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Dementia

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Differentiating the dementias: a neurological approach Saiffuddin Sheriff Shaik MRCP, Anoop Ranjan Varma DM, FRCP, MD

With improving lifespan, primary degenerative and vascular dementias are increasingly being recognised as prominent health problems. The four commonest causes of primary dementia are Alzheimer’s disease, frontotemporal dementia, vascular dementia and dementia with Lewy bodies. An accurate diagnosis is critical for the proper management and treatment of these disorders. Here, Dr Shaik and Dr Varma describe the clinical and imaging characteristics of each of these types of dementia.

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ementia has been traditionally seen as a generalised impairment of intellect and memory. It is commonly defined as acquired diffuse intellectual impairment with no disturbance of consciousness.1 This approach is perpetuated in textbooks: ‘the general clinical picture is similar in all [primary dementias] – a general progressive deterioration of intellect, memory and personality’;2 ‘the clinical picture is almost identical … both [Alzheimer’s and Pick’s disease] have progressive dementia … consensus of opinion that differential diagnosis can be made only at autopsy’. 3 Interestingly, progressive dementia was not qualified any further in terms of the types of cognitive deficits seen, because the term in itself was seen to be a sufficient description. These traditional definitions continue to be entrenched even in relatively recent textbooks, for example dementia denotes ‘deterioration of all intellectual or cognitive functions’.4 Careful clinicopathological analyses in the ensuing years have led to the recognition of different clinical patterns in patients with diverse pathologies.5 With the elucidation of non-Alzheimer dementias, eg frontotemporal dementia6-9 and dementia with Lewy bodies,10-12 it has become evident that these disorders occur far more commonly than previously thought. It has also become clear that Alzheimer’s disease cannot be assumed to be the cause of all degenerative dementias. The last three decades have seen a rising interest in the differentiation of various forms of dementia13,14 and current approaches view dementia as a generic term encompassing the neuropsychological syndromes accompanying brain diseases.15 That these syndromes can be clinically differentiated, each characterised by identifiable clinical deficits determined by the topographical distribution of pathology, is a concept that has enthused many involved in contemporary dementia research. www.progressnp.com

Figure 1. Alzheimer’s disease. Coronal MRI (left) and SPECT images showing mild atrophy and reduced blood flow in the parietal regions

Dementia, therefore, includes chronic progressive disorders with distinctive cognitive and behavioural changes, neurological symptoms and signs, and changes on imaging (single photon emission tomography [SPECT] and magnetic resonance imaging [MRI]). A critical neurological and neuropsychological analysis (supported by neuroimaging) aids the delineation of the various forms of dementias. Approach to assessing a patient with dementia Patient history is vital and should be obtained from the carer as well as the patient. Special attention should be paid to the mode of onset, progression, fluctuations and evolution of the disorder. All cognitive (memory, language, calculation, perception, spatial function and complex executive tasks) and behavioural (character change, apathy, disinhibition, mood, hallucinations, delusions, repetitive-stereotypies, obsessive-compulsive behaviours) functions should be explored. Almost all dementia patients present with poor memory. However, a careful history will distinguish severe memory impairment (inability to keep track of day and date, mislaying of personal possessions and rapid loss of information) from patchy and vari-

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able loss. Mere word-finding difficulty should be distinguished from primar y language impairment, which includes word errors, poor spelling, and difficulty in reading and writing. Losing track of tasks or conversations suggests a short memor y span. Difficulty in laying cutlery, dressing or negotiating environment (being lost in unfamiliar or familiar surroundings, bumping into furniture) denotes visuospatial impairment. Inability to recognise family, friends or objects, eg microwave, refrigerator, could be due to a perceptual deficit. Severe amnesia, especially in Alzheimer’s disease, may sometimes lead to misidentification of one’s own image in a mirror. The history of change in character and personality must be carefully analysed. Superficially, any cognitive change is reported to be a change in personality by most carers. However, personality change is significant only when it includes clear departure from previous character accompanied by behavioural change and breakdown of social and personal conduct. Behavioural changes (affect and social behaviour, eating and vegetative behaviours, repetitive behaviours, hallucinations and delusions) can be further explored along the principles outlined in the Manchester Behavioural questionnaire.16 A thorough neurological examination must additionally incorporate observation of behaviour and evaluation of visual attention and orientation, myoclonus, sensory attention and tactile localisation, praxis and primitive reflexes. Myoclonus is absent in fronto temporal dementia. Primitive reflexes, eg grasp reflexes, are observed in frontotemporal dementia but are uncommon in mild-to-moderate Alzheimer’s disease. The differentiation of dementias in a clinical setting is strongly dependent on careful neuropsychological analysis. Qualitative evaluation is of paramount value and no amount of quantification (scores) can override the importance of the neuropsychologist as an observer of behaviour.17,18 For Cortical

