pontonigral degeneration and related neurodegenerative disorders

linked to chromosome 17. Proc Natl Acad Sci U S A 95: 13103–13107.

12. Constantinidis J, Richard J, Tissot R (1974). Pick‟s disease: histological and clinical

correlations. Eur Neurol 11: 208–217.

13. Cummings JL. Anatomic and behavioral aspects of frontal-subcortical circuits. Ann N

Y Acad Sci. 1995;769:1–13.

14. Davies RR, Kipps CM, Mitchell J, Kril JJ, Halliday GM, Hodges JR. Progression in

frontotemporal dementia: Identifying a benign behavioral variant by magnetic

resonance imaging. Arch Neurol. 2006;63:1627–31.

15. Davis J, Tremont G. Impact of frontal systems behavioral functioning in dementia on

caregiver burden. J Neuropsychiatry Clin Neurosci 2007;19:43–9.

16. Diehl J, Kurz A. Frontotemporal dementia: patient characteristics, cognition, and

behaviour. Int J Geriatr Psychiatry. 2002;17:914-918.

17. Foster NL, Wilhelmsen K, Sima AA, et al. (1997). Frontotemporal dementia and

parkinsonism linked to chromosome 17: a consensus conference. Conference

Participants. Ann Neurol 41: 706–715.-

18. Gislason TB, Sjogren M, Larsson L, Skoog I. The prevalence of frontal variant

frontotemporal dementia and the frontal lobe syndrome in a population based sample

of 85 year olds. J Neurol Neurosurg Psychiatry. 2003;74:867-871.

19. Gorno-Tempini ML, et al. Cognition and anatomy in three variants of primary

progressive aphasia. Ann Neurol. 2004;55:335–46.

51

20. Grace J, Malloy PF. Frontal Systems Behavior Scale (FrSBe): professional manual.

Lutz, FL: Psychological Assessment Resources, 2001.

21. Gregory C, Lough S, Stone V, Erzinclioglu S, Martin L, Baron-Cohen S, et al. Theory

of mind in patients with frontal variant frontotemporal dementia and Alzheimer‟s

disease: Theoretical and practical implications. Brain. 2002;125:752–64

22. Gustafson L, Passant U, Grasbeck A, Brun A. Clinical variability of frontotemporal

dementia. In: Miyoski K, Shapiro C, Gavilia M, Morika Y, eds. Contemporary

Neuropsychiatry. Tokyo, Japan: Springer-Verlag; 2001:152-157.

23. Hodges JR, Patterson K. Nonfluent progressive aphasia and semantic dementia: A

comparative neuropsychological study. J Int Neuropsychol Soc. 1996;2:511–24.

24. Hodges JR, Davies R, Xuereb J, et al. Survival in frontotemporal dementia.

Neurology. 2003;61:349-354.

25. Hodges JR, Patterson K. Semantic dementia: A unique clinicopathological syndrome.

Lancet Neurol. 2007;6:1004–14.

26. Hosler BA, Siddique T, Sapp PC, et al. (2000). Linkage of familial amyotrophic

lateral sclerosis with frontotemporal dementia to chromosome 9q21-q22. JAMA 284:

1664–1669.

27. Hudson LP, Munoz DG, Miller L, et al. (1993). Amygdaloid sclerosis in temporal

lobe epilepsy. Ann Neurol 33: 622–631

28. Hutton M, et al. Association of missense and 50-splice site mutations in tau with the

inherited dementia FTDP-17. Nature 1998; 393: 702–5.

29. Isabelle Le Ber et al., Demographic, neurological and behavioural characteristics and

brain perfusion SPECT in frontal variant of frontotemporal dementia. Brain. 2006

Nov; 129(Pt 11):3051-65.

52

30. Johnson JK, Diehl Jet al; Frontotemporal lobar degeneration: demographic

characteristics of 353 patients. Arch Neurol. 2005 Jun;62(6):925-30.

31. Josephs KA. Frontotemporal dementia and related disorders: Deciphering the enigma.

Ann Neurol. 2008;64:4–14.

32. Kertesz A. Pick complex: An integrative approach to fronto-temporal dementia:

Primary progressive aphasia, corticobasal degeneration, and progressive supranuclear

palsy. Neurologist. 2003;9:311–7.

33. Kertesz A, Blair M, McMonagle P, Munoz DG , The diagnosis and course of

frontotemporal dementia.. Alzheimer Dis Assoc Disord. 2007 Apr-Jun;21(2):155-63.

34. Knibb JA, Hodges JR. Semantic dementia and primary progressive aphasia: A

problem of categorization? Alzheimer Dis Assoc Disord. 2005;19:S7–14.

35. Knopman D, et al. Longitudinal Tracking of FTLD. Toward developing Clinical Trial

Methodology. Alzheimer Dis Assoc Disord 2007; 21: S58–63.

36. Knopman DS, Mastri AR, Frey WHd, et al. (1990). Dementia lacking distinctive

histologic features: a common non- Alzheimer degenerative dementia. Neurology 40:

251–256.

