The Neuroradiology Journal 19: 433-440, 2006
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Dementia: What is it All About? O.P. ALMEIDA University of Western Australia & Royal Perth Hospital; Crawley, Perth, Australia
Key words: Dementia, Alzheimer’s disease, vascular dementia, vascular cognitive impairment, dementia with Lewy bodies, Parkinson, frontotemporal dementia, focal dementia, semantic dementia, progressive aphasia, pathophysiology, pathology, treatment, imaging
SUMMARY – Dementia is an increasingly frequent clinical syndrome that is characterised by deficits in multiple cognitive domains, changes in behaviour and functional deterioration. Alzheimer’s disease, together with vascular dementia, account for 2/3 of all cases of dementia. Other less frequent causes of dementia include dementia with Lewy bodies and frontotemporal dementia. This paper reviews the clinical, pathophysiological and neuroimaging aspects of these four prevalent causes of dementia.
Introduction As the World’s population ages, the number of people with chronic health problems and degenerative disorders will continue to increase. Amongst them, dementia stands out as one of the most challenging public health issues of the XXI century. The prevalence of dementia practically doubles every 5 years after the age of 65, affecting as many as 1 in 3 people after the age of 80 years. Current estimates suggest that by 2030 there will be 63 million people with dementia worldwide, but our societies remain largely unprepared to deal with the devastating personal, social and financial impact of such an epidemic. What is Dementia? Dementia is a clinical syndrome characterised by deficits in multiple cognitive domains, changes in behaviour and functional deterioration. The ICD-10 definition of dementia states that ‘dementia is a syndrome due to disease of the brain, usually of a chronic and progressive nature, in which there is disturbance of multiple higher cortical functions, including memory, thinking, orientation, comprehension, calculation, learning capacity, language, and judgement. Consciousness is not clouded. Impairment of cognitive function is commonly
accompanied, and occasionally preceded, by deterioration in emotional control, social behaviour, or motivation’ (Who, 1992). The assessment of people who present for the investigation of a possible dementia syndrome includes six key-aspects: (1) clinical history, (2) cognitive function, (3) behaviour, (4) functional and social capacity (including evaluation of carer stress), (5) physical examination, and (6) investigations. The information collated as a result of such an assessment should enable the clinician to confirm or discard the diagnosis of dementia, determine the most likely cause of the syndrome, and devise a suitable management plan. The sections below briefly describe the key clinical and pathological aspects of the four most frequent causes of dementia. Alzheimer’s Disease Alzheimer’s disease (AD) is the name given to a progressive neurodegenerative condition that leads to irreversible cognitive decline, impaired activities of daily living and a range of behavioural and psychological symptoms. AD is the most frequent cause of dementia, accounting for approximately 50-60% of all cases. Surprisingly, until the early 1970s AD was considered to be a rare disease that affected mostly people in their 40s and 50s, whilst the most common form of ‘senile dementia’, which affected pri433
Dementia: What is it All About?
O.P. Almeida
Table 1 Diagnostic criteria for Alzheimer’s disease according to NINCDS-ADRDA (adapted and simplified)
Probable • Diagnosis of dementia confirmed by clinical examination and documented by objective cognitive testing (such as with the Mini-Mental State Examination) • Cognitive deficits apparent in at least two areas of cognitive function • Progressive cognitive decline, including worsening of memory deficits • Absence of impaired consciousness • Onset of symptoms between ages 40 and 90 years, most often after age 65 • Absence of systemic or brain disorders that could account for the symptoms The diagnosis of probable AD is supported by: • Progressive deterioration of specific cognitive deficits (e.g., aphasia, agnosia, apraxia) • Deterioration in activities of daily living or behaviour • Family history • Normal CSF exam • Non-specific EEG changes • Structural brain imaging evidence of progressive cerebral cortical atrophy The diagnosis of probable AD is consistent with: • Plateau period in the course of the illness • Presence of psychological and behavioural symptoms and disorders, including depression, delusions, hallucinations, agitation, insomnia, catastrophic reactions, loss of weight, as well as neurological signs and symptoms such as increased muscle tone, myoclonus, disturbances of gait, etc • Seizures in patients with severe dementia • Normal brain imaging for age The diagnosis of probable AD is uncertain in the presence of: • Rapid or abrupt onset of symptoms • Focal neurological signs or symptoms • Seizures occurring early in the course of the illness Possible • Diagnosis of dementia • Clinical presentation, onset and course of symptoms is not typical • Dementia is associated with other neurological disorders that could lead to dementia, but are considered not to be responsible for the presenting symptoms • Cognitive deficit restricted to one cognitive domain, but no other cause for the deficit can be identified Definite • Probable AD and histopathological evidence of AD Adapted from McKhann et al. (1984)
marily older people, was thought to be due to atherosclerosis of the blood vessels of the brain. This view was challenged by the seminal neuropathological study of Tomlinson et Al 38. They found that patients with senile dementia displayed exactly the same brain abnormalities as patients with AD, which led to the subsequent expansion of the concept of AD. The diagnosis of AD continues to be based on the clinical assessment of patients, as diagnostic markers remain elusive. The NINCDS-ADRDA criteria is the most widely used to determine the diagnosis of AD 30, which can be established at 3 different levels of certainty. ‘Definite AD’ requires the clinical diagnosis and neuropatho434