Subcortical

Cortico-subcortical

• Alzheimer’s disease • frontotemporal degeneration

• vascular dementia • progressive supranuclear palsy • multiple system atrophy • Huntington’s disease • multiple sclerosis • hydrocephalus

• dementia with Lewy bodies • Creutzfeldt-Jakob disease • corticobasal degeneration

Table 1. Classification of the dementias 12

example, memor y can be impaired both in Alzheimer’s disease and frontotemporal dementia, but for widely different reasons, ie retention disorder (Alzheimer’s disease) and secondary to problems in retrieval and organisation (frontotemporal dementia).19 Severe amnesia with disorientation in time and place suggests medial temporal pathology; primar y language impairment occurs with dominant perisylvian lesions; acalculia and a short memor y span are associated with parietal deficit; visuospatial disorientation is seen in biparietal disorder; perceptual deficit (agnosia) is due to temporal pathology; and apraxias accompany parietal disease. Executive dysfunction and early personality change are seen with affliction of the frontal cortices. The characteristics of a subcortical deficit are discussed below. The Mini-Mental State Examination (MMSE) is a heavily left hemisphere (predominantly verbal memory and language) based instrument and of less value in detecting frontotemporal dementia. However, it remains a useful bedside instrument in the detection and quantification of cognitive deficits. The frontal assessment battery (FAB) is sensitive and specific in differentiating frontotemporal dementia from Alzheimer’s disease. 20 The Cambridge Cognitive Examination (CAMCOG) and Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog) are standardised instruments in the neuro psychological evaluation of dementias. For detailed and accurate characterisation of the dementias, neuropsychological assessment by experienced neuropsychologists (adept at analysing the qualitative reasons for possible failure of various tests) is desirable. However, such services are few and far between in the UK. A practical approach to diagnosing the dementias would include neuropsychological analysis based on histor y and subsequent intelligent deployment of bedside tools (such as MMSE, FAB, etc) to detect the broad underlying patterns of deficits. Additional data from appropriately interpreted imaging will help clinicians to arrive at a diagnosis with improved accuracy.21 The history, neurological signs and patterns of neuropsychological deficits together point to the clinical diagnosis in various dementias. The diagnostic process requires pattern recognition and hence familiarity with various usual and unusual presentations of the dementias. Distinct dementia syndromes are described below. They are usefully classified into cortical, subcortical and cortico-subcortical groups (see Table 1). The four most common types of dementias (Alzheimer’s, frontotemporal dementia, vascular


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Dementia

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dementia and dementia with Lewy bodies) will be discussed in detail. Cortical dementias Patients with cortical dementias (such as Alzheimer’s and frontotemporal dementia) look well and have few physical signs. The distinction lies in the careful analysis of patients’ behaviours and neuropsychological deficits. Alzheimer’s disease Alzheimer’s disease predominantly affects the medial temporal and temporoparietal cortex.22 The earliest symptom is usually insidious loss of memory. Patients have difficulty remembering day-to-day events and are frequently unable to keep track of the day and date. They may misplace personal possessions. They may also have linguistic problems when the perisylvian temporoparietal areas are involved. Speech is halting with difficulty in finding the right word. Patients may make word errors and be unable to comprehend conversations, especially complex ones. Patients lose literacy skills (reading and writing), and may experience difficulty in reckoning change and dealing with financial affairs. Visuospatial impairment may result in difficulty in dressing, aligning cutlery, negotiating stairs or finding the way; initially in unfamiliar surroundings and later in the patient’s own home. Usually in the later stages, patients may fail to recognise faces, including those of their spouse, children and even their own reflection in the mirror.23-25 Despite these severe cognitive deficits, social graces and façade are well preserved. The degree of insight is inversely proportional to the severity of amnesia. Patients remain physically well and neurological examination reveals few signs. Extrapyramidal signs (bradykinesia and rigidity) and myoclonus emerge with the evolution of the disorder. Neuropsychological investigation reveals dense amnesia with loss of information over time, a short memor y span, visuospatial and constructional impairment, primar y language deficits including paraphasias, alexia and agraphia in varying combinations.13,17,26 EEG shows nonspecific slow waves. Structural imaging shows atrophy with hippocampal emphasis, whereas functional imaging (PET and SPECT scans) shows characteristic parietotemporal cerebral blood flow abnormalities (see Figure 1). Deficits in the anterior regions are usually a feature of later stages. www.progressnp.com

