Dementia

Educational Objectives

The goal of this program is to improve the prevention, diagnosis, and treatment of dementia. After hearing and assim­ilating this program, the clinician will be better able to:

1.   Distinguish between the cognitive impairment associated with normal aging, mild cognitive impairment, and dementia.

2.   Assess the differential diagnosis of dementia.

3.   Recognize the relationship between depression and dementia.

4.   Evaluate the patient who presents with depression in mid to late life.

5.   Discuss interventions that could potentially reduce the risk for dementia.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of in­terest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Tariot is a consultant to and/or has received research support from AC Immune, AstraZeneca, Avid, Baxter Healthcare, Eisai, Epix Phrameceuticals, Forest Laboratories, Memory Pharmaceuticals, Myriad Pharmaceuticals, sanofi-aventis, Toyama, Abbott Laboratories, Glax­oSmithKline, Medivation, Merck & Co, Merz, Pfizer, Takeda Pharmaceuticals North America, Wyeth Laboratories, and Elan. He has also received educational fees from Lundbeck. In his lecture, Dr. Tariot discusses the off-label or investigational use of a therapy, product, or device. Dr. Marano and the planning committee reported nothing to disclose.

Acknowledgements

Dr. Tariot was recorded at Unambiguous, Unsurpassable Utterances from Umbelliferous Ubermensch, held November 7-8, 2009, in Madison, WI, and sponsored by the University of Wisconsin School of Medicine and Public Health and the Madi­son Institute of Medicine. Dr. Marano was recorded at 15th Update on the Treatment of Alzheimer’s and Related Disorders: Defining the Standard of Care, held April 4, 2009, in Baltimore, MD, and sponsored by Johns Hopkins School of Medicine and the Johns Hopkins Alzheimer’s Disease Research Center. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

When Should I Worry About Memory?

Pierre N. Tariot, MD, Research Professor of Psychiatry, University of Arizona College of Medicine, and Direc­tor, Memory Disorders Center, Banner Alzheimer’s Institute, Phoenix, AZ

Cognitive impairment associated with normal aging: loss of memory for words and names; slowed processing speed; difficulty sustaining attention when faced with competing environmental stimuli; no functional impairment

Mild cognitive impairment: memory impairment beyond that expected for person’s age; memory impairment in­creasing over last 6 to 12 mo; other cognitive functions generally unimpaired; daily function not significantly im­paired; not dementia; subjective complaint not usually useful (real changes more apparent to others than to self); »80% of people with mild cognitive impairment already have emerging dementia that will convert to frank de­mentia within 5 yr (usually Alzheimer disease [AD]); prediction of who will convert currently difficult, but in near future, biomarkers may be available to accompany clinical assessment; study indicates high level of psycho­pathology (eg, anxiety, irritability, depression, paranoia)

Clinical management: no treatments approved by Food and Drug Administration (FDA); monitor alcohol use, med­ications (eg, analgesics, psychotropics, over-the-counter drugs); provide prophylaxis for cardiovascular risk factors; treat anxiety and affective disorders, but eschew benzodiazepines

Unapproved treatments: acetylcholinesterase inhibitors studied exhaustively; most results negative; some defini­tive studies of donepezil (Aricept) showed positive effect, “but not enough to define practice”; speaker advises discussing both known and unknown effects of acetylcholinesterase inhibitors with patient and family; no other agents (eg, vitamins, memantine) adequately tested or show evidence of benefit

Dementia: syndromal term that refers to loss of cognitive function associated with impaired daily functioning, even­tual marked change in emotions and temperament, and, in late stages, with neurologic dysfunction; of 50 to 100 causes of dementia, AD by far most common

Warning signs of early dementia: difficulty with learning and retaining information, vocabulary, and orientation; trouble with daily tasks; changes that interfere with function; behavior changes (eg, passivity, irritation, suspi­ciousness); concerns should trigger evaluation of cognition, function, and behavior

Barriers to early diagnosis of AD: average time between appearance of initial symptoms and diagnosis of possible dementia »4 yr; average time between diagnosis and initiation of therapy »2 yr; shortness of visits and con­straints on reimbursement most significant barriers

Differential diagnosis: includes AD, vascular dementia, dementia with parkinsonian features, Lewy body dementia, and frontotemporal dementia

Alzheimer disease: insidious onset; relentless progression of cognitive dysfunction (usually, but not always, mem­ory), with subsequent generalization to other domains (eg, language, visuospatial function, executive function, problem-solving, insight, sequencing of events, prioritizing); minimal psychopathology in early stage; no promi­nent neurologic abnormalities

Vascular dementia: risk factors same as those for stroke (eg, heart disease, arrhythmia, congestive heart failure, hy­pertension, dyslipidemia, diabetes, smoking, family history of stroke); history of focal or nonfocal events; focal findings on examination; supported by imaging; imaging reports of “white matter changes consistent with micro­vascular disease” not diagnostic; such changes seen in »80% of normal older individuals; diagnosis difficult; ac­counts for only 5% of patients with dementia; look for pattern of stabilization, decline, stabilization, decline