logical confirmation, ‘probable AD’ is used to describe typical cases when histopathological confirmation is not available, and ‘possible AD’ indicates the presence of atypical clinical features in the absence of any other alternative clinica or histopathological diagnosis (table 1). The sensitivity and specificity of the clinical diagnosis of AD is approximately 80-90% when the neuropathological diagnostic criteria for AD are used as the gold standard 8. Typically, patients with AD show impaired ability to learn and retain new information (often referred to as impaired short-term memory). As the disease progresses, the memory deficits tend to become more pronounced and wide-
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spread leading to increasing difficulty to recall learnt material (often referred to as impaired long-term memory). The language deficits (receptive, conductive or expressive aphasia) may also become more prominent with time and are commonly accompanied by impairment in other cognitive domains: apraxia (impaired ability to execute coordinated and purposeful movements), agnosia (impaired ability to attribute appropriate meaning to perception), executive dysfunction (impaired ability to plan, sequence, organise, infer, generalise, categorise, etc.), visuospatial difficulties, agraphia and dyscalculia, among others. Motor, sensory and gait disturbances, as well as seizures, are uncommon until the later stages of the illness. In addition to the cognitive deficits, AD is associated with progressive functional decline and an array of behavioural and psychological disturbances. Performing complex daily activities, such as shopping or controlling one’s finances, becomes increasingly more difficult with time until even the most basic activities can no longer be performed without assistance (for example, eating, grooming, using the toilet). These functional deficits can be further complicated by the presence of psychotic symptoms, depression, agitation, changes in sleep and eating habits, personality changes, and disturbances of psychomotor activity (such as wandering). Behavioural and psychological symptoms (BPSD) affect almost all patients with AD at some point during the course of their illnesses 7. The diagnostic workup of a patient with suspected AD includes a number of investigations that aim to identify potential contributing factors or alternative causes of the dementia syndrome. These routinely include thyroid function tests, folate (often red cell folate) and B12 concentrations, full blood count, urea and electrolytes, liver function tests, fasting glucose and, if appropriate, syphilis and HIV serology, screening for heavy metals, and test for the presence of the 14-3-3 protein in the cerebrospinal fluid (a positive test is consistent with the diagnosis of Creutzfeldt-Jakob disease – CJD). Neuroimaging plays an important role in the investigation and diagnosis of AD, particularly by excluding alternative causes of dementia. The findings of structural imaging (magnetic resonance imaging – MRI and computed tomography – CT) may not be particularly informative in the early stages of the illness, but evidence of progressive generalised cerebral cortical atrophy is supportive of the diagnosis
The Neuroradiology Journal 19: 433-440, 2006
of AD. Atrophy of medial temporal lobe structures seems to occur early in the course of the illness 21 and new computerised methods enable us to visualise those changes using overlapping scans 14. Single photon emission computed tomography (SPECT) and positron emission tomography (PET) of patients with AD often reveals a pattern of temporo-parietal hypometabolism. New PET procedures using tracers that bind to beta-amyloid (a constituent of the senile plaques found in the brains of people with AD) may offer further information to facilitate the early diagnosis of AD 21, although the specificity and sensitivity of such an approach remain to be established. The pathophysiological mechanisms underlying the development of AD are complex and seem likely to involve environmental as well as biological factors. Several mutations to the amyloid precursor protein gene (chromosome 21), presenilin 1 gene (chromosome 14) and presenilin 2 gene (chromosome 1) have been associated with autosomal dominant familial AD with early onset (i.e., before age 65 years). However, these mutations account for less than 1% of all cases of AD. A particular polymorphism of the apolipoprotein E gene (presence of the e4 allele) has been associated with increased risk of AD, particularly before age 70 years 5. The most popular theory to explain the pathogenesis of AD suggests that this increased genetic vulnerability favours the abnormal accumulation of the beta-amyloid peptide (Aß), which is believed to have neurotoxic properties and to contribute, by an as yet unknown mechanism, to the abnormal phosphorylation of a microtubule associated protein known as ‘tau’. The accumulation of Aß contributes to the formation of senile plaques, whereas the phosphorylation of tau leads to the development of paired helical filaments and, ultimately, neurofibrillary tangles and neuronal death 19. Senile plaques, neurofibrillary tangles and neuronal loss are the key-neuropathological abnormalities observed in the brains of patients with AD. The approach to the treatment of patients with AD can be divided into three areas: treatment of the cognitive deficits, management of the BPSD, and preventive strategies. Cholinesterase inhibitors (donepezil, rivastigmine and galantamine) and memantine are the only approved options for the treatment of the cognitive deficits of AD at present. These agents have modest but well-established efficacy, and questionable cost-effectiveness (AD2000 Collaborative Group 4,35) (table 2). There is only 435
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Table 2 Medications currently in use for the clinical treatment of Alzheimer’s disease
Donepezil
Rivastigmine
Galantamine
Memantine
Time to top serum concentration (hr)
3-5
0.5-2
0.5-1
3-7
Absorption affected by food
No
Yes
Yes
No
Serum half-life (hr)
70-80
2
5-7
60-80
Protein binding (%)
96
40
0-20
45
5 mg daily – 10 mg daily
1.5 mg twice daily – 6 mg twice daily
4 mg twice daily – 12 mg twice daily
5 mg daily – 10 mg twice daily
Dose (initial - maximum) Modified from Cummings, 2004.