Figure 2. Frontotemporal dementia. Coronal MRI (left) and SPECT images showing severe atrophy and reduced blood flow in the frontal regions

Frontotemporal degeneration Frontotemporal degeneration is associated with severe atrophy of the frontal lobes and the anterior temporal lobes.15,27 The precise syndrome depends on the preferential site of atrophy within the frontal and temporal lobes, ie predominant bifrontal: frontotemporal dementia; predominant temporal: semantic dementia; predominant left frontotemporal: progressive non-fluent aphasia. Frontotemporal dementia is the second most common cause of presenile dementia. 7,28 The most prominent early features are changes in personality, and social and personal behaviour. There is rapid inability to manage one’s own affairs and patients may lose their jobs due to lack of judgement. Behavioural changes range from disinhibition/overactivity to apathy/inertia. Patients may become disinhibited, overactive and restless with a fatuous, unconcerned affect. They may clown, sing and dance, usually in a stereotypical fashion. Alternatively, patients may become apathetic and inert, lacking in drive and motivation, showing little response to stimuli. As the disease progresses, disinhibition may give way to apathy but not vice versa. There is early loss of insight and patients are not distressed or concerned by their failures. In all patients there is emotional shallowness with loss of sympathy and empathy.15,29 Stereotyped behaviours including repetitive actions and complex rituals may occur. Patients may cram food or develop a sweet tooth.16 Patients look well physically and neurological examination, including extrapyramidal signs (rigidity, bradykinesia) and primitive (eg grasp) reflexes, reveals few signs. Myoclonus does not occur. Neuropsychological evaluation reveals frontal behaviours (rapid, impulsive behaviours with inability to check responses, apathy and inflexibility). Tests sensitive to frontal lobe function reveal severe difficulties in organisation and strategic skills, and mental set shifting. Responses are concrete and per-


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severative. Formal memory tests may reveal an inefficient memory due to impaired attention. However, patients are not clinically amnesic and remain oriented in time and place. Speech is usually economical and concrete. There is an absence of visuospatial impairment. Constructional abnormalities may occur due to poor strategy and organisation, but overall spatial configuration is maintained.15,30 EEG is normal. MRI shows severe frontal and anterior temporal atrophy and SPECT shows cerebral blood flow defects in similar areas (see Figure 2). Semantic dementia Patients with semantic dementia lose the meaning of words and objects.31-33 Speech is fluent and effortless but empty and full of semantic (verbal) paraphasias and the repertoire becomes progressively limited. Patients fail to recognise objects but are able to copy and match objects accurately. Visuospatial skills and day-to-day memory are well preserved. Behavioural changes involve repetitive stereotypies, obsessional behaviours and food fads.33 With progression, frontal behaviours (disinhibition, apathy) may emerge. CT/MRI scans reveal severe temporal atrophy that may be asymmetric. SPECT reveals reduced cerebral blood flow in temporal and later frontal regions (see Figure 3). EEG is normal. Progressive non-fluent aphasia In patients with progressive non-fluent aphasia, the prominent defect is a circumscribed language disorder. With progression of the disorder, mutism supervenes.15 There is selective left frontotemporal atrophy on MRI and reduced cerebral blood flow on SPECT in the left hemisphere (see Figure 4). Motor neurone disease Some patients may have frontotemporal degeneration associated with motor neurone disease and therefore have a short lifespan.34 Subcortical dementias Several disorders affect subcortical structures (white matter, basal ganglia, thalamus) with relative sparing of the cerebral cortex. 35 These include vascular dementia, Parkinson’s disease, Huntington’s disease and progressive supranuclear palsy. These disorders are characterised by a plethora of physical signs (in contrast to the cortical dementias) and an absence of cortical features (visuospatial deficit, agnosia, aphasia and apraxia). Subcortical dementia is characterised by bradyphrenia (slowness and rigidity of thinking) with difficulty in planning, organising and sequencing mental events. These patients are forgetful but their amnesia is not severe. They may be apathetic and exhibit difficulties in tasks requiring mental 14

