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Dementia
BASIC INFORMATION
DEFINITION
Dementia means loss of mental functions. It is a syndrome of acquired and persistent cognitive decits that includes memory impairment in association with impairments in abstract thinking, judgment, or other disturbances of higher cortical function (e.g., aphasia, apraxia, agnosia, executive functioning) or personality change. The disturbances are severe enough to interfere signicantly with work, usual social activities, or relationships with others. Dementia is not diagnosed if the symptoms occur exclusively in the context of delirium. It must be an acquired loss of function, and hence is distinguished from developmental disorders such as mental retardation. Dementia can have many etiologies, as will be noted. (Adapted from DSM-III-R and DSM-IV.) ICD-9CM CODES 290.0 Senile dementia, uncomplicated DSM-IV: Dementia of the Alzheimers type, late onset 290.1 Presenile dementia DSM-IV: Dementia of the Alzheimers type, early onset, uncomplicated 290.4 Arteriosclerotic dementia DSM-IV: Vascular dementia 294.1 Dementia in conditions classied elsewhere (code rst underlying physical condition, e.g., listed as follows) DSM-IV: Dementia due to: 331.0 Alzheimers disease 331.82 Dementia with Lewy bodies 331.19 Frontotemporal dementia 310.1 Mild memory disturbances, not amounting to dementia, associated with senile brain disease 294.9 Unspecied organic brain syndrome (chronic) DSM-IV: Cognitive Disorder NOS proximately 2% at age 65 and 34% to 68% at age 85 and older. PREDOMINANT ETIOLOGY: Alzheimers disease (AD) is by far the most common cause of dementia. Approximately 55% to 70% of all dementias have a signicant contribution from Alzheimers pathology and approximately 35% of all dementias may be attributable to pure AD. Vascular dementia and dementia with Lewy bodies are thought to be the next most common etiologies. Prevalence rates of dementia etiologies vary across ethnic groups. PREDOMINANT SEX: Varies by dementia diagnosis; AD is more common in females; vascular dementia and dementia with Lewy bodies is more common in males; frontotemporal dementia appears to occur equally in males and females. PREDOMINANT AGE: Incidence and prevalence increase over age 65 and are highest at age 85 and older; average age of onset is younger in frontotemporal dementia and some relatively rare, familial subtypes of AD (see as follows). PEAK INCIDENCE AND PREVALENCE: Age 85 and older. GENETICS: First-degree relatives may be at increased risk for certain types of dementia (e.g., AD, frontotemporal dementia); apolipoprotein 4 allele is a genetic risk factor for AD but is not diagnostic. Genetic disorders causing dementia include Huntingtons disease, CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), and early-onset familial AD. Some forms of frontotemporal dementia have genetic linkages. Genetics and family history: Risk of AD is about four times greater in patients with a rst-degree relative with AD. ApoE 4 allele on chromosome 19 increases risk of AD and shifts age of onset 3 to 7 years earlier than in those with sporadic onset who do not have an 4 allele; risk is further increased in presence of rst-degree relative with AD. Approximately 2% of AD cases are early-onset familial AD related to mutations in either chromosome 14 (presenilin 1), 1 (presenilin 2), or 21 (amyloid precursor protein). Almost all patients with Down syndrome will develop AD pathology after age 40. Key cognitive features: Memory impairment is cardinal feature; impairment in language, visuoconstructional ability, executive functioning, and other cognitive domains follows. Motor and sensory function generally intact until late stages. Neurologic features: Normal exam early. Later stages can be associated with extrapyramidal or parkinsonian features. Impairment in gait, speech, urinary and fecal continence, and reemergence of primitive reexes may occur in nal stages. Key neuroimaging features: Useful for ruling out alternate (e.g., neoplasm, hydrocephalus) or concomitant (e.g., vascular lesions) causes of dementia. MRI may reveal diffuse cortical atrophy with ex vacuo ventricular enlargement particularly in temporal horns of lateral ventricle due to hippocampal volume loss; severity of imaging ndings generally increases with severity of dementia. Temporoparietal hypometabolism on SPECT or PET. Neuroimaging is not diagnostic. Course: Insidious onset with gradual progression; memory is usually rst symptom. Average survival is about 8 years depending on age at diagnosis and concomitant medical conditions; survival may be up to 20 years. VASCULAR DEMENTIA (VAD) Prevalence: VaD is the second or third most common cause of dementia, accounting for about 10% to 30% of all dementia cases; prevalence increases with age; more common in men. Core features: Focal neurologic signs/symptoms. Neuroimaging evidence of cerebrovascular disease.