limited systematic data available to guide the management of the behavioural and psychological symptoms associated with dementia, with most published trials being restricted to the investigation of antipsychotic medications. A recent systematic review concluded that there is sufficient evidence in support of the efficacy of olanzapine and risperidone for the treatment of BPSD, although these agents do not seem to be more efficacious than haloperidol 9 . Worryingly, however, treatment of patients with atypical antipsychotic agents is associated with a small increase in the risk of stroke (24% vs 0.5-2% for placebo). Data on other antipsychotic agents remains too sparse to guide evidence-based practice. There are no established interventions to prevent or reduce the rate of progression of AD. The excitement and hope surrounding the introduction of the Aß vaccine was dashed by poor safety outcomes, which included severe encephalitis and several cases of death, and to the observation that those who survived experienced no obvious clinical benefit from the procedure 33,16. Similarly, the use of estradiol replacement therapy, with or without progestin, does not decrease the risk of AD in women – to the contrary, the results from the Women Health Initiative Study have shown that women treated with hormone replacement therapy are more likely to develop dementia over a 5-year period than women treated with placebo 2,36. The potential usefulness of other preventive strategies remains to be established (e.g., treatment of hypertension, use of statins to reduce total cholesterol, lowering of total plasma homocysteine with B-vitamins, physical activity, etc.). 436
Vascular & Mixed Dementia Vascular dementia (VD) is considered the second most frequent cause of dementia in Western societies, accounting for approximately 20% of all dementia cases. The current concept of VD is based on the assumption that progressive cerebrovascular disease or discrete strokes can lead to cognitive impairment and dementia. As such, both the ICD-10 and DSM-IV classification systems require clinical (e.g., unilateral spastic weakness of the limbs, unilaterally increased tendon reflexes, extended plantar response, pseudobulbar palsy, etc.) and laboratory (imaging) evidence of cerebrovascular damage that is considered to be aetiologically related to the dementia. But the boundaries of what is called vascular dementia are contentious, with some authors being restrictive (i.e., diagnosis only made in association with a discrete stroke or series of strokes) and others inclusive in their diagnostic approach (including poststroke dementia, multi-infarct dementia, subcortical ischaemic vascular dementia, strategic infarct dementia, hypoperfusion dementia, haemorrhagic dementia, dementia caused by specific arteriopathies, mixed AD + VD, vascular mild cognitive impairment). To complicate things further, poststroke dementia is not consistently associated with the diagnosis of VD. In fact, AD alone or mixed dementia (AD+VD) account for 20-60% of all cases of poststroke dementia 24. Conversely, numerous communitydwelling older adults display neuroimaging findings indicative of previous strokes that are both clinically and cognitively silent. In other words, making the link between cerebrovascular lesions and dementia is not simple.
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During the past few years, a growing body of evidence has emerged in support of a strong association between AD and cerebrovascular disease, with some authors suggesting that mixed AD + VD might account for 70% of the cases of dementia in Western societies 13. For example, stroke and AD have numerous overlapping risk factors (increasing age, hypertension, diabetes, high plasma homocysteine, APOE4 genotype, smoking, sedentary lifestyle, high serum cholesterol, low educational attainment, etc.) and evidence from the Nun Study suggests that the clinical expression of AD is modulated by cerebrovascular burden – i.e., the greater the number of cerebrovascular lesions, the lower the number of plaques and tangles required for AD symptoms to become apparent 37. The management of VD can be divided into symptomatic and preventive. At present, symptomatic treatment is based on the off-label use of cholinesterase inhibitors. Two large randomised placebo controlled trials of donepezil for the treatment of VD are available. Their results indicate that 24-week treatment with donepezil is associated with improved cognitive function, clinical global impression and activities of daily living in patients with mild to moderate dementia 27. The evidence in support of the use of rivastigmine and galantamine remains inconclusive 10. Likewise, there is currently no evidence that memantine might be useful for the treatment of patients with VD 31. Vascular dementia seems
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a particularly suitable target for preventive strategies. There is currently no compelling evidence from clinical trials that the management of risk factors for cardiovascular disease can in fact prevent VD, but there is good reason to believe that this would be a sound public health strategy to pursue (i.e., smoking cessation, physical activity, healthy diet, and treatment of hypertension, diabetes and hyperlipidemia). Secondary preventive strategies are starting to emerge, and preliminary results look promising. Antiplatelet therapy with clopidogrel or aspirin as well as the lowering of cholesterol concentrations with statins are associated with a relative risk reduction of recurrent strokes of approximately 20% 18, whereas lowering blood pressure by 10 mm Hg is associated with a relative risk reduction of strokes of 30% 23. It is unclear, however, if this risk reduction of strokes is associated with a similar reduction in the risk of VD. Finally, decreasing plasma homocysteine by using B-vitamins does not seem to decrease the risk of strokes, and there is now concern that B-vitamin supplementation may in fact cause harm 6,25. Dementia with Lewy Bodies The intracytoplasmic inclusion described by Friedrich Lewy in the early 1900s was initially observed in the basal forebrain of patients with
Table 3 Consensus criteria for the diagnosis of dementia with Lewy bodies
Description The progressive cognitive decline is of sufficient magnitude to interfere with normal social or occupational function. Memory deficits may not occur in the early stages of the illness, but become usually evident with its progression. Deficit in attention, fronto-subcortical and visuospatial skills may be prominent. Core features (at least 2/3) • Fluctuating cognition with pronounced variations in attention and alertness. • Recurrent visual hallucinations, which are typically well formed and detailed • Spontaneous motor features of parkinsonism Supportive features include • Repeated falls • Syncope • Transient loss of consciousness • Neuroleptic sensitivity (potentially severe adverse reactions) • Systematised delusions • Hallucinations in modalities other than visual • Depression • REM sleep behaviour disorder Adapted from McKeith et al., 1996
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Table 4 Consensus criteria for the diagnosis of frontotemporal dementia Lund and Manchester Groups, 1994 (modified and simplified)
Clinical presentation: changes in character and disordered social conduct are the dominant features initially and throughout the course of the illness Core diagnostic features: • Insidious onset and gradual progression • Early decline in social and interpersonal conduct • Early impairment in the regulation of personal conduct • Early emotional blunting • Early loss of insight Supportive diagnostic features Behavioural • Decline in personal hygiene and grooming • Mental rigidity and inflexibility • Distractability and impersistence • Hyperorality and dietary changes • Perseverative and stereotypical behaviour • Utilization behaviour Speech and language • Altered speech output • Stereotypy of speech • Echolalia • Perseverative speech • Mutism Physical signs • Primitive reflexes • Incontinence • Akinesia, rigidity and tremor • Low or labile blood pressure Investigations • Cognitive tests: impaired executive (frontal) function and relatively well preserved memory and visuospatial abilities • Electroencephalography: normal • Brain imaging (structural of functional): predominant frontal or anterior temporal abnormalities
