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Cognitive Testing in Patients with Suspected Dementia

T. Schenkenberg, Ph.D.

Department of Neurology

OBJECTIVES

1. To know the diagnostic criteria for the diagnosis of dementia

2. To list five causes of dementia

3. To understand the importance of age-based norms when evaluating cognition in the elderly

4. To recognize that there are reversible causes of dementia

5. To name three basic tests used in the evaluation of possible dementia

DEMENTIA -- DEFINITION

1. A progressive loss of intellectual abilities of sufficient severity to interfere with social and/or occupational functioning. “Dementia” is a descriptive term, not a specific disease or condition. There are dozens of pathophysiologic causes of dementia. Because dementia is seen in the context of so many conditions, dementia is one of the most common findings encountered by neurologists who see adult patients.

A. MAGNITUDE OF THE PROBLEM

1. The population over 65 years of age is increasing rapidly--from 23 million in 1978 (11% of the population) to 51 million by 2030 (about 19% of the population).

2. If life expectancy continues to rise, and the mean age of onset of dementia does not, some authors have projected that about 45% of the population would develop dementia at some point during their lives (with life expectancy extending into the late 90’s).

3. Close to 3 million people are in nursing homes in the USA now. About two-thirds of them suffer from dementia.

4. Annual cost of formal and informal care is in the neighborhood of $75,000 per year per patient. “Long term care insurance” has become a major industry.

5. Estimates suggest that there might be 4 million people in the USA with Dementia of the Alzheimer’s Type. Some estimates are that there will be 12 million by 2050.

B. DIAGNOSTIC CRITERIA (DSM III-R, not DSM IV)

1. Demonstrable impairment in short-term and long-term memory

2. At least one of the following:

n impairment of abstract thinking

n impaired judgement

n other disturbances of higher cortical functioning (e.g., apraxia, acalculia, agnosia, language dysfunction)

n personality change

3. The disturbances in 1 and 2 above significantly interfere with work or social

activities/relationships and represent changes from an earlier level of function

4. NOT occurring exclusively during delirium.

5. There is an “organic” factor related etiologically to the disturbance. (The point here is that, although depression in many cases has an organic basis, the authors of this definition are trying to exclude psychiatric causation for the observed cognitive change.)

C. THE PROBLEM OF DIFFERENTIAL DIAGNOSIS

Well over 50 different conditions have been identified which are associated with intellectual deficits in adults. A variety of general medical conditions can affect cognitive function (e.g., uremia, vitamin deficiencies, toxins). Remember, many of these causes are treatable. Thus, the diagnosis of “dementia” does not necessarily have dire prognostic implications. Indeed, the search for “treatable causes” is the next step once one has determined that a dementia is present.

It is vitally important to consider depression and toxic-metabolic encephalopathies (conditions affecting brain function) in the differential because both can cause changes in cognitive efficiency or function which can be reversed.

--Depression can produce complaints of poor cognitive function by way of the self-deprecating attitude of the depressed person. The depressed person’s preoccupation with negative, morose issues can disrupt his/her concentration, producing poor performance on cognitive tests. Finally, the actual physiological processes associated with depression (perhaps an abnormality in monoamine neurotransmission or cortical metabolism) could directly interfere with mental function, especially in the areas of attention and concentration.

--The efficiency of neuronal function depends on a variety of factors including glucose content, oxygenation level, hormonal state, and electrolyte balance of the extracellular environment. Systemic diseases that interfere with cardiac, renal, hematological, hepatic, endocrine, or pulmonary function can disrupt this balance and can trigger a metabolic encephalopathy. Furthermore, many analgesics, hypnotics, sedatives, antihypertensives, antiarryhthmics, antiepileptics, antidepressants and antipsychotics can directly interfere with neuronal function and cause a toxic encephalopathy. This is particularly a concern in the elderly, i.e., the most common population in which questions of dementia occur, because so many elderly individuals are taking multiple medications. Most toxic encephalopathies have an acute onset and do not fit the picture of dementia. Others, however, have a chronic course and may lead to a clinical picture with the characteristics of dementia.

The list of possible causes of dementia includes, but is not limited to, the following (some categories overlap):

So-called primary dementias, e.g., Dementia of the Alzheimer’s Type, Pick’s disease, Creutzfeldt-Jakob disease (prion diseases) and variants, Kraepelin’s disease, Parkinson-dementia complex of Guam, Huntington’s chorea, Lewy-body Disease, frontotemporal dementia, primary progressive aphasia.

Vascular disorders, e.g., stroke, multi-infarct dementia, CADASIL (Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), asterides, Binswanger’s disease.

Other progressive diseases (e.g., Parkinson’s disease, Hallervorden-Spatz disease, spinocerebellar degenerations, progressive supranuclear palsy).

