MATTERS OF THE MIND
| EVALUATION OF PATIENT WITH DEMENTIA—Jeffrey L. Cummings, MD, Professor of Neurology, David Geffen
School of Medicine at the University of California, Los Angeles
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| Critical areas of mental status examination: attention—abnormal in delirium; review medication list; memory—
impairment must be present for diagnosis of dementia; critical tests include orientation and learning (eg, 3-word test);
language—naming test (eg, name parts of eyeglasses); visuospatial function—clock- and cube-drawing test; executive
function—assess judgment and planning skills; evaluate patient’s understanding of problem and likelihood of ability to
care for self; determine whether patient integrating current mental status abilities into thinking; assess behavior and mood
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| Activities of daily living (ADLs): impaired in patients with dementia; not impaired in patients with mild cognitive
impairment (MCI; prodromal phase of dementia)
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| Motor assessment: look for lateralized signs (eg, drift on one side, frank weakness when testing flexion or extension on
one side) and parkinsonism; gait assessment; test tone and evaluate spontaneous movement
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| Mental status assessment: Mini-Mental Status Examination (MMSE)—30 questions (<24 correct abnormal); particularly
helpful for Alzheimer’s disease (AD); misses early cases of AD and does not change in late cases; takes 10 to 12 min;
Mini-Cog—AD most common dementia; memory abnormalities most common presentation of AD; highest sensitivity
with 3-word recall test (3 points); clock-drawing test (1 point); suspect dementia syndrome in patients who make >2 errors
(eg, missing 2 words or missing one word and failing clock-drawing test); word-list generation—ask patient to name as
many animals as they can in 1 min (18 normal; <12 abnormal; 12-18 requires interpretation); assesses language and executive
function
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| Laboratory testing and imaging studies: complete blood cell count (CBC); electrolytes; serum urea nitrogen
(BUN); serum glucose; cholesterol; thyrotropin (TSH); vitamin B12 ; magnetic resonance imaging (MRI) or computed tomography
(CT) should be performed at least once in clinical course; fluorodeoxyglucose-positron emission tomography
(FDG-PET; measure of brain metabolism; paid for by Centers for Medicare and Medicaid Services [CMS] if used to determine
whether patient has frontotemporal dementia); lumbar puncture (LP) highly specific and highly sensitive; increased
level of tau protein and decreased level of amyloid β(α β) protein reflect pathologic process of AD
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| Differential diagnostic paradigm: 1) consider dementia; 2) contribution of abnormal laboratory testing; 3) integration
of focal neurologic signs in differential diagnostic approach; 4) parkinsonism; 5) if none present and patient has
gradual onset and slow progression, consider other diseases; 6) consider rare atypical diseases
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 | Dementia: impairment of memory and impairment in one other cognitive domain (eg, language, constructions, executive
function); decline from previous level of function; disabling (ADLs compromised); not due to delirium
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| Abnormal laboratory testing: consider hypothyroidism, vitamin B12 deficiency, organ failure (eg, congestive heart failure
[CHF], renal failure), medication-induced encephalopathies (particularly with psychotropic agents), alcoholism and substance
abuse, and infections (VDRL and HIV testing and sedimentation rate, depending on patient history and exposure);
patient 85 yr of age who presents with elevated TSH and hypothyroidism likely to have AD and hypothyroidism (risk for
AD 40%, risk for hypothyroidism 1%; mixed cases and comorbidity common)
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| Normal laboratory tests with focal neurologic signs: vascular dementia—characterized by dementia syndrome; presence
of cerebrovascular disease (focal signs and abnormal imaging study required for diagnosis); determine whether
dementia related to cerebrovascular disease; onset of dementia within 3 mo of stroke or abrupt onset with stepwise decline;
most patients have mixed dementia; uncommon for patient to have pure cerebrovascular disease with history of
dementia during life; in patients with vascular dementia, cholinesterase inhibitors often successful because many patients
also have AD; evaluation—look for gait changes; patients often have short stride and short step height (“parkinsonian