Parkinson’s disease (PD). It was not until the late 1970s that reports of dementia associated with cortical Lewy bodies became more frequent and ultimately led to the systematic description of a subtype of dementia known as ‘dementia with Lewy bodies’ (DLB). Consensus diagnostic guidelines were published in the mid 1990s 29 (table 3) and have been widely adopted in research, although cases of DLB would be labeled as AD, dementia in PD or unspecified dementia according to ICD-10 or DSM-IV, as there is no specific category for DLB in these diagnostic systems. The relationship between DLB and dementia in PD remains to be clarified. DLB is thought to account for 10-20% of all cases of dementia. From a pathophysiological point of view, Lewy bodies are associated with abnormalities of the α-synuclein protein. 438
α-synuclein immunochemistry is now available for neuropathological studies 17. Neuroimaging findings provide a valuable aid to the diagnosis of DLB. In contrast to AD, structural MRI of patients with DLB shows relatively well preserved medial temporal lobe structures. In contrast, functional imaging (PET or SPECT) of patients with DLB shows profound occipital hypometabolism that appears to affect the primary visual cortex and associated areas 32. Numerous reports have suggested that patients with DLB benefit from treatment with cholinesterase inhibitors, but systematic evidence remains scant. The results of a randomized placebo controlled trial of rivastigmine for the treatment of 120 patients with DLB showed a decrease in the intensity and severity of behavioural symptoms at the end of 20
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weeks, but no obvious cognitive gain compared to placebo 28. Frontotemporal Dementia Frontotemporal dementia (FTD) is a generic label given to a group of non-AD and non-Parkinson neurodegenerative disorders that, as the name suggests, affects primarily the frontal and temporal lobes. Changes in behaviour are prominent amongst patients with FTD and may be the most obvious clinical feature throughout the course of the illness. Language and executive function deficits are often apparent and appear in association with focal neurological signs, structural imaging evidence of focal atrophy of the frontotemporal lobes, and SPECT/PET demonstration of marked hypometabolism of anterior brain structures. FTD is a relatively uncommon type of dementia, with an estimated prevalence of 15 cases per 100,000 people aged 45 to 64 years 34. Most cases of FTD have onset between ages 45 and 65 years, with the condition affecting both sexes equally. Approximately 50% of patients report a positive family history of FTD or FTD-spectrum disorder. The diagnosis of FTD is not used consistently in clinical practice or in research, although consensus criteria with good sensitivity and specificity are available (table 4). The closest ICD-10 and DSM-IV diagnoses for FTD would be dementia due to Pick’s disease, but many patients with FTD would need to be classified as suffering from ‘unspecified dementia’. FTD is part of the frontotemporal lobe degenerative disorders that include primary progressive aphasia (PPD)(mostly limited to the left frontotemporal lobes) and semantic dementia (SD)(mostly limited to the temporal lobes). FTD, PPD and SD share a number of histopathological features, including tau pathology. The latter can lead to the formation of Pick’s bodies (intracytoplasmic inclusion) and Pick’s cells, or to the development of tangles. It is now known that those pathological changes arise in association with
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mutations to the tau gene on chromosome 17 in cases of familial FTD 20. Sporadic and familial cases have similar clinical phenotypes, although some reports suggest that certain phenotypes resembling progressive nuclear palsy (PSP) and cortical basal degeneration (CBD) may arise as a result of specific mutations. There is currently no pharmacological treatment for FTD. A handful of small trials investigating the clinical usefulness of selective serotonin reuptake inhibitors (SSRI) have produced inconclusive results (FTD is associated with abnormalities in the metabolism of serotonin, most likely leading to hyperactivity rather than underactivity of the serotonin system) 15. Conclusions Dementia is one of the most important and challenging health problems of this century. Numerous diseases and conditions can lead to the development of dementia 2,3, although the clinical syndromes described under the headings of AD and VD comprise, together, approximately 70% of all cases. Advances in genetics and molecular biology have led to the tentative separation of the most frequent types of neurodegenerative dementias into three groups, according to abnormalities in the metabolism of Aß (AD-related disorders), α-synuclein (DLB, PD and dementia associated with PD) and tau (FTD, SD, PPA, PSP, CBD and motor neuron disease). Progress in structural and functional neuroimaging has also contributed to the better delineation of these clinical syndromes, although we have not as yet succeeded in translating this growing body of knowledge into effective treatments. Acknowledgements The drafting of this paper was partly supported by a project grant from the National Health and Medical Research Council of Australia (NHMRC project grant 403996).
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23 Lawes CMM, Bennett DA, Feigin VL et Al: Blood pressure and stroke: an overview of published reviews. Stroke 35: 1024-33, 2004. 24 Leys D, Hénan H, Mackowiak-Cordoliani MA et Al: Poststroke dementia. Lancet Neurol 4: 752-59, 2005. 25 Lonn E, Yusuf S, Arnold MJ et Al: Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 2006: 354. 26 Lund and Manchester Groups: Consensus statement: clinical and neuropathological criteria for frontotemporal dementia. J Neurol Neursurg Psychiatry 57: 416-8, 1994. 27 Malouf R, Birks J: Donepezil for vascular cognitive impairment. Cochrane Database Syst Rev 2004, Issue 1. Art. No.: CD004395. pub2. 28 McKeith IG, Del Ser T, Spano P et Al: Efficacy of rivastigmine in dementia with Lewy bodies: a randomized, double-blind, placebo-controlled international study. Lancet 356: 2031-36, 2000. 29 McKeith IG, Galasko D, Kosala K et Al: Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 47: 1113-24, 1996. 30 McKhann G, Drachman D, Folstein M et Al: Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34: 939-44, 1984. 31 McShane R, Areosa Sastre A, Minakaran N: Memantine for dementia. Cochrane Database Syst Rev 2006: Issue 2. Art. No.: CD003154. pub5. 32 Minoshima S, Foster NL, Sima AA et Al: Alzheimer’s disease versus dementia with Lewy bodies: cerebral metabolic distinction with autopsy confirmation. Ann Neurol 50: 358-65, 2001. 33 Nicoll JA, Wilkinson D, Holmes C et Al: Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med 9: 448-52, 2003. 34 Ratnavalli E, Brayne C, Dawson K et Al: The prevalence of frontotemporal dementia. Neurology58: 161521, 2002. 35 Reisberg B, Doody R, Stöffler A et Al: Memantine in moderate to severe Alzheimer’s disease. N Engl J Med 348: 1333-41, 2003. 36 Shumaker SA, Legault C, Kuller L et Al: Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women’s Health Initiative Memory Study. JAMA 291: 2947-58, 2004. 37 Snowdon DA, Greiner LH, Mortimer JA et Al: Brain infarction and the clinical expression of Alzheimer’s disease: The Nun Study. JAMA 277: 813-7, 1997. 38 Tomlinson BE, Blessed G, Roth M: Observations on the brains of demented old people. J Neurol Sci 11: 205-42, 1970. 39 World Health Organization: The ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines. World Health Organization: Geneva 1992.