Dementia with parkinsonian features: requires specialist to distinguish between AD with parkinsonian features, Lewy body dementia, and Parkinson disease with dementia

Lewy body dementia: indicated by slowly progressive, but peculiarly fluctuating course “like … chronic delirium”; characterized by fluctuating cognitive impairment, atypical and nonprogressive parkinsonian features (with onset of dementia after that), and dysautonomia with unexplained falls; hallmark  —  vivid psychopathology with formed hallucinations and/or microhallucinations

Frontotemporal dementia: early but mild cognitive impairment; hallmark  —  marked change in personality or lan­guage

Evaluation of possible dementia: patient history; differential diagnosis (looking at cognition, function, and behav­ior); Mini-Mental State Examination (MMSE); category retrieval; clock draw (patient asked to draw clock set to, eg, 11:10); complete blood count; imaging studies; many optional tests (eg, genetic testing, structural magnetic resonance imaging (sMRI), biomarkers in blood and urine, functional positron emission tomography (fPET) ex­pected to become routine in »5 yr

Impact of AD: cost of care  —  currently »$120 billion/yr in United States; by 2050, »$1.2 trillion/yr; physical and psychologic toll on caregivers  —  high risk for major depression and medical morbidity associated solely with de­mands of providing care

Brain fitness strategies: epidemiologic studies suggest medications for other physical conditions may confer brain health or protection against dementia (controversial; speaker does not recommend); no evidence for benefit of nu­triceuticals; stress reduction; depression highly correlated with cognitive dysfunction; pearl  —  if first onset of de­pression occurs late in life, patient has high likelihood of developing AD; physically active adults have lower risk for AD (requires equivalent of ³40-min brisk walk 3 times/wk); other lifestyle choices  —  avoid sports with poten­tial for brain trauma; smoking cessation; moderate consumption of red wine (4-14 4-oz servings/wk) possibly ben­eficial; equivalent of Mediterranean diet healthiest diet (brightly colored fruits and vegetables; fish; olive oil; dairy in moderation; minimize red meat and simple carbohydrates); mental activity (must involve mental effort [“some­thing stimulating that you don’t ordinarily do”]); memory or other cognitive training techniques (benefit can be sig­nificant, but limited to specific function addressed)

Conclusions: brain aging inevitable; many age-related changes mitigated by healthy lifestyles and memory-training techniques (eg, look, snap, connect technique)

Distinguishing Between Dementia and Depressionin Patients Under 65

Christopher Marano, MD, Assistant Professor of Psychiatry and Behavioral Sciences, Division of Geriatric Psychiatry and Neuropsychiatry, Johns Hopkins University School of Medicine, Baltimore, MD

Introduction: depression and dementia are syndromes, not etiologies; Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) definition of dementia  —  impairment in memory and ³1 other domain of cog­nition; these must cause functional impairment; deficits not solely due to delirium; definition of major depressive syndrome  —  presence of 5 of 9 symptoms that cause functional impairment unrelated to bipolar disorder; symp­toms cannot be better accounted for by another condition

Etiologies: dementia  —  include AD, cerebrovascular disease, Lewy body disease, and other brain diseases (eg, HIV infection); unknown whether depression causes dementia, but depression often earliest symptom of AD; depression  —  include AD, cerebrovascular disease, substance and prescribed medication use (eg, alcohol, inter­feron), genetic predisposition, and reaction to psychosocial stressors

Relationship between depression and dementia: cognitive impairment can be feature of depressive episode, but does not always resolve with treatment of depression; conversely, depression also common (£50%) in dementia; recent meta-analysis showed depression approximately doubles chance of having Alzheimer’s dementia; un­known whether depression is prodrome of or independent risk factor for dementia (evidence exists for both)

Pseudodementia: occurs when individual appears to be demented due to severity of depression; in study of older patients, 70% converted to true dementia within 5 yr, even if cognitive impairment resolved with treatment of de­pression

Depression as risk factor: longer interval between diagnoses of depression and AD associated with increased risk for development of AD; on autopsy, more plaques and tangles seen in brains of patients with lifetime history of depression

Possible trajectories linking depression and dementia: 1) depression results in no cognitive deficit, and cognition remains stable over time; 2) some shrinking of hippocampus occurs in both depression and dementia, perhaps re­sulting in mild cognitive impairment that remains stable over time; 3) patient already has neuropathology of AD that may progress to mild cognitive impairment and later to AD; 4) combination of AD neuropathology and cere­brovascular disease may cause frontal striatal damage, which leads to depression; 5) cerebrovascular disease in and of itself results in depression and vascular dementia

Frontotemporal dementia: initial symptoms can mimic those of depression; overlapping symptoms include emo­tional blunting, decline in personal hygiene, distractibility and impersistence, hyperorality and dietary changes, weight changes, and altered speech output