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PHYSICAL FINDINGS & CLINICAL PRESENTATION

See Fig. 1-13. Physical ndings and clinical presentation differ across dementia etiologies.

ETIOLOGY
ALZHEIMERS DISEASE Prevalence: AD is the most common cause of dementia; contributes to dementia in approximately 55% to 70% of all cases; pure AD accounts for approximately 35% of all cases. Core features: Gradually progressive memory impairment with insidious onset. Impairment in executive function, spatial abilities, and language follow later. Behavioral dysregulation may also occur later. Pathology: Extraneuronal plaques (protein: amyloid-42). Intraneuronal neurobrillary tangles (protein: hyperphosphorylated form of tau). Denitive diagnosis requires clinicopathologic correlation.

SYNONYMS
Senile dementia Presenile dementia Senile psychosis

EPIDEMIOLOGY & DEMOGRAPHICS

INCIDENCE: Annual dementia incidence rate approximately doubles every 5 years after age 65; approximately 7 to 9 per 1000 at age 65-69 and 85 to 118 per 1000 at age 85 and older. PREVALENCE: Approximately 8% to 10% of U.S. population (4 million to 6 million) above age 65 have dementia; prevalence approximately doubles every 5 years after age 65; prevalence is ap-

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Dementia
Cognitive complaint/symptom

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Section I

Clinical hx Physical and neuro exam MSA and behavior assmt Labs and imaging Reversible causes

DISEASES AND DISORDERS

Within normal limits

Objective cognitive/behavioral dysfunction

Equivocal

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Normal aging Age-associated cognitive decline Possible MCI

Neuropsychology Psychiatric Other explanations

Possible dementia

Neuropsychological assessment for diagnosis, etiology, baseline for future comparison

FIGURE 1-13

Specific diagnosis/probable etiology

Evaluation of dementia. ADLs, Activities of daily living

Impairment in executive functioning, speed of mental processing, with relatively mild memory decits in most cases (particularly true for VaD due to microvascular disease). Apathy may be prominent. Pathology: VaD can result from largevessel or small-vessel disease or a combination of the two. Most VaD cases are caused by small-vessel disease. Mendez and Cummings (2003) identify three main pathologic mechanisms of VaD: Large-vessel (macrovascular) VaD typically arises from multiple bilateral thromboembolic infarctions; involvement of cortical regions. Small-vessel (microvascular) VaD typically arises from arteriosclerotic changes in subcortical arteries causing injury to periventricular and deep white matter and to subcortical grey nuclei (e.g., caudate, putamen, and thalamus). The injuries include complete infarction (i.e., lacunar infarction) and incomplete infarction that appear as diffuse white matter lesions on neuroimaging (i.e., hyperintense on T2 MRI sequences; hypodense on CT). In some cases, a single strategic small-vessel infarction in a critical circuit (e.g., left thalamus) may cause multiple cognitive decits of sufcient

severity to warrant a diagnosis of dementia. Diffuse white matter lesions may also cause dementia, if sufciently extensive (i.e., involves 25% of white matter). Episodes of hypoperfusion hypoxia. Genetics and family history: Increased risk with family history of stroke. Genetic causes are relatively rare; CADASIL is one cause of dementia due to microvascular disease; it is autosomal dominant and linked to mutation in the notch3 gene on chromosome 19. Key cognitive features: When due to multiple cortical infarcts, the pattern of cognitive impairment may vary depending on location of infarcts (e.g., language decits from left hemisphere lesion, spatial decits from right hemisphere lesion). Subcortical ischemic vascular disease is characterized by decits in psychomotor processing speed, mental exibility, executive function, and memory retrieval. Single subcortical strategic infarct (i.e., anterior thalamus) may be sufcient to cause widespread cognitive dysfunction and dementia. Apathy may be prominent.