Prof. Osvaldo P. Almeida Unit of Geriatric Psychiatry (M573) University of Western Australia 35 Stirling Highway - Crawley - Perth Western Australia 6009 Australia Email: [email protected]
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Dementia: What is it All About? O.P. ALMEIDA University of Western Australia & Royal Perth Hospital; Crawley, Perth, Australia
Key words: Dementia, Alzheimer’s disease, vascular dementia, vascular cognitive impairment, dementia with Lewy bodies, Parkinson, frontotemporal dementia, focal dementia, semantic dementia, progressive aphasia, pathophysiology, pathology, treatment, imaging
SUMMARY – Dementia is an increasingly frequent clinical syndrome that is characterised by deficits in multiple cognitive domains, changes in behaviour and functional deterioration. Alzheimer’s disease, together with vascular dementia, account for 2/3 of all cases of dementia. Other less frequent causes of dementia include dementia with Lewy bodies and frontotemporal dementia. This paper reviews the clinical, pathophysiological and neuroimaging aspects of these four prevalent causes of dementia.
Introduction As the World’s population ages, the number of people with chronic health problems and degenerative disorders will continue to increase. Amongst them, dementia stands out as one of the most challenging public health issues of the XXI century. The prevalence of dementia practically doubles every 5 years after the age of 65, affecting as many as 1 in 3 people after the age of 80 years. Current estimates suggest that by 2030 there will be 63 million people with dementia worldwide, but our societies remain largely unprepared to deal with the devastating personal, social and financial impact of such an epidemic. What is Dementia? Dementia is a clinical syndrome characterised by deficits in multiple cognitive domains, changes in behaviour and functional deterioration. The ICD-10 definition of dementia states that ‘dementia is a syndrome due to disease of the brain, usually of a chronic and progressive nature, in which there is disturbance of multiple higher cortical functions, including memory, thinking, orientation, comprehension, calculation, learning capacity, language, and judgement. Consciousness is not clouded. Impairment of cognitive function is commonly
accompanied, and occasionally preceded, by deterioration in emotional control, social behaviour, or motivation’ (Who, 1992). The assessment of people who present for the investigation of a possible dementia syndrome includes six key-aspects: (1) clinical history, (2) cognitive function, (3) behaviour, (4) functional and social capacity (including evaluation of carer stress), (5) physical examination, and (6) investigations. The information collated as a result of such an assessment should enable the clinician to confirm or discard the diagnosis of dementia, determine the most likely cause of the syndrome, and devise a suitable management plan. The sections below briefly describe the key clinical and pathological aspects of the four most frequent causes of dementia. Alzheimer’s Disease Alzheimer’s disease (AD) is the name given to a progressive neurodegenerative condition that leads to irreversible cognitive decline, impaired activities of daily living and a range of behavioural and psychological symptoms. AD is the most frequent cause of dementia, accounting for approximately 50-60% of all cases. Surprisingly, until the early 1970s AD was considered to be a rare disease that affected mostly people in their 40s and 50s, whilst the most common form of ‘senile dementia’, which affected pri433
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Table 1 Diagnostic criteria for Alzheimer’s disease according to NINCDS-ADRDA (adapted and simplified)
Probable • Diagnosis of dementia confirmed by clinical examination and documented by objective cognitive testing (such as with the Mini-Mental State Examination) • Cognitive deficits apparent in at least two areas of cognitive function • Progressive cognitive decline, including worsening of memory deficits • Absence of impaired consciousness • Onset of symptoms between ages 40 and 90 years, most often after age 65 • Absence of systemic or brain disorders that could account for the symptoms The diagnosis of probable AD is supported by: • Progressive deterioration of specific cognitive deficits (e.g., aphasia, agnosia, apraxia) • Deterioration in activities of daily living or behaviour • Family history • Normal CSF exam • Non-specific EEG changes • Structural brain imaging evidence of progressive cerebral cortical atrophy The diagnosis of probable AD is consistent with: • Plateau period in the course of the illness • Presence of psychological and behavioural symptoms and disorders, including depression, delusions, hallucinations, agitation, insomnia, catastrophic reactions, loss of weight, as well as neurological signs and symptoms such as increased muscle tone, myoclonus, disturbances of gait, etc • Seizures in patients with severe dementia • Normal brain imaging for age The diagnosis of probable AD is uncertain in the presence of: • Rapid or abrupt onset of symptoms • Focal neurological signs or symptoms • Seizures occurring early in the course of the illness Possible • Diagnosis of dementia • Clinical presentation, onset and course of symptoms is not typical • Dementia is associated with other neurological disorders that could lead to dementia, but are considered not to be responsible for the presenting symptoms • Cognitive deficit restricted to one cognitive domain, but no other cause for the deficit can be identified Definite • Probable AD and histopathological evidence of AD Adapted from McKhann et al. (1984)
marily older people, was thought to be due to atherosclerosis of the blood vessels of the brain. This view was challenged by the seminal neuropathological study of Tomlinson et Al 38. They found that patients with senile dementia displayed exactly the same brain abnormalities as patients with AD, which led to the subsequent expansion of the concept of AD. The diagnosis of AD continues to be based on the clinical assessment of patients, as diagnostic markers remain elusive. The NINCDS-ADRDA criteria is the most widely used to determine the diagnosis of AD 30, which can be established at 3 different levels of certainty. ‘Definite AD’ requires the clinical diagnosis and neuropatho434