shuffle” without resting tremor; lower-half parkinsonism); incontinence; dementia, gait changes, and incontinence
classic triad of normal-pressure hydrocephalus (diagnosis rare; reversible; management approach different); pseudobulbar
palsy (patients have unusual laughter or crying) common; brisk reflexes; extensor plantar responses; most abnormalities
in motor domain; cognitive aspects—executive dysfunction; psychomotor retardation; apathy; depression more
common than in AD; psychosis may occur; in dementia syndrome, more executive dysfunction and less memory dysfunction
than in AD
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| Parkinsonism: Parkinson’s disease with dementia—patients have bradykinesia, rigidity, and rest tremor; responds to
dopamine compounds; in cross-sectional studies, dementia occurs in 40% of patients (cumulative incidence ≈80%);
most patients have cognitive impairment sufficient to meet criteria for dementia; cognition fluctuates (may lead to confusion
with delirium); neuropsychiatric features include hallucinations, delusions, depression, and anxiety; dementia
with Lewy bodies—α-synuclein protein abnormalities; in some cases, Lewy bodies do not remain confined to brainstem
and extend into cortex; 2 of 3 features (ie, parkinsonism, visual hallucinations, fluctuating cognition); supporting
features for diagnosis include delusions, depression, and rapid eye movement (REM) sleep behavior disorder (atypical of
other dementia; occurs in ≈40% of patients; patients act out dreams)
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| Gradual onset and slow progression: AD—meets all criteria for dementia (ie, impairment in memory and one other domain);
acquired and disabling; progresses gradually; no focal signs; no early gait changes; no early seizures; no other potential
cause of dementing disorder; amyloid in center of neuritic plaques critical toxic event in AD (most new therapies aimed at
reducing amyloid production, increasing its removal, or decreasing its toxicity); neuritic plaques distributed in frontal lobes
in parietal regions, less so in frontal regions; PET shows reduction of metabolism in temporoparietal regions bilaterally;
neurofibrillary tangles appear more highly correlated with behavioral abnormalities; frontotemporal dementia—onset at
age 45 to 65 yr; behavioral changes (eg, apathy and disinhibition) precede memory loss; disinhibition usually social type
(eg, inappropriate comments, lewdness, tactlessness); in some cases, language changes present (subtypes include
frontotemporal dementia with nonfluent aphasia or fluent aphasia); Pick’s disease not most common cause; patients worsen
with cholinesterase inhibitors
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| Atypical dementias: eg, Creutzfeldt-Jakob disease; few patients fall outside of differential diagnostic approach
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| ALZHEIMER’S DISEASE AND MILD COGNITIVE IMPAIRMENT—Dr. Cummings
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| Risk factors for AD: age; female sex; apolipoprotein-E4 genotype; hypercholesterolemia; hyperhomocysteinemia; diabetes;
head injury; psychologic stress; hypertension; tobacco smoking
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| Protective factors: higher education; higher cognitive activity during aging years; more active leisure activity; higher
levels of physical activity; diet with high antioxidant content (eg, omega-3 fatty acids, vitamins E, C, B6 , B12 , and
folate); modest use of alcohol; statins; nonsteroidal anti-inflammatory drugs (NSAIDs; data confusing); treating hypertension
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| Mild cognitive impairment: impairment of memory or other cognitive function; 1.5 SDs below age-matched normals;
no impairment of ADLs; patients do not meet criteria for dementia; important risk state (patients convert to dementia at
rate of 15% per year); treatment—no approved treatment; large study found donepezil slowed rate of conversion from
MCI to AD, compared to placebo and vitamin E (no difference between placebo and vitamin E; no difference in total
number of patients who converted to AD); not all patients progress to AD or dementia; amnestic form of MCI usually
prodromal form of AD; treatment with cholinesterase inhibitors may delay progression to AD
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| Amyloid production and accumulation: leads to neuritic plaques and cascade of neurofibrillary tangles, oxidation,
inflammation, and excitotoxicity, leading to cell death and cholinergic deficit; therapy—vaccination with amyloid associated
with risk for allergic encephalitis in humans, but research encouraging; immunization (antibodies raised ex-ternally
and infused intravenously) undergoing trial studies; β-secretase and γ-secretase inhibitors and modulators;