Figure 3. Semantic dementia. Coronal MRI (left) and SPECT images showing severe atrophy and reduced blood flow in the temporal regions

Figure 4. Primary nonfluent aphasia. Coronal MRI (left) and axial SPECT images showing atrophy and reduced blood flow in the left frontoparietotemporal regions

manipulation, eg mental arithmetic, comprehending complex syntax, reversing digits or sequences, eg months of the year.36 Vascular dementia Vascular dementia includes multi-infarct dementia, stroke with dementia and subcortical vascular dementia. It is being increasingly recognised that subcortical small vessel disease is a prominent cause of vascular dementia.37,38 Consequently, the classical stepwise course with relatively acute deteriorating events is not a necessary requisite for a possible vascular cause for the dementing syndrome. Patients present with physical and mental decline. They look unwell and old for their age. Neurological examination reveals focal signs (dysarthria, pyramidal weakness, rigidity, akinesia, ataxia and gait disorder). Neuropsychology testing detects a subcortical deficit (as described above).36 MRI shows nonspecific atrophy with deep white matter lesions and/or lacunes. SPECT may show patchy uptake or mild frontal change (see Figure 5). Although subcortical dementia may resemble the neuropsychological deficits (frontal) of frontotemporal dementia, the presence of florid neurological signs and the absence of a prominent personality change and preservation of insight differentiate it.


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Cortico-subcortical dementias Creutzfeldt-Jakob disease is a rare but classical multifocal rapid and aggressive cortico-subcortical disorder. However, dementia with Lewy bodies is the commoner and far more prevalent form of corticosubcortical dementia.12 Dementia with Lewy bodies Dementia with Lewy bodies is characterised by cognitive, behavioural and physical symptoms and signs in varying combinations. This variability in presentation is the subject of much nosological debating.39 The recognition of the clinical syndrome is of practical relevance with therapeutic significance. Patients develop poor memory, mental confusion, incoherent speech and distractibility. They may lose their way. The behavioural syndrome is prominent and usually comprises of visual hallucinations and misperceptions. The visual hallucinations are formed and may comprise of, for example, little animals or people. Patients may also imagine ‘seeing’ objects, people or animals in patterns of curtains, carpets or stained glass windows. They can exhibit dramatic fluctuations between periods of lucidity and confusional states. They also show a physical decline with bradykinesia, rigidity and sometimes tremor. If the behavioural syndrome is treated with neuroleptics it may lead to sudden deterioration and even death (neuroleptic sensitivity).40 Neurological examination reveals extrapyramidal signs (rigidity, akinesia) and myoclonus. Neuro psychological evaluation reveals a fluctuating mental state with interference, intrusions, distractibility, confabulatory responses, misperceptions and visuospatial dysfunction.41 EEG can be grossly abnormal and reveal periodic complexes. 42 MRI shows atrophy and blood flow SPECT shows changes similar to Alzheimer’s disease43 (see Figure 6). Diagnosis The process of diagnosis involves the building up of a clinical picture successively at each step, from the history, to the neurological examination and finally to the neuropsychological assessment. Since clinical psychologists are increasingly carrying out neuropsychological assessments in isolation, it is useful to discuss the findings in multidisciplinar y meetings. Alternatively, free interchange of information between neurologists and neuropsychologists (similar to the long-established tradition of close discussions between neurologists and neuroradiologists) improves diagnostic accuracy. www.progressnp.com

Figure 5. Vascular dementia. Axial MRI showing severe deep white matter hyperintensities and lacune (left); axial SPECT showing patchy reduction of blood flow (right)

Figure 6. Dementia with Lewy bodies. Sagittal SPECT showing posterior reduction in blood flow

