THIRUVANANTHAPURAM, KERALA

Transcription

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 1

2 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 Date: Prof. Dr. Muralidharan Nair Professor & Head, Dept of Neurology 2

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 3

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 4

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. 5

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. 6

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 7

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. 8

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. 9

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 10

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) 11

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 12

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 wordbased 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 13

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 Voxelbased 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 14

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). 15

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, 16

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. 17

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). 18

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, 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 19

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. 20

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 21

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. 22

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) 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. 23

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 patients suspected to have FTD on screening 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 43 cases included in study 35 Behavior variant 8 Language variant 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 24

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. Number of patients(%) 2 (9%) 6 (14%) bvftd PNFA SD 35 (81%) Total FTD Patients= 43 Figure 2 : bvftd- Behavioral variant, PNFA- Progressive Non Fluent Aphasia, SD- Semantic Dementia 25

26 bvftd subtypes AbvFTD DbvFTD Mixed bvftd 8 No. of patients 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. 26

27 No. of patients new dementia/mci FTD Year 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 Total New patients FTD patients Hospital incidence rate 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 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 27

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 (65%) 12 (35%) PNFA 6 4 (66%) 2 (34%) Semantic dementia 2 1 (50 %) 1 (50%) Total (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. 28

29 Presenile Vs Senile onset total bvftd PNFA SD < 65 yrs > 65 yrs 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 bvftd PNFA SD ANOVA p value Total 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 years with a standard deviation of 10.5 years. Mean age of onset for bvftd, PNFA & SD was 55.94, and 67.5 respectively. On applying one way 29

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 D-bvFTD Mixed Total 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. 30

31 FTD N Mean Std. Deviation Minimum Maximum ANOVA p value bvftd PNFA SD (NS) Total Table 5: mean interval from onset to diagnosis of FTD type. ( NS- not significant) Subtype N Mean Std. Deviation Minimum Maximum ANOVA p value AbvFTD DbvFTD Mixed bvftd Total Table 6: mean interval from onset to diagnosis of bvftd subtype (NS) 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 and 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. 31

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. 32

33 Neurological signs Primary reflexes Grasping Frequency 36% 10% Sucking 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 PNFA + SD NS 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. 33

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 with a range of 2 to 27. Mean MMSE of the bvftd group was whereas that of the language variant was 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. 34

35 Mental rigidity Hoarding Selfish Behavior OCD Excessive talk Attention Food fadism Addiction Aggression Executive dysfunction Language Apathy Initial presenting symptom no.of patients Figure 6: Presenting symptom at disease onset as reported by caregiver. 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. 35

36 Frequency of behavioral symptoms in % Figure 8 : Frequency of characteristic symptoms described in FTD Figure 9 (below): Relative proportion of FTD symptoms Frequency of Behavior symptoms in 43 patients Emotional incontinence Hallucination/Delusions Sign board 3 40 Stereotypy 8 35 Perseveration 7 36 Utilization/Hyperorality Hoarding 4 39 Social incontinence Sexual disinhibition Food fadism present absent Addiction 7 36 Anger outbursts/agitation Restlessness Apathy Loss of insight

37 Figure 10 depicts the frequency of these 15 symptoms in the subtypes of bvftd. AbvFTD DbvFTD mixed bvftd Emotional incontinence Hallucination/Delusions Sign board 0 3 Stereotypy Perseveration Utilization/Hyperorality Hoarding Social incontinence Sexual disinhibition food fadism Addiction Anger Restlessness Apathy Loss of Insight 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

38 FTD type N Mean Std. Deviation Minimum Maximum ANOVA p value FrSBe total score FrSBe Apathy score FrSBe Disinhibition score bvftd PNFA SD Total bvftd PNFA SD Total bvftd PNFA SD Total FrSBe Executive dysfunction score bvftd PNFA SD Total Table 9: Total and subscale FrSBe score for the 3 FTD types Mean differences are not significant in post-hoc Scheffe tests at levels

39 FTD subtype N Mean Std. Deviation Minimum Maximum ANOVA p value FrSBe total score FrSBe Apathy score FrSBe Disinhibition score AbvFTD DbvFTD Mixed bvftd Total AbvFTD DbvFTD Mixed bvftd Total AbvFTD DbvFTD Mixed bvftd Total AbvFTD FrSBe Executive dysfunction score DbvFTD Mixed bvftd Total Mean differences are significant in post-hoc Scheffe tests at 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

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 40

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 earlyonset (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 earlyonset 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 6 th decade (<65 yrs age, which is defined as early onset or presenile dementia). As earlier reported by Rosso et al.,2003, a quarter of our patients presented after age 65 years. However contrary to published literature, both of our semantic dementia presented at a mean age of 67 years. However the sample size is too small to draw any final conclusion. Nonetheless, although FTD is considered to be a predominantly presenile cause of dementia, many patients had an onset of symptoms after the age of 65 years. A recent study (Gislason et al., 2003) found that 3% of a population of 85-year-old patients met the clinical criteria for 41

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 42

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. 43

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 ) as compared to that of AbvFTD ( T score ), it failed to reach a level of statistical significance. 44

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. 45

46 FTLD is a relatively rare disorder, and our sample was therefore small, despite recruitment from 2005 to 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. 46

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. 47

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 2 nd or 3 rd 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. 48

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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 56

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 57

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) 58

59 FrSBe Score 59

60 FrSBe Score continued 60

61 End of FrSBe Score. 61