37. Kril JJ, Halliday GM. Clinicopathological staging of frontotemporal dementia

severity: Correlation with regional atrophy. Dement Geriatr Cogn Disord

2004;17:311–5.

38. Libon DJ, Xie SX, Moore P, Farmer J, Antani S, McCawley G, et al. Patterns of

neuropsychological impairment in frontotemporal dementia. Neurology.

2007;68:369–75

39. Litvan I,et al. Clinical research criteria for the diagnosis of progressive supranuclear

palsy (Steele–Richardson–Olszewski syndrome): report of the NINDS-SPSP

international workshop. Neurology 1996; 47: 1–9.

53

40. Lomen-Hoerth C, Anderson T, Miller B (2002). The overlap of amyotrophic lateral

sclerosis and frontotemporal dementia. Neurology 59: 1077–1079.

41. Mesulam MM (1982). Slowly progressive aphasia without generalized dementia. Ann

Neurol 11: 592–598.

42. Mioshi E, Kipps CM, Dawson K, Mitchell J, Graham A, Hodges JR. Activities of

daily living in frontotemporal dementia and Alzheimer disease. Neurology.

2007;68:2077–84

43. Mohandas E, Rajmohan V. Frontotemporal dementia: An updated overview. Indian J

Psychiatry 2009;51:65-9

44. Neary D, Snowden JS, Northen B, et al. (1988). Dementia of frontal lobe type. J

Neurol Neurosurg Psychiatry 51:353–361.

45. Norton LE, Malloy PF, Salloway S. The impact of behavioral symptoms on activities

of daily living in patients with dementia. Am J Geriatr Psychiatry 2001;9:41– 8.

46. Paulsen JS, et al. Frontal behavioral syndromes in cortical and subcortical dementia.

Assessment 1996;3:327–37.

47. Perry RJ, Graham A, Williams G, Rosen H, Erzinçlioglu S, Weiner M, et al. Patterns

of frontal lobe atrophy in frontotemporal dementia: a volumetric MRI study. Dement

Geriatr Cogn Disord. 2006;22:278–87

48. Pick A (1892). Uber die Beziehungen der senilen Hirnatrophie zur Aphasie. Prager

Medizinische Wochenschrift 17: 165–167

49. Rabinovici GD, et al. Abeta amyloid and glucose metabolism in three variants of

primary progressive aphasia. Ann Neurol. 2008;64:388–401.

50. Rascovsky K, Hodges JR, et al. Diagnostic criteria for the behavioral variant of

frontotemporal dementia (bvFTD): Current limitations and future directions.

Alzheimer Dis Assoc Disord. 2007;21:S14–8

54

51. Ratnavalli E, Brayne C,DawsonK, et al. (2002). The prevalence of frontotemporal

dementia. Neurology 58: 1615–1621.

52. Roeber S, Mackenzie IR, Kretzschmar HA, Neumann M. TDP-43-negative FTLD-U

is a significant new clinico-pathological subtype of FTLD. Acta Neuropathol.

2008;116:147–57.

53. Roberson ED, Hesse JH, Rose KD, et al. (2005). Frontotemporal dementia progresses

to death faster than Alzheimer disease. Neurology 65: 719–725.

54. Rosen HJ, Allison SC, Ogar JM, Amici S, Rose K, Dronkers N, et al. Behavioral

features in semantic dementia vs other forms of progressive aphasias. Neurology.

2006;67:1752–6.

55. Rosen HJ, et al. Patterns of brain atrophy in frontotemporal dementia and semantic

dementia. Neurology. 2002;58:198–208.

56. Rosness TA, Haugen PK, Passant U, Engedal K. Frontotemporal dementia: A

clinically complex diagnosis. Int J Geriatr Psychiatry. 2008;23:837–42

57. Rosso SM, Landweer EJ, Houterman M, et al. Medical and environmental risk factors

for sporadic frontotemporal dementia: a retrospective case-control study. J Neurol

Neurosurg Psychiatry. 2003;74:1574-1576.

58. Seelaar H, et al. Distinct genetic forms of frontotemporal dementia. Neurology.

2008;71:1220–6

59. Skibinski G, et al. Mutations in the endosomal ESCRTIII-complex subunit CHMP2B

in frontotemporal dementia. Nat Genet 2005; 37: 806–8.

60. Snowden JS, Neary D, Mann DMA. Fronto-Temporal Lobar Degeneration: Fronto-

Temporal Dementia, Progressive Aphasia, Semantic Dementia. New York,

NY:Churchill Livingstone Inc; 1996.

55

61. Snowden J, Goulding P, Neary D (1989). Semantic dementia: a form of circumscribed

cerebral atrophy. Behav Neurol 2: 167–182.

62. Spinella M, Lyke J. Executive personality traits and eating behavior. Int J Neurosci

2004;114:83–93.