antifibrillization agents reduce toxicity by preventing amyloid molecules from binding together to form plaque; protein-
metal attenuating agents (chelating agents that prevent metal from exacerbating amyloid-related injury); peroxisome proliferator-activated
receptor (PPAR)-agonists (eg, rosiglitazone, pioglitazone) and statins reduce amyloid deposition in
brain; neurofibrillary tangle—produced by phosphorylation of tau protein by kinases; glycogen synthase kinase 3- β
(GSK-3 β) inhibitors (eg, lithium, valproate) undergoing study; antioxidant strategies—diets high in vitamin E and C
associated with reduced risk; curcumin (curry spice; ≈5 times more powerful antioxidant than vitamin E; as beneficial as
vaccination in transgenic mice) undergoing study; vitamin E (2000 IU/day; concern about dose) as well as selegiline
(more expensive with more side effects [eg, visual hallucinations] than vitamin E) slow course of moderate to severe AD
(no advantage to using both simultaneously); excitotoxicity—therapy aimed at blocking N-methyl-D-aspartate (NMDA)
receptor to reduce calcium entry into cell and to ameliorate calcium-related neurodegeneration; in vitro data suggest neuroprotection,
but clinical data suggest symptomatic response; memantine (Namenda) approved by Food and Drug Administration
(FDA) for symptomatic therapy in moderate to severe AD; cholinesterase inhibitors—marked cholinergic
deficit in AD; used to inhibit metabolism of acetylcholine in synaptic cleft; donepezil (Aricept), rivastigmine (Exelon),
and galantamine (eg, Razadyne) equally efficacious; galantamine and donepezil given once daily; rivastigmine given bid;
more side effects with rivastigmine; transdermal rivastigmine to be available; to be approved by FDA, antidementia
agents must be superior to placebo on global and cognitive measures; weaker outcomes on functional effects on ADLs,
behavior, caregiver effects (eg, time required for care), and delay to nursing home placement; ≈25% of patients improve
(eg, ≈1 point in improvement on MMSE [standard error of measurement in AD 2 to 3 points]); delay of progression in
80% of patients after 6 to 12 mo of use; used to maintain (not improve) function; persistence of therapy important (short-
term trial not worthwhile); gastrointestinal side effects in some patients; commonly used in combination with memantine;
better data sets with galantamine for cerebrovascular disease plus AD; better data sets with rivastigmine for parkinsonism
and dementia
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| Neuropsychiatric symptoms: neuropsychiatric inventory (NPI) allows caregivers to provide score for delusions, hallucinations,
depression, anxiety, apathy, irritability, aggression, disinhibition, and aberrant motor behavior (eg, wandering)
in population of mixed-severity dementia; 70% of patients have episodes of agitation or aggression; anxiety and
depression common, delusions and hallucinations less common; psychotropic agents in AD—no FDA-approved therapies
for neuro-psychiatric abnormalities or symptoms in AD; preliminary data available on atypical antipsychotics for
psychosis and agitation (slightly better for agitation); some data support anticonvulsants for agitation, although most recent
studies show no benefit, compared to placebo; selective serotonin reuptake inhibitors (SSRIs) diminish depression
and anxiety in AD; cholinesterase inhibitors and memantine associated with reduced behavioral disturbances; atypical
antipsychotics associated with increased risk for stroke and death (black box warning for use in elderly; inform patient
and family of risk and document thoroughly); risk for death increased from ≈2.3 in placebo group to ≈4.6 in treatment
group
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| Summary: cognitive enhancers—all cholinesterase inhibitors approved for mild to moderate AD, donepezil approved
for severe AD; memantine approved for moderate to severe AD; vitamin E and selegiline associated with reduced progression
in moderate to severe AD; psychotropics can be used for behavioral disturbances (important to recognize vulnerabilities);
care of caregiver important (80% of care provided by caregiver [usually spouse])
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| ADDITIONAL THOUGHTS ON DEMENTIA—Robert M. Howse, Jr, MD, Associate Program Director, Geriatrics Fellowship
Program, Lancaster General Hospital, Lancaster, PA
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| Signs and symptoms: loss of ADLs or failure to maintain instrumental ADLs (eg, no longer able to manage checkbook);
depression; arthritic problems; orthopedic disorders; missed office appointments; noncompliance; slower movement;
getting lost or wandering in office
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| Mental status examination: MMSE—30 points; score of <21 indicates dementia; 21 to 24 “watershed area”; St.