logical confirmation, ‘probable AD’ is used to describe typical cases when histopathological confirmation is not available, and ‘possible AD’ indicates the presence of atypical clinical features in the absence of any other alternative clinica or histopathological diagnosis (table 1). The sensitivity and specificity of the clinical diagnosis of AD is approximately 80-90% when the neuropathological diagnostic criteria for AD are used as the gold standard 8. Typically, patients with AD show impaired ability to learn and retain new information (often referred to as impaired short-term memory). As the disease progresses, the memory deficits tend to become more pronounced and wide-
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spread leading to increasing difficulty to recall learnt material (often referred to as impaired long-term memory). The language deficits (receptive, conductive or expressive aphasia) may also become more prominent with time and are commonly accompanied by impairment in other cognitive domains: apraxia (impaired ability to execute coordinated and purposeful movements), agnosia (impaired ability to attribute appropriate meaning to perception), executive dysfunction (impaired ability to plan, sequence, organise, infer, generalise, categorise, etc.), visuospatial difficulties, agraphia and dyscalculia, among others. Motor, sensory and gait disturbances, as well as seizures, are uncommon until the later stages of the illness. In addition to the cognitive deficits, AD is associated with progressive functional decline and an array of behavioural and psychological disturbances. Performing complex daily activities, such as shopping or controlling one’s finances, becomes increasingly more difficult with time until even the most basic activities can no longer be performed without assistance (for example, eating, grooming, using the toilet). These functional deficits can be further complicated by the presence of psychotic symptoms, depression, agitation, changes in sleep and eating habits, personality changes, and disturbances of psychomotor activity (such as wandering). Behavioural and psychological symptoms (BPSD) affect almost all patients with AD at some point during the course of their illnesses 7. The diagnostic workup of a patient with suspected AD includes a number of investigations that aim to identify potential contributing factors or alternative causes of the dementia syndrome. These routinely include thyroid function tests, folate (often red cell folate) and B12 concentrations, full blood count, urea and electrolytes, liver function tests, fasting glucose and, if appropriate, syphilis and HIV serology, screening for heavy metals, and test for the presence of the 14-3-3 protein in the cerebrospinal fluid (a positive test is consistent with the diagnosis of Creutzfeldt-Jakob disease – CJD). Neuroimaging plays an important role in the investigation and diagnosis of AD, particularly by excluding alternative causes of dementia. The findings of structural imaging (magnetic resonance imaging – MRI and computed tomography – CT) may not be particularly informative in the early stages of the illness, but evidence of progressive generalised cerebral cortical atrophy is supportive of the diagnosis
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of AD. Atrophy of medial temporal lobe structures seems to occur early in the course of the illness 21 and new computerised methods enable us to visualise those changes using overlapping scans 14. Single photon emission computed tomography (SPECT) and positron emission tomography (PET) of patients with AD often reveals a pattern of temporo-parietal hypometabolism. New PET procedures using tracers that bind to beta-amyloid (a constituent of the senile plaques found in the brains of people with AD) may offer further information to facilitate the early diagnosis of AD 21, although the specificity and sensitivity of such an approach remain to be established. The pathophysiological mechanisms underlying the development of AD are complex and seem likely to involve environmental as well as biological factors. Several mutations to the amyloid precursor protein gene (chromosome 21), presenilin 1 gene (chromosome 14) and presenilin 2 gene (chromosome 1) have been associated with autosomal dominant familial AD with early onset (i.e., before age 65 years). However, these mutations account for less than 1% of all cases of AD. A particular polymorphism of the apolipoprotein E gene (presence of the e4 allele) has been associated with increased risk of AD, particularly before age 70 years 5. The most popular theory to explain the pathogenesis of AD suggests that this increased genetic vulnerability favours the abnormal accumulation of the beta-amyloid peptide (Aß), which is believed to have neurotoxic properties and to contribute, by an as yet unknown mechanism, to the abnormal phosphorylation of a microtubule associated protein known as ‘tau’. The accumulation of Aß contributes to the formation of senile plaques, whereas the phosphorylation of tau leads to the development of paired helical filaments and, ultimately, neurofibrillary tangles and neuronal death 19. Senile plaques, neurofibrillary tangles and neuronal loss are the key-neuropathological abnormalities observed in the brains of patients with AD. The approach to the treatment of patients with AD can be divided into three areas: treatment of the cognitive deficits, management of the BPSD, and preventive strategies. Cholinesterase inhibitors (donepezil, rivastigmine and galantamine) and memantine are the only approved options for the treatment of the cognitive deficits of AD at present. These agents have modest but well-established efficacy, and questionable cost-effectiveness (AD2000 Collaborative Group 4,35) (table 2). There is only 435
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Table 2 Medications currently in use for the clinical treatment of Alzheimer’s disease
Donepezil
Rivastigmine
Galantamine
Memantine
Time to top serum concentration (hr)
3-5
0.5-2
0.5-1
3-7
Absorption affected by food
No
Yes
Yes
No
Serum half-life (hr)
70-80
2
5-7
60-80
Protein binding (%)
96
40
0-20
45
5 mg daily – 10 mg daily
1.5 mg twice daily – 6 mg twice daily
4 mg twice daily – 12 mg twice daily
5 mg daily – 10 mg twice daily
Dose (initial - maximum) Modified from Cummings, 2004.