63. Varma AR, Snowden JS, Lloyd JJ, et al. Evaluation of the NINCDS-ADRDA criteria

in the differentiation of Alzheimer‟s disease and frontotemporal dementia. J Neurol

Neurosurg Psychiatry. 1999;66:184-188.

64. Watts GD, et al. Inclusion body myopathy associated with Paget disease of bone and

FTD is caused by mutant valosin-containing protein. Nat Genet 2004; 36: 377–81.

65. Wittenberg D, Possin KL, Rascovsky K, Rankin KP, Miller BL, Kramer JH. The

early neuropsychological and behavioral characteristics of frontotemporal dementia.

Neuropsychol Rev. 2008;18:91–102.

56

ANNEXURE

Consensus Criteria for Diagnosis of bvFTD (Neary et al, 1998)

The clinical diagnostic features of FTD: Clinical profile

Character change and disordered social conduct are the dominant features initially and

throughout the disease course. Instrumental functions of perception, spatial skills, praxis, and

memory are intact or relatively well preserved.

I. Core diagnostic features

A. Insidious onset and gradual progression

B. Early decline in social interpersonal conduct

C. Early impairment in regulation of personal conduct

D. Early emotional blunting

E. Early loss of insight

II Supportive diagnostic features

A. Behavioral disorder

1. Decline in personal hygiene and grooming, 2. Mental rigidity and inflexibility

3.Distractibility and impersistence 4. Hyperorality and dietary changes 5. Perseverative and

stereotyped behaviour 6. Utilization behavior

B. Speech and language

1. Altered speech output: a. Aspontaneity and economy of speech b. Press of speech

2. Stereotypy of speech 3. Echolalia 4. Perseveration 5. Mutism

C. Physical signs

1. Primitive reflexes 2. Incontinence 3. Akinesia, rigidity, and tremor 4. Low and labile blood

pressure

D. Investigations

1. Neuropsychology: significant impairment on frontal lobe tests in the absence of severe

amnesia, aphasia, or perceptuospatial disorder 2. Electroencephalography: normal on

conventional EEG despite clinically evident dementia 3. Brain imaging (structural and/or

functional): predominant frontal and/or anterior temporal abnormality

57

Consensus Criteria for Diagnosis of PNFA (Neary et al, 1998)

The clinical diagnostic features of progressive nonfluent aphasia:

Clinical profile- Disorder of expressive language is the dominant feature initially and

throughout the disease course. Other aspects of cognition are intact or relatively well

preserved.

I. Core diagnostic features

A. Insidious onset and gradual progression

B. Nonfluent spontaneous speech with at least one of the following: agrammatism, phonemic

paraphasias, anomia

II Supportive diagnostic features

A. Speech and language:

1. Stuttering or oral apraxia 2. Impaired repetition 3. Alexia, agraphia 4. Early preservation of

word meaning 5. Late mutism

B. Behavior

1. Early preservation of social skills 2. Late behavioral changes similar to FTD

C. Physical signs: late contralateral primitive reflexes, akinesia, rigidity, and tremor

D. Investigations

1. Neuropsychology: nonfluent aphasia in the absence of severe amnesia or perceptuospatial

disorder

2. Electroencephalography: normal or minor asymmetric slowing

3. Brain imaging (structural and/or functional): asymmetric abnormality predominantly

affecting dominant (usually left) hemisphere

58

Consensus Criteria for Diagnosis of Semantic Dementia (Neary et al, 1998)

Clinical profile: Semantic disorder (impaired understanding of word meaning and/or object

identity) is the dominant feature initially and throughout the disease course. Other aspects of

cognition, including autobiographic memory, are intact or relatively well preserved.

I. Core diagnostic features

A. Insidious onset and gradual progression

B. Language Disorder characterized by

1. Progressive, fluent, empty spontaneous speech 2. Loss of word meaning, manifest by

impaired naming and comprehension 3. Semantic paraphasias and/or

C. Perceptual disorder characterized by

1. Prosopagnosia: impaired recognition of identity of familiar faces and/or

2. Associative agnosia: impaired recognition of object identity

D. Preserved perceptual matching and drawing reproduction

E. Preserved single-word repetition

F. Preserved ability to read aloud and write to dictation orthographically regular words

II. Supportive diagnostic features

A. Speech and language

1. Pressure of speech 2. Idiosyncratic word usage 3. Absence of phonemic paraphasias

4.Surface dyslexia and dysgraphia 5. Preserved calculation

B. Behavior

1. Loss of sympathy and empathy 2. Narrowed preoccupations 3. Parsimony

C. Physical signs

1. Absent or late primitive reflexes 2. Akinesia, rigidity, and tremor

D. Investigations

1. Neuropsychology: Profound semantic loss, manifest in failure of word comprehension

and naming and/or face and object recognition

2. Electroencephalography: normal

3. Brain imaging (structural and/or functional): predominant anterior temporal abnormality

(symmetric or asymmetric)

59

FrSBe Score

60

FrSBe Score continued…

61

End of FrSBe Score.