Neurologic features: Focal neurologic signs or symptoms (e.g., exaggerated deep tendon reexes, extensor plantar response, spastic limb weakness) that vary with location and size of lesions. Key neuroimaging features: Evidence of cortical or subcortical infarction. Diffuse areas of high signal on T2weighted MRI (low signal on CT), particularly in periventricular and deep white matter regions. Clinical or radiologic evidence of cerebrovascular disease required for diagnosis. Absence of cortical or hippocampal atrophy adds condence to differential diagnosis of VaD vs. AD. Course: Difcult to predict. May have abrupt onset with stepwise course. Onset and course may be more gradual, especially when due to subcortical small-vessel disease. Onset and progression may be gradual with punctuated declines associated with discrete cerebrovascular events. High mortality rate and lower life expectancy than AD; 50% survival rate from symptom onset is about 6.7

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Mild deficits, ADLs generally intact

At least mild deficits in memory and other cognitive domains, clear impact on ADLs

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Dementia
years; heart disease or stroke is common cause of death. DEMENTIA WITH LEWY BODIES (DLB) Prevalence: Second or third most common cause of dementia; accounts for approximately 14% to 20% of all dementia cases. Almost two thirds are male. Majority do not have pure DLB but also have concomitant AD pathology. Core features: Parkinsonism Cognitive uctuations Visual hallucinations (occur in 40% to 70% of cases) Usually vivid, well-formed of humans or animals Dementia plus two core features are needed for diagnosis of probable DLB; one core feature is needed for possible DLB. Other supportive features: Repeated falls Syncope; transient loss of consciousness Delusions Rapid eye movement (REM) sleep behavior disorder Neuroleptic sensitivity Pathology: Lewy body inclusions (protein: mainly -synuclein, but ubiquitin and tau are also present) in diffuse brain regions including cortical neurons. Genetics and family history: No genes identied in sporadic DLB cases. A rare autosomal dominant form exists related to mutations in -synuclein gene on chromosome 4. Key cognitive features: Marked attentional uctuations. Frontal-executive dysfunction. Prominent visuospatial impairment. Decits occur in memory, confrontational naming, and praxis; may not be as severe as in AD. Neurologic features: Extrapyramidal signs present in 25% to 50% at diagnosis and most develop it over disease course. Up to 25% of autopsy-conrmed cases may not have report of extrapyramidal symptoms. Axial bias to symptoms; i.e., greater postural instability, gait impairment, and facial impassivity and relatively less tremor than in Parkinsons disease. Key neuroimaging features: Less pronounced hippocampal/medial temporal lobe atrophy compared with AD. Quantitative volumetric measurements may show atrophy of putamen. Neuroimaging not diagnostic. Course: Initial symptoms could be parkinsonism followed by cognitive impairment or the opposite: cognitive symptoms followed by parkinsonism. Shorter survival times than AD; about 7.7 3.0 years from onset of cognitive symptoms. FRONTOTEMPORAL DEMENTIA (FTD) Prevalence: Accounts for approximately 2% to 5% of all dementia cases. Accounts for 20% of neurodegenerative dementias in people under 65 years old. Average age of onset is 57 years with a typical range of 51 to 63. Core features: Personality changes are most prominent symptom and typically precede cognitive changes: Decline in social comportment Impaired regulation of personal conduct May become disinhibited but are more likely to display apathy Lack of attention to personal hygiene can be supportive of diagnosis Pathology: FTD is the main syndrome of frontotemporal lobar degeneration (FTLD)a spectrum of dementing disorders involving degeneration of the frontal and anterior temporal lobes. Mendez and Cummings (2003) describe three main pathologic variants of FTD: Lacking distinctive histology (FTLDldh): neuronal loss, astrogliosis with spongiosis in frontotemporal cortex Pick bodies (FTLD-Pick): severe frontal atrophy (knife-like gyri); enlarged neurons called Pick cells and neuronal Pick body inclusions (tau-positive, ubiquitin-positive); FTLD-Pick is diagnosed when Pick bodies are present irrespective of presence of Pick cells Motor neuron disease (MND): involvement of anterior horn cells with or without ubiquitin inclusions Genetics and family history: 38% to 50% of cases have positive history of similar dementia in rst-degree family member. Several mutations in tau gene have been found in familial FTD. Some cases associated with mutations on chromosome 17; linkage to chromosome 3 in some families; presenilin 1 may be involved in some phenotypes. Key cognitive and behavioral features: Early blunting of emotional responsiveness; loss of basic emotions. Executive cognitive impairment prominent. Compulsive behaviors are common: Klver-Bucy syndrome may occur: emotional blunting, reduction or loss of fear responding, oral exploration of the environment with dietary preference alterations, hypermetamorphosis (exploration of environmental stimuli as soon as noticed), sensory agnosia, altered sexual behavior. Reduction of verbal output. Pattern of memory decits suggests retrieval impairment rather than storage impairment characteristic of AD. Neurologic features: Neurologic features may be absent early with exception of primitive (frontal release) reexes (grasp, snout, suck). Parkinsonism may be present; may precede dementia and may resemble progressive supranuclear gaze palsy; fasciculations may occur. Urinary or fecal incontinence may occur later. Key imaging features: MRI might not be sensitive to early changes; the majority of patients will eventually show anterior-posterior asymmetry of cortical atrophy, being greater in frontal and anterior temporal lobe regions than in posterior brain regions. SPECT reveals frontotemporal hypometabolism Neuroimaging not diagnostic by itself. Course: Initial and most prominent symptoms are usually changes in personality, social awareness, and behavior, especially disinhibition or apathy. Mean age of onset is 57 years with a range of 51 to 63 years. Duration is typically 8 to 11 years; may be shorter in MND variant. MISCELLANEOUS CAUSES OF DEMENTIA Toxic-metabolic etiologies (4%, including alcohol, recreational drugs, medications); infectious (3%); other movement disorders (6%, e.g., Parkinsons disease, progressive supranuclear palsy, Huntingtons disease, corticobasal degeneration); normal pressure hydrocephalus (2.5%); other psychiatric (4%); and miscellaneous (1%, e.g., dementia due to AIDS, head trauma) POTENTIALLY REVERSIBLE CAUSES OF DEMENTIA Medication toxicity/drug interactions; hydrocephalus; brain tumor; infection; electrolyte imbalance; malnutrition; metabolic (i.e., B12 deciency, hepatic encephalopathy); and endocrine disorders (i.e., hypothyroidism) COGNITIVE CHANGES IN NORMAL AGING General slowing of mentation and physical responses; declines occur in complex and divided attention, ability to recall names, executive and visuospatial functions; reduced efciency in learning and spontaneous recall of