limited systematic data available to guide the management of the behavioural and psychological symptoms associated with dementia, with most published trials being restricted to the investigation of antipsychotic medications. A recent systematic review concluded that there is sufficient evidence in support of the efficacy of olanzapine and risperidone for the treatment of BPSD, although these agents do not seem to be more efficacious than haloperidol 9 . Worryingly, however, treatment of patients with atypical antipsychotic agents is associated with a small increase in the risk of stroke (24% vs 0.5-2% for placebo). Data on other antipsychotic agents remains too sparse to guide evidence-based practice. There are no established interventions to prevent or reduce the rate of progression of AD. The excitement and hope surrounding the introduction of the Aß vaccine was dashed by poor safety outcomes, which included severe encephalitis and several cases of death, and to the observation that those who survived experienced no obvious clinical benefit from the procedure 33,16. Similarly, the use of estradiol replacement therapy, with or without progestin, does not decrease the risk of AD in women – to the contrary, the results from the Women Health Initiative Study have shown that women treated with hormone replacement therapy are more likely to develop dementia over a 5-year period than women treated with placebo 2,36. The potential usefulness of other preventive strategies remains to be established (e.g., treatment of hypertension, use of statins to reduce total cholesterol, lowering of total plasma homocysteine with B-vitamins, physical activity, etc.). 436
Vascular & Mixed Dementia Vascular dementia (VD) is considered the second most frequent cause of dementia in Western societies, accounting for approximately 20% of all dementia cases. The current concept of VD is based on the assumption that progressive cerebrovascular disease or discrete strokes can lead to cognitive impairment and dementia. As such, both the ICD-10 and DSM-IV classification systems require clinical (e.g., unilateral spastic weakness of the limbs, unilaterally increased tendon reflexes, extended plantar response, pseudobulbar palsy, etc.) and laboratory (imaging) evidence of cerebrovascular damage that is considered to be aetiologically related to the dementia. But the boundaries of what is called vascular dementia are contentious, with some authors being restrictive (i.e., diagnosis only made in association with a discrete stroke or series of strokes) and others inclusive in their diagnostic approach (including poststroke dementia, multi-infarct dementia, subcortical ischaemic vascular dementia, strategic infarct dementia, hypoperfusion dementia, haemorrhagic dementia, dementia caused by specific arteriopathies, mixed AD + VD, vascular mild cognitive impairment). To complicate things further, poststroke dementia is not consistently associated with the diagnosis of VD. In fact, AD alone or mixed dementia (AD+VD) account for 20-60% of all cases of poststroke dementia 24. Conversely, numerous communitydwelling older adults display neuroimaging findings indicative of previous strokes that are both clinically and cognitively silent. In other words, making the link between cerebrovascular lesions and dementia is not simple.
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During the past few years, a growing body of evidence has emerged in support of a strong association between AD and cerebrovascular disease, with some authors suggesting that mixed AD + VD might account for 70% of the cases of dementia in Western societies 13. For example, stroke and AD have numerous overlapping risk factors (increasing age, hypertension, diabetes, high plasma homocysteine, APOE4 genotype, smoking, sedentary lifestyle, high serum cholesterol, low educational attainment, etc.) and evidence from the Nun Study suggests that the clinical expression of AD is modulated by cerebrovascular burden – i.e., the greater the number of cerebrovascular lesions, the lower the number of plaques and tangles required for AD symptoms to become apparent 37. The management of VD can be divided into symptomatic and preventive. At present, symptomatic treatment is based on the off-label use of cholinesterase inhibitors. Two large randomised placebo controlled trials of donepezil for the treatment of VD are available. Their results indicate that 24-week treatment with donepezil is associated with improved cognitive function, clinical global impression and activities of daily living in patients with mild to moderate dementia 27. The evidence in support of the use of rivastigmine and galantamine remains inconclusive 10. Likewise, there is currently no evidence that memantine might be useful for the treatment of patients with VD 31. Vascular dementia seems
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a particularly suitable target for preventive strategies. There is currently no compelling evidence from clinical trials that the management of risk factors for cardiovascular disease can in fact prevent VD, but there is good reason to believe that this would be a sound public health strategy to pursue (i.e., smoking cessation, physical activity, healthy diet, and treatment of hypertension, diabetes and hyperlipidemia). Secondary preventive strategies are starting to emerge, and preliminary results look promising. Antiplatelet therapy with clopidogrel or aspirin as well as the lowering of cholesterol concentrations with statins are associated with a relative risk reduction of recurrent strokes of approximately 20% 18, whereas lowering blood pressure by 10 mm Hg is associated with a relative risk reduction of strokes of 30% 23. It is unclear, however, if this risk reduction of strokes is associated with a similar reduction in the risk of VD. Finally, decreasing plasma homocysteine by using B-vitamins does not seem to decrease the risk of strokes, and there is now concern that B-vitamin supplementation may in fact cause harm 6,25. Dementia with Lewy Bodies The intracytoplasmic inclusion described by Friedrich Lewy in the early 1900s was initially observed in the basal forebrain of patients with
Table 3 Consensus criteria for the diagnosis of dementia with Lewy bodies
Description The progressive cognitive decline is of sufficient magnitude to interfere with normal social or occupational function. Memory deficits may not occur in the early stages of the illness, but become usually evident with its progression. Deficit in attention, fronto-subcortical and visuospatial skills may be prominent. Core features (at least 2/3) • Fluctuating cognition with pronounced variations in attention and alertness. • Recurrent visual hallucinations, which are typically well formed and detailed • Spontaneous motor features of parkinsonism Supportive features include • Repeated falls • Syncope • Transient loss of consciousness • Neuroleptic sensitivity (potentially severe adverse reactions) • Systematised delusions • Hallucinations in modalities other than visual • Depression • REM sleep behaviour disorder Adapted from McKeith et al., 1996