Louis University Mental Status examination and Montreal Cognitive Assessment help round out diagnosis of AD; 70%
to 75% of patients with dementia have AD; pretest probability provides higher accuracy than MMSE
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| Laboratory evaluation: rapid plasma reagin (RPR) testing no longer recommended, unless in high-risk or endemic
area; LP no longer routinely recommended unless Creutzfeldt-Jakob disease on clinical presentation
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| Common diagnoses: MCI—memory loss and 1 or 2 problems with thinking fields; seen often; unclear whether precursor
to dementia; incidence of AD, ≈70%, Lewy body dementia, ≈15%, and vascular dementia, ≈10%; 10 to 15 other types
of neurologic degenerative disease can cause dementia as presenting syndrome (rare)
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| Dementia in AD: multiple cognitive deficits and memory loss; difficulty with language, spatial and temporal orientation,
knowledge, and processing how to move forward with life; gradual and progressive; presents later in life; decline in
ADLs and instrumental ADLs; not due to other diseases or to delirium; not due to axis 1 diagnosis (depression can often
present as dementia, especially in elderly men); psychotic disorders (eg, late-onset schizophrenia) not uncommon (especially
in women) and can present similarly to dementia
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| Treatment: MCI—treating hypertension, treating hyperlipidemia, and using antiplatelet agent can help prevent decline
in ADLs, instrumental ADLs, and formal testing; study on donepezil vs vitamin E or placebo showed “no real differences”
at 3 yr; cognitive training probably helps prevent progression
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| Vascular dementia: defined as 1) dementia worsened or initiated by cerebrovascular accidents; 2) not due to other
types of dementia; definition under development
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| Lewy body dementia: defined as dementia with parkinsonism and hallucinations (visual or auditory); rapidly progressive
course; presents earlier in life; medication sensitivity—medications used for Parkinson’s disease cause oversedation,
delirium, and illness and may significantly aggravate hallucinations in patients with Lewy body dementia; difficult
to determine drug regimen to treat motor problems that resemble Parkinson’s disease; antipsychotics often oversedating
or may have unpleasant side effects and worsen condition
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| Levels of care: home; structured or assisted living; skilled nursing facility; family members become increasingly unable
to manage patient’s urinary incontinence, fecal incontinence, and difficult behavior (eg, aggressiveness, wandering, refusing
care); patients often require 24-hr supervision and care and placement in facility
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Suggested Reading
Geldmacher DS: Treatment guidelines for Alzheimer's disease: redefining perceptions in primary care. Prim Care
Companion J Clin Psychiatry 9:113, 2007; Giovannetti T et al: Environmental adaptations improve everyday action
performance in Alzheimer's disease: Empirical support from performance-based assessment. Neuropsychology
21:448, 2007; Gonyea JG et al: Project CARE: a randomized controlled trial of a behavioral intervention group for
Alzheimer's disease caregivers. Gerontologist 46:827, 2006; Hanyu H et al: Are subjective memory complaints mandatory
for the diagnosis of mild cognitive impairment? Intern Medicine 46:791, 2007; Holsinger T et al: Does this
patient have dementia? JAMA 297:2391, 2007; Jelic V et al: Diagnostic imaging devices in Alzheimer's disease. Expert
Rev Med Devices 4:475, 2007; Licht EA et al: Cognitive Differences between Early- and Late-Onset Alzheimer's
Disease. Am J Alzheimers Dis Other Demen 22:218, 2007; Marksteiner J et al: Cerebrospinal fluid
biomarkers for diagnosis of Alzheimer's disease: Beta-amyloid(1-42), tau, phospho-tau-181 and total protein. Drugs Today
(Barc) 43:423, 2007; Smith T et al: The Montreal Cognitive Assessment: validity and utility in a memory clinic
setting. Can J Psychiatry 52:329, 2007; Wesnes K: Rivastigmine tartrate with a focus on dementia associated with
Parkinson's disease. Drugs Today (Barc) 43:349, 2007.
Educational Objectives
| The goals of this program are to improve the evaluation of patients for dementia and to review management options
for Alzheimer’s disease and mild cognitive impairment. After hearing and assimilating this program, the participant
will be better able to:
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| Test critical areas of mental status to diagnose dementia.
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| Describe appropriate laboratory tests and imaging studies for diagnosing and distinguishing the various dementias
.
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| Discuss protective factors and newer treatment strategies for Alzheimer’s disease.
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| Identify and prevent progression of mild cognitive impairment.
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| Differentiate Parkinson’s disease with dementia from dementia with Lewy bodies.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members 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. Cummings has received research support
from ACADIA Pharmaceuticals, Athenagen, AVANIR Pharmaceuticals, Eisai Inc, EnVivo Pharmaceuticals, Forest Pharmaceuticals,
Inc, Janssen Pharmaceutical, Lilly and Co, Memory Pharmaceuticals, Merck & Co, Inc, Myriad Genetics, Inc,
Neurochem Inc, Novartis Pharmaceuticals, Ono Pharmaceutical Co, Ltd, Pfizer Inc, Sanofi-Aventis, and Takeda Pharmaceutical
Co, Ltd.
Acknowledgements
Dr. Cummings spoke in Los Angeles, CA, at the 34th Annual Family Practice Refresher Course, presented May 29 to
June 2, 2007, by the David Geffen School of Medicine at the University of California, Los Angeles. Dr. Howse was recorded
in Lancaster, PA, at the 31st Semi-Annual Family Practice Review, presented March 25-30, 2007, by Temple University
School of Medicine and Lancaster General Hospital. The Audio-Digest Foundation thanks the speakers and the
sponsors for their cooperation in the production of this program.
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