It must be emphasised that investigations aid the diagnostic process but are not pathognomonic of a dementia. It is common to receive reports suggesting that a dementia is vascular, based on white matter hyperintensities on MRI (interpreted as ischaemic). However, such changes occur widely across Alzheimer’s disease, vascular dementia, frontotemporal dementia and dementia with Lewy bodies 44,45 and provide relative (not absolute) differences between these disorders. Conversely, a normal MRI would be a strong argument against vascular dementia. Characteristic blood flow changes on SPECT and atrophy on MRI increase the likelihood of one dementia against another, but are also not absolutely specific.46,47 Genetic tests Alzheimer disease Three decades of genetic research in Alzheimer’s disease have broadened our understanding of the pathogenetic mechanisms in dementia.48 Three causative genes have been implicated in autosomal dominant Alzheimer’s disease: amyloid protein precursor gene (APP), locus on chromosome 21 and presenilin genes (PS1 and PS2) on chromosomes 14


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Dementia

Alzheimer’s disease

Frontotemporal dementia

Vascular dementia

Dementia with Lewy bodies

History

memory loss, early personality change spatial disorientation, stereotyped behaviour language failure

mental and physical decline

confusion, physical slowness

Neurology

myoclonus early primitive reflexes akinesia, rigidity (late) occasional akinesia, rigidity

pyramidal weakness, ataxia pseudobulbar palsy

akinesia, rigidity, myoclonus

Memory

severe amnesia

variable loss

variable loss

variable loss/amnesia

Language

aphasia

adynamic speech, mutism

dysarthria

incoherent, rambling

Visuo-spatial spatial disorientation function

preserved

preserved

spatial disorientation

Perception

primary recognition failure

preserved

preserved

misperceptions

Conduct

appropriate concern

inappropriate unconcern

appropriate concern

appropriate concern

Mental effort

high

low

slow

slow

Motor skills

impaired spatial configuration

impaired sequencing

impaired sequencing

impaired sequencing/ spatial configuration

CT/MRI

hippocampal atrophy

severe anterior atrophy

prominent white matter change/lacune

atrophy

SPECT

posterior

anterior

patchy

posterior

EEG

slow

normal

slow

grossly slow

Table 2. Clinical, neuropsychological and imaging characteristics of Alzheimer’s, frontotemporal, vascular and Lewy body dementias

and 1. The APOE4 allele48,49 poses a genetic risk for developing late-onset Alzheimer’s disease. Until recently, clinical gene testing only included APOE genotyping and testing for PS1 mutations; these may be broadened to include PS2 and APP genes in the future. However, most genetic tests are not clinically appropriate for the vast majority of patients with Alzheimer’s disease.50 Frontotemporal lobar degeneration Around 40 per cent of patients report a family history of dementia, and 10-20 per cent have a clear pattern of autosomal dominant inheritance. 51 Gene mutations are found in 30-40 per cent of cases with positive family histor y. 52 Mutations in the tau gene, MAPT were shown to cause familial frontotemporal dementia with parkinsonism linked to chromosome 17q21 (FTDP-17).53 However, despite advances in genetic 16

testing there remained a number of linked families in whom no mutations in MAPT could be identified. This led to the identification of progranulin (PGRN) gene in 2006.54 Summary Dementias encompass distinct neuropsychological syndromes reflecting the topographic selectivity of the underlying pathology. Alzheimer’s disease, frontotemporal dementia, vascular dementia and dementia with Lewy bodies are the four commonest causes of primary dementing disorders. A careful clinical (history and neurological examination) and neuropsychological analysis delineates these disorders. Neuroimaging (MRI and SPECT) provides supportive evidence for the diagnosis, and where strikingly discordant with the clinical diagnosis, this