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Table 4 Consensus criteria for the diagnosis of frontotemporal dementia Lund and Manchester Groups, 1994 (modified and simplified)
Clinical presentation: changes in character and disordered social conduct are the dominant features initially and throughout the course of the illness Core diagnostic features: • Insidious onset and gradual progression • Early decline in social and interpersonal conduct • Early impairment in the regulation of personal conduct • Early emotional blunting • Early loss of insight Supportive diagnostic features Behavioural • Decline in personal hygiene and grooming • Mental rigidity and inflexibility • Distractability and impersistence • Hyperorality and dietary changes • Perseverative and stereotypical behaviour • Utilization behaviour Speech and language • Altered speech output • Stereotypy of speech • Echolalia • Perseverative speech • Mutism Physical signs • Primitive reflexes • Incontinence • Akinesia, rigidity and tremor • Low or labile blood pressure Investigations • Cognitive tests: impaired executive (frontal) function and relatively well preserved memory and visuospatial abilities • Electroencephalography: normal • Brain imaging (structural of functional): predominant frontal or anterior temporal abnormalities
Parkinson’s disease (PD). It was not until the late 1970s that reports of dementia associated with cortical Lewy bodies became more frequent and ultimately led to the systematic description of a subtype of dementia known as ‘dementia with Lewy bodies’ (DLB). Consensus diagnostic guidelines were published in the mid 1990s 29 (table 3) and have been widely adopted in research, although cases of DLB would be labeled as AD, dementia in PD or unspecified dementia according to ICD-10 or DSM-IV, as there is no specific category for DLB in these diagnostic systems. The relationship between DLB and dementia in PD remains to be clarified. DLB is thought to account for 10-20% of all cases of dementia. From a pathophysiological point of view, Lewy bodies are associated with abnormalities of the α-synuclein protein. 438
α-synuclein immunochemistry is now available for neuropathological studies 17. Neuroimaging findings provide a valuable aid to the diagnosis of DLB. In contrast to AD, structural MRI of patients with DLB shows relatively well preserved medial temporal lobe structures. In contrast, functional imaging (PET or SPECT) of patients with DLB shows profound occipital hypometabolism that appears to affect the primary visual cortex and associated areas 32. Numerous reports have suggested that patients with DLB benefit from treatment with cholinesterase inhibitors, but systematic evidence remains scant. The results of a randomized placebo controlled trial of rivastigmine for the treatment of 120 patients with DLB showed a decrease in the intensity and severity of behavioural symptoms at the end of 20
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weeks, but no obvious cognitive gain compared to placebo 28. Frontotemporal Dementia Frontotemporal dementia (FTD) is a generic label given to a group of non-AD and non-Parkinson neurodegenerative disorders that, as the name suggests, affects primarily the frontal and temporal lobes. Changes in behaviour are prominent amongst patients with FTD and may be the most obvious clinical feature throughout the course of the illness. Language and executive function deficits are often apparent and appear in association with focal neurological signs, structural imaging evidence of focal atrophy of the frontotemporal lobes, and SPECT/PET demonstration of marked hypometabolism of anterior brain structures. FTD is a relatively uncommon type of dementia, with an estimated prevalence of 15 cases per 100,000 people aged 45 to 64 years 34. Most cases of FTD have onset between ages 45 and 65 years, with the condition affecting both sexes equally. Approximately 50% of patients report a positive family history of FTD or FTD-spectrum disorder. The diagnosis of FTD is not used consistently in clinical practice or in research, although consensus criteria with good sensitivity and specificity are available (table 4). The closest ICD-10 and DSM-IV diagnoses for FTD would be dementia due to Pick’s disease, but many patients with FTD would need to be classified as suffering from ‘unspecified dementia’. FTD is part of the frontotemporal lobe degenerative disorders that include primary progressive aphasia (PPD)(mostly limited to the left frontotemporal lobes) and semantic dementia (SD)(mostly limited to the temporal lobes). FTD, PPD and SD share a number of histopathological features, including tau pathology. The latter can lead to the formation of Pick’s bodies (intracytoplasmic inclusion) and Pick’s cells, or to the development of tangles. It is now known that those pathological changes arise in association with
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mutations to the tau gene on chromosome 17 in cases of familial FTD 20. Sporadic and familial cases have similar clinical phenotypes, although some reports suggest that certain phenotypes resembling progressive nuclear palsy (PSP) and cortical basal degeneration (CBD) may arise as a result of specific mutations. There is currently no pharmacological treatment for FTD. A handful of small trials investigating the clinical usefulness of selective serotonin reuptake inhibitors (SSRI) have produced inconclusive results (FTD is associated with abnormalities in the metabolism of serotonin, most likely leading to hyperactivity rather than underactivity of the serotonin system) 15. Conclusions Dementia is one of the most important and challenging health problems of this century. Numerous diseases and conditions can lead to the development of dementia 2,3, although the clinical syndromes described under the headings of AD and VD comprise, together, approximately 70% of all cases. Advances in genetics and molecular biology have led to the tentative separation of the most frequent types of neurodegenerative dementias into three groups, according to abnormalities in the metabolism of Aß (AD-related disorders), α-synuclein (DLB, PD and dementia associated with PD) and tau (FTD, SD, PPA, PSP, CBD and motor neuron disease). Progress in structural and functional neuroimaging has also contributed to the better delineation of these clinical syndromes, although we have not as yet succeeded in translating this growing body of knowledge into effective treatments. Acknowledgements The drafting of this paper was partly supported by a project grant from the National Health and Medical Research Council of Australia (NHMRC project grant 403996).
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Prof. Osvaldo P. Almeida Unit of Geriatric Psychiatry (M573) University of Western Australia 35 Stirling Highway - Crawley - Perth Western Australia 6009 Australia Email: [email protected]