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Dementia
new information but memory storage is maintained. Terms used to describe cognitive changes in aging: normal aging, ageassociated cognitive decline, age-associated memory impairment. MILD COGNITIVE IMPAIRMENT (MCI) MCI is a syndrome (not an etiology) dened by subjective and objective impairment in memory or other cognitive domains that represents a decline and is greater than expected for age, but is of insufcient severity to signicantly affect activities of daily living or to warrant a diagnosis of dementia. The term mild cognitive impairment is often used to describe this period, but the term is not universally accepted and alternatives have been proposed (e.g., cognitive impairment no dementia). Diagnostic criteria for MCI were developed based on those at high risk for AD. Criteria include subjective memory complaint, objective memory impairment for age/education on formal testing; generally intact global cognitive functioning; generally persevered daily functioning; and no dementia. These criteria are now thought to describe amnestic MCIa group with an approximately 12% annual rate of conversion to AD (vs. 1% to 2% for normal elderly). Current MCI conceptualization includes other subtypes that might go on to develop different types of dementia. Patients with aphasia are more likely than dementia patients to recognize and respond to what is happening around them; and to remember people, places, and routines. DEMENTIA VS. DEPRESSION Depression with cognitive impairment is common in the elderly and may be a risk factor for dementia. Moreover, depression occurs in 12% to 20% of patients with dementia. Cognitive decits: attention, psychomotor processing speed, executive functioning, and memory retrieval; may reect reduced concentration, loss of interest, and motivation. Neuropsychologic testing may be helpful. Depressed patients are likely to benet from cueing and recognition formats during memory testing, whereas AD patients do not. Follow-up assessment after a period of treatment may be needed to rule out dementia. DEMENTIA VS. DELIRIUM Delirium generally has a more rapid onset than dementia. Marked attentional disturbances/ uctuations are more common in delirium. Delirium can be superimposed on a preexisting dementia or mild cognitive impairment. NORMAL AGING VS. MCI The key judgments are whether the complaints and severity of cognitive impairment represent a decline that exceeds normal aging; the extent to which the impairments disrupt normal functioning; and whether they are better explained by psychiatric disorder, substance abuse, medication effects, situational stressors, or other nonneurodegenerative etiologies. Neuropsychologic testing may be very helpful. MCI VS. MILD DEMENTIA The key judgments are the scope and severity and stability of cognitive or behavioral impairment and the degree to which they affect daily functioning. Neuropsychologic testing may be very helpful. Frontal release signs Apraxias MENTAL STATUS ASSESSMENT (MSA) Evaluate arousal, orientation, attention/mental control, memory, language, conceptual or semantic knowledge, praxis (ability to perform skilled movements, e.g., ask the patient to pretend to light a cigarette), mental calculations, visuoconstructional abilities, executive functions, and behavior. Mini Mental State Exam (MMSE): the most commonly administered formal mental status test; takes 5 to 10 minutes (see Appendix 2); can be supplemented with assessment of executive functions and abstract reasoning. Executive function 1. Alternating gures: copy and continue producing alternating gures (e.g., O O). Look for loss of sequence or perseverations. 2. Alternating movements: place both hands on a table, one in a st, one palm down; then alternate repeatedly. Demonstrate briey and then have the patient continue independently. Look for loss of sequence. Abstract conceptualization: similarities (e.g., How are an apple and a banana alike? include more than one similarity pair e.g., boat-car, watch-ruler, desk-bookcase). Look for concrete responses; differences instead of similarities. Responses can be inuenced by educational and intellectual background. Mini-Cog exam consists of a 3-item memory test and clock drawing; it takes 2 to 3 minutes to administer. It may be as accurate as the MMSE in a primary care setting. Behavior: appearance; mood and affect; level of insight; thought content and process; psychosis; anxiety disorders; sleep and appetite.