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prompts re-evaluation of the basis for making that clinical diagnosis. Alzheimer’s disease is a posterior cortical disorder characterised by amnesia, aphasia, visuospatial disorientation and apraxia. Bilateral parietotemporal defects on SPECT are strongly supportive of the diagnosis of Alzheimer’s disease. By contrast, frontotemporal dementia is an anterior cortical syndrome. An early change in personality, conduct disorder, loss of insight and prominent behavioural changes constitute the distinct clinical picture. MRI and SPECT reveal severe anterior atrophy and reduced blood flow. EEG is normal. Subcortical small vessel dementia can present with a slowly progressive syndrome. The presence of vascular risk and focal neurological signs support the diagnosis of vascular dementia. A subcortical dementia on neuropsychological analysis is typical. Although severe vascular changes including lacunes on MRI are strongly supportive of the diagnosis of vascular dementia, the presence of white matter lesions in isolation are not pathognomonic and can be seen across Alzheimer’s, frontotemporal dementia and dementia with Lewy bodies. Patients with Lewy body dementia have widespread pathology across subcortical and cortical (most dominant in the parietotemporal regions) regions. The classical picture comprises of a parkinsonian syndrome, with prominent visual hallucinations, cognitive decline with a fluctuating confusional syndrome, neuroleptic sensitivity and myoclonus. Blood flow SPECT shows deficits similar to Alzheimer’s disease. EEG may be grossly slow. Cholinesterase inhibitors, especially rivastigmine, may dampen behaviours ver y effectively. A proper dementia diagnosis helps predict prognosis and allows patients to be managed better in their psychosocial setting. Cholinesterase inhibitor therapies can improve behaviours and delay the progression of these relentless disorders. Evidence is established for the role of cholinesterase inhibitors in Alzheimer’s disease and dementia with Lewy bodies (dementias where neurochemical cholinergic deficit has been demonstrated pathologically). Consequently, correct diagnosis will aid appropriate pharmacotherapy. In addition, behaviours in dementia with Lewy bodies can improve with cholinesterase inhibitor therapy. Accurate diagnosis may, therefore, spare the inappropriate and even harmful usage of antipsychotics for the management of behaviours in dementias, especially dementia with Lewy bodies. Declaration of interests None declared. www.progressnp.com

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Dr Shaik is a Specialist Registrar and Dr Varma is a Consultant in the Department of Neurology, Greater Manchester Neurosciences Centre, Salford Royal Hospital, Manchester References 1. Marsden CD. Assessment of dementia. In: Fredriks JAM, ed. Handbook of Neurology. Amsterdam: Elsevier 1985;46:221-32. 2. Lishman WA. The senile dementias, presenile dementia and pseudodementias. In: Organic Psychiatry, The Psychological Consequences of Cerebral Disorder. Oxford: Blackwell, 1987:370-427. 3. Merritt HH. Degenerative and heredodegenerative diseases. In: A Textbook of Neurology. Philadelphia: Lea and Febiger, 1967:440-565. 4. Victor M, Ropper AH. Delirium and other confusional states. In: Adams and Victor’s Principles of Neurology. 9th edn. McGraw Hill, 2009:398-409. 5. Neary D, Snowden JS, Bowen DM, et al. Neuropsychological syndromes in presenile dementia due to cerebral atrophy. J Neurol Neurosurg Psychiatry 1986;49:163-74. 6. Brun A. Frontal lobe degeneration of non-Alzheimer type I. Neuropathology. Arch Gerontology 1987;6:193-208. 7. Gustafson L. Frontal lobe degeneration of non-Alzheimer type II. Clinical picture and differential diagnosis. Arch Gerontology Geriatrica 1987;6:209-23. 8. Mann DMA, South PW. The topographic distribution of brain atrophy in frontal lobe dementia. Acta Neuropathologica 1993;83:334-40. 9. Neary D, Snowden JS, Northen B, et al. Dementia of frontal lobe type. J Neurol Neurosurg Psychiatry 1988;51:353-61. 10. Byrne EJ, Lennox G, Goodwin-Austin LB. Dementia associated with cortical Lewy bodies: proposed diagnostic criteria. Dementia and Related Cognitive Disorders 1991;2:283-4. 11. Kosaka K, Yoshimura M, Ikeda K, et al. Diffuse type of Lewy body disease: progressive dementia with abundant cortical Lewy bodies and senile changes of varying degree – a new disease? Clinical Neuropathology 1984;3:185-92. 12. McKeith IG, Perry RH, Fairbairn AF, et al. Operational criteria for senile dementia of Lewy body type (SDLT). Psychol Med 1992;22:911-22. 13. Dunn B, Owen A, Sahakian B. Neuropsychological assessment of dementia. In: O’Brien J, et al, eds. Dementia. London: Arnold 2000: 49-59. 14. Rossor M. Improving diagnosis of dementia. In: Maj M, Sartorius N, eds. Dementia. Chichester: John Wiley and Sons, 2000:165-8. 15. Snowden JS, Neary D, Mann DMA. Fronto-temporal Lobar Degeneration: Fronto-temporal Dementia, Progressive Aphasia, Semantic Dementia. New York: Churchill Livingstone, 1996. 16. Bathgate D, Snowden JS, Varma A, et al. Behaviour in frontotemporal dementia, Alzheimer’s disease and vascular dementia. Acta Neurol Scandinavica 2001;103(6):367-78. 17. Snowden JS. Neuropsychological evaluation and the diagnosis and differential diagnosis of dementias. Reviews in Clinical Gerontology 1999;9:65-72. 18. Walsh K, Darby D. Neuropsychology A Clinical Approach. Edinburgh: Churchill Livingston, 1999. 19. Varma AR, Snowden JS, Lloyd JJ, et al. Evaluation of the NINCDSADRDA criteria in the differentiation of Alzheimer’s disease and frontotemporal dementia. J Neurol Neurosurg Psychiatry 1999;66:184-8. 20. Slachevsky A, Villalpando JM, Sarazin M, et al. Frontal assessment battery and differential diagnosis of frontotemporal dementia and Alzheimer’s disease. Arch Neurol 2004;61:1104-7. 21. Schmand B, Eikelenboom P, van Gool WA, et al. Value of neuropsychological tests, neuroimaging and biomarkers for diagnosing Alzheimer’s disease in younger and older age cohorts. J Am Geriatr Soc 2011;59:1705-10. 22. Neary D. Classification of the dementias. Reviews in Clin Gerontol 1999;9:55-64. 23. Berg L, Morris JC. Diagnosis. In: Terry RD, Katzman R, Bick KL, eds. Alzheimer Disease. New York: Raven Press Ltd, 1994:9-25. 24. Neary D, Snowden JS. The differential diagnosis of dementias caused