Evaluation: watch for red flags of dementia; obtain detailed history, including personality changes, risk factors for dementia (eg, substance use, HIV infection); do thorough review of systems, including significant weight loss, urinary incontinence, unexplained falls, and history of stroke, seizure, or head injury with loss of consciousness; perform complete physical and neurologic examinations

Mental status examination: include MMSE for evaluation of cognition in all patients; if red flags occur, consider more extensive evaluation

Modified MMSE: adds 4 new test items and more scoring gradations to standard MMSE

Clock-drawing task: several available; provides information that can indicate presence of cognitive impairment

Montreal Cognitive Assessment (MoCA): takes about same time as MMSE, with some additions; available free at www.mocatest.org

Laboratory evaluation: complete blood count; electrolyte levels; liver function tests; thyroid-stimulating hormone level; vitamin B₁₂ and folate levels; syphilis screen (either rapid plasma reagin [RPR] or Venereal Disease Re­search Laboratory [VDRL]); depending on circumstances, consider measures of inflammation (erythrocyte sedi­mentation rate [ESR] or C-reactive protein [CRP]), autoimmune disease (rheumatoid factor [RF] or antinuclear antibody [ANA]), HIV test, Lyme disease test, lumbar puncture, and/or electroencephalography

Neuroimaging: no hard-and-fast rule on whether to obtain neuroimaging on patients with depression in mid to late life; if red flags seen, consider computed tomography (CT) of head or MRI (preferred); if concern high for fron­totemporal dementia, consider PET or single proton emission computed tomography (SPECT; Medicare ap­proved to distinguish Alzheimer dementia from frontotemporal dementia)

Misdiagnosis of delirium: delirium common in acute-care settings and may present with depressive symptoms; study found that of 67 consecutive patients referred to psychiatry for evaluation of depression, 28 delirious; com­mon symptoms included low mood, feelings of worthlessness, and frequent thoughts of death; delirium initially considered in differential diagnosis of referring physician in only 3 patients

Preventing dementia: potentially modifiable risk factors include smoking, high blood pressure in midlife, high body mass index in midlife, high cholesterol in midlife, and diabetes; unknown whethter controlling these risk factors prevents dementia, but may help; Mediterranean diet (rich in polyunsaturated fats and antioxidants) appears pro­tective for heart disease and possibly for cognition

Key components of Mediterranean diet: ample fruits and vegetables; healthy fats (eg, olive oil, canola oil); small portions of nuts; red wine in moderation (study suggests same effect with any alcohol; lower quantity recom­mended for women than for men); fish on regular basis; minimal red meat

Other cognitive protective factors: physical and mental exercise

Treatment: if unsure whether patient has depression, dementia, or both, treat for depression first and monitor for re­sponse; in general, antidepressants have favorable risk/benefit profiles and are effective

Suggested Reading

Bhalla RK et al: Patterns of mild cognitive impairment after treatment of depression in the elderly. Am J Geriatr Psychia­try 17:308, 2009; Dillon C et al: Late- versus early-onset geriatric depression in a memory research center. Neuropsychiatr Dis Treat 5:517, 2009; Dorenlot P et al: Major depression as a risk factor for early institutionalization of dementia patients living in the community. Int J Geriatr Psychiatry 20:471, 2005; Dujardin K et al: Apathy may herald cognitive decline and dementia in Parkinson’s disease. Mov Disord Nov 11, 2009. [Epub ahead of print]; Friedland RP et al: Patients with Al­zheimer’s disease have reduced activities in midlife compared with healthy control-group members. Proc Natl Acad Sci U S A 98:3440, 2001; Gage FH: Neurogenesis in the adult brain. J Neurosci 22:612, 2002; Peila R et al: Joint effect of the APOE gene and midlife systolic blood pressure on late-life cognitive impairment: the Honolulu-Asia aging study. Stroke 32:2882, 2001; Peters R: The prevention of dementia. Int J Geriatr Psychiatry 2009, 24:452; Rogers WA, Fisk AD: Hu­man Factors Interventions for the Health Care of Older Adults. Mahwah, NJ: Lawrence Erlbaum Associates, 2001; Small GW: The Memory Bible: An Innovative Strategy for Keeping Your Brain Young. New York: Hyperion, 2002; Tsuno N, Homma A: What is the association between depression and Alzheimer’s disease? Expert Rev Neurother 9:1667, 2009; Tuma TA: Outcome of hospital-treated depression at 4.5 years. An elderly and a younger adult cohort compared. Br J Psy­chiatry 176:224, 2000; Tyas SL et al: Mid-life smoking and late-life dementia: the Honolulu-Asia Aging Study. Neurobiol Aging 24:589, 2003; van Praag H, Kempermann G, Gage FH: Neural consequences of environmental enrichment. Nat Rev Neurosci 1:191, 2000.