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Section I
DISEASES AND DISORDERS

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DIAGNOSIS
Two-step process: 1. Is dementia present? and if so 2. What is the most likely etiology? No denitive test or algorithm for determining the presence or absence of dementia exists; differentiating normal aging from MCI and MCI from mild dementia is difcult.

DIFFERENTIAL DIAGNOSIS
Determining etiology requires careful assessment of cognitive and behavioral symptoms, neurologic features, and the onset and temporal course of illness along with laboratory and neuroimaging assessments. Determining etiology requires differentiating non-AD dementia from AD. DEMENTIA VS. AMNESIA Amnesia is isolated and profound memory impairment; dementia involves multiple cognitive domains. DEMENTIA VS. APHASIA Difcult because many cognitive tests require a strong language component. Nonverbal testing may reveal intact non-language-based cognitive functions.

LABORATORY TESTS
Blood Thyroid panel or thyroid stimulating hormone Complete blood count, vitamin B12, folate Electrolytes, BUN, creatinine Liver function tests Glucose Syphilis or AIDS if high clinical suspicion Other tests directed by differential diagnosis Urinalysis Lumbar puncture: optional; if suspicion of cancer, infectious process, atypical presentation (e.g., rapid progression) EEG: if history of seizures, rapid decline, suspicion of Creutzfeldt-Jacob disease