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(DLB). Neurology 1996;47:1113-24. 40. McKeith IG. Dementia with Lewy bodies. Br J Psychiatry 2002;180:144-7. 41. Doubleday EK, Snowden JS, Varma AR, et al. Qualitative performance characteristics differentiate dementia with Lewy bodies and Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2002;72:602-7. 42. Barber PA, Varma AR, Lloyd JJ, et al. The electroencephalogram in dementia with Lewy bodies. Acta Neurol Scandinavica 2000;101(1):53-6. 43. Varma AR, Talbot PR, Snowden JS, et al. 99Tcm-HMPAO SPECT findings in Lewy body disease. J Neurol 1997;244:349-59. 44. Barber R, Scheltens P, Gholkar A, et al. White matter lesions on magnetic resonance imaging dementia with Lewy bodies, Alzheimer’s disease, vascular dementia and normal aging. J Neurol Neurosurg Psychiatry 1999;67:66-72. 45. Varma AR, Laitt R, Lloyd JJ, et al. Diagnostic value of high signal abnormalities on T2 weighted MRI in the differentiation of Alzheimer’s, frontotemporal and vascular dementias. Acta Neurol Scandinavica 2002;105:355-64. 46. Varma AR, Adams W, Lloyd JJ, et al. Diagnostic patterns of regional atrophy on MRI and regional cerebral blood flow on SPECT in young onset patients with Alzheimer’s disease, frontotemporal dementia and vascular dementia. Acta Neurol Scandinavica 2002a:105:261-9. 47. McNeill R, Sare GM, Manoharan M, et al. Accuracy of SPECT in differentiating Frontotemporal dementia from Alzheimer’s disease. J Neurol Neurosurg Psychiatry 2007;78:350-5. 48. Bertram L, Lill CM, Tanzi RE. The genetics of Alzheimer disease: back to the future. Neuron 2010;21:68(2):270-81. 49. Bekris LM, Yu CE, Bird TD, et al. Genetics of Alzheimer disease. J Geriatr Psychiatry Neurol 2010;23(4):213-7. 50. Howard KL, Filley CM. Advances in genetic testing for Alzheimer’s disease. Rev Neurology 2009;26-32. 51. Leyton CE, Hodges JR. Frontotemporal dementia: Recent advances and current controversies. Ann Indian Acad Neurol 2010;13(Suppl. 2):S74-S80. 52. Rosso SM, Donker Kaat L, Baks T, et al. Frontotemporal dementia in the Netherlands: Patient characteristic and prevalence estimates from a population based study. Brain 2003;126(9):2016-22. 53. Foster NL, Wilhelmsen K, Sima AA, et al. Fronto temporal dementia and parkinsonism linked to chromosome 17: a consensus conference. Ann Neurol 1997;41(6):706-15. 54. Baker M, Mackenzie IR, Pickering-Brown SM, et al. Mutations in progranulin gene cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 2006;442(7105):916-9.

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