WORKUP
CLINICAL HISTORY Key symptoms; onset and progression; impact on activities of daily living. Obtain information from a reliable informant. Obtain a medication history and identify those that can disrupt cognition. Screen for depression. Family history of dementia. Review of systems. PHYSICAL AND NEUROLOGIC EXAM General health Focal neurologic signs

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Dementia
Neuroimaging: CT or MRI of the head is appropriate to rule out hydrocephalus, mass lesions, and subdural hematomas and to assess for extent of cortical and subcortical atrophy, and cerebrovascular lesion load; SPECT or PET for cerebral metabolism may be helpful, especially for FTD Use lowest dose needed and try to wean off as soon as possible. Potential increased risk of cerebrovascular accidents. Avoid use of antipsychotics in patients with diffuse Lewy body dementia. Benzodiazepines can occasionally be useful usually as second line therapy. Depression: selective serotonin reuptake inhibitors can be effective for the treatment of coexisting depression among those with dementia. Reduce/control risk factors for cognitive impairment: cerebrovascular risk; medications that may contribute to cognitive impairment; alcohol; depression.

PREVENTION
Reduction of cardiovascular risk factors including treatment of hypertension, hypercholesterolemia, and diabetes. Promoting cognitive exercises and mental activity can help ward off progression. Maintaining a healthy social life.

TREATMENT
NONPHARMACOLOGIC THERAPY
Ensure patient safety: e.g., driving, wandering, cooking, ironing, tool use, medication management, nutrition, hygiene and grooming, nancial management. Establish routines, avoid chaotic or overstimulating environments. Family education. Caregiver support/respite: support groups, daycare, sharing caregiving with other family members. Cerebrovascular risk factor control includes adequate treatment of hypertension, hypercholesterolemia, and diabetes.

DISPOSITION
Deterioration over time is a common feature of most dementias. Goals of currently available treatments are to slow course and maximize functioning. Transition to assisted living facilities may be helpful as dementia worsens; nursing home placement may follow.

PATIENT/FAMILY EDUCATION
Alzheimers Association local support groups can offer useful education for families and caregivers.

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SUGGESTED READINGS
Knopman DS et al: Practice parameter: diagnosis of dementia (an evidence-based review). Report of the quality standards subcommittee of the American Academy of Neurology, Neurology 56:1143-1153, 2001. McKeith I et al: Dementia with Lewy bodies, Lancet Neurol 3:19-28, 2004. Mendez MF, Cummings JL: Dementia: A Clinical Approach, ed 3, Philadelphia, 2003, Butterworth Heinemann. Petersen RC: Mild cognitive impairment as a diagnostic entity, J Intern Med 256:183-194, 2004. Roman GC: Vascular dementia revisited: diagnosis, pathogenesis, treatment, and prevention, Med Clin North Am 86:477-499, 2002. Rosenstein LD: Differential diagnosis of the major progressive dementias and depression in middle and late adulthood: a summary of the literature of the early 1990s, Neuropsychol Rev 8:109-167, 1998. Strub RL, Black FW: The Mental Status Examination in Neurology, ed 4, Philadelphia, 2000, FA Davis. AUTHORS: STEPHEN CORREIA, PH.D., and LYNN MCNICOLL, M.D.

REFERRAL Neuropsychologic

PHARMACOLOGIC THERAPY

Cognitive impairment: Acetylcholinesterase inhibitors (i.e., donepezil, galantamine, rivastigmine) approved for AD; they slow the course of cognitive decline, not disease modifying. May also be useful for vascular dementia. Memantine (NMDA receptor antagonist) for moderate to severe AD. For dementias other than AD, there are few pharmacologic options. Agitation and psychosis: Atypical antipsychotics including risperidone and olanzapine are widely used but not FDA approved.

assessment can help determine presence/absence of dementia and the pattern of cognitive impairment may help identify etiology. Geriatric psychiatry if depression or other psychiatric disturbance is prominent. Neurology referral is necessary to assess general neurologic status, especially if motor, sensory, or gait disturbance is present.

PEARLS & CONSIDERATIONS

Search for and treat potentially reversible causes of dementia. Treat psychiatric disturbances (e.g., depression, agitation, psychosis, but be careful with antipsychotics in DLB).

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