Metabolic disorders (e.g., myxedema, disorders of the parathyroid, Wilson’s disease, hypoglycemia, remote effects of carcinoma, Cushing’s syndrome, uremia).

“Normal pressure hydrocephalus.”

Deficiency diseases (e.g. Wernicke-Korsakoff syndrome, pellagra, Marchiafava-Bignami disease, vitamin B12 deficiency).

Toxins and drugs (e.g., metals, carbon monoxide, organic compounds, drugs/medications).

Space occupying lesions, e.g., neoplasm, cyst.

Trauma (e.g., open and closed head injury, “dementia pugilistica,” subdural hematoma).

Infection (e.g., HIV, brain abscess, meningitis, encephalitis, syphilis, Lyme disease)

Other (e.g., multiple sclerosis, muscular dystrophies, dialysis dementia, systemic lupus)

D. THE WORKUP

History, physical exam, mental status exam (more to come on the mental status exam during Physical Diagnosis in April, stay tuned!). Labs (to include serologic tests for syphilis, B12, folate, sed rate, thyroid function. Imaging studies. Neuropsychological testing (cognitive testing). Other studies such as: chest x-ray, EEG, lumbar puncture, SPECT, PET, EMG, EKG, CBC, liver function tests, HIV, electrolytes, antiphospholipid, antinuclear or paraneoplastic antibodies, heavy metals, tox screens and other specialized studies as dictated by the diagnostic possibilities raised.

E. TWO EXAMPLES: DEMENTIA OF THE ALZHEIMER’S TYPE AND WERNICKE-KORSAKOFF’S SYNDROME

1. Dementia of the Alzheimer’s Type (DAT)

--While likely to be a heterogeneous designation (“convergence syndrome”), DAT accounts for about 50% of the conditions causing dementia.

--Historical features: insidious onset as early as the 5^th decade.

--Even sex distribution, although the Framingham study and studies from Sweden suggest that more women than men might be affected (age-adjusted).

--5% of cases are autosomal dominant with mutations in chromosomes 21, 14 and 1. Chromosome 14 mutations are most common. These known mutations do not account for all families in which this appears to be transmitted as an autosomal dominant. Earlier age of onset in the cases of autosomal dominant transmission, perhaps as early as the 30’s and 40’s.

--There are also cases which are said to be “familial” in which the disease prevalence is higher in a family than it is in the general population. The presence of DAT in a first- degree relative increases the total lifetime risk from 23% to 48%.

--Again, the prevalence doubles every five years above age 65. Markers on chromosome 19 and 12 are related to increased risk.

--Initial stages: Memory impairment, misplaces things, repeating the same comments, I say, repeating the same comments. Word finding difficulty. May be less decisive, needs more reassurance, less effective in activities. Driving skill might decline, especially in complex, demanding or unfamiliar settings. Reactive depression related to subjective awareness of loss. (This points out the issue of the “disjunctive fallacy,” i.e., the notion that the problem has to be singular….indeed, there are often two problems occurring in that reactive discouragement/depression is very common in patients who recognize that they are losing ground cognitively.) Physical exam may be normal.

--Intermediate stage: Other cognitive domains are affected such as language, reasoning, spatial orientation, executive function. Difficulty with new information. Attentional deficits. Judgement and insight falter. Independent living becomes very difficult or impossible. Erosion of decorum and hygiene. May “wander.” Possible delusions, hallucinations, agitation. On physical exam may see Babinski responses, frontal lobe release signs, motor impersistence, mirror movements, “geganhalten” or “oppostition” to passive manipulation of a limb.

--Final stage: Incontinence, inability to recognize family members, difficulties with mobility and feeding. Virtual loss of “self” with regard to comportment and cognitive function. Sensory and motor functions typically remain relatively intact until late in the course, but extrapyramidal deficits such as myoclonus, rigidity, cogwheeling, and gait instability become increasingly frequent.

--Clinical and Laboratory Diagnosis: Time is often an important ally. Comparison testing over 6 to 12 months can be helpful in determining whether there is a truly progressive problem present. It is also important to note that many patients have two organic causes of dementia occurring together, e.g., vascular disease and DAT. Unequivocal diagnosis only on postmortem exam. There are currently no laboratory tests which provide a definitive diagnosis. This is a diagnosis by exclusion, excluding other specific causes, in combination with a pattern which is compatible with DAT (DSM terminology) or Probable Alzheimer’s Disease or PRAD (NINCDS-ADRDA terminology).

“In essence, PRAD or DAT is used to designate a clinical state where progressive impairments of memory and at least one other cognitive domain induce a chronic decline from previous levels of social, professional, and domestic functioning in the absence of other identifiable causes for dementia.” (There are problems with this definition. For example, Pick’s Disease also fits this description since there is no way to rule it out absolutely, and thus it would fall into the group assumed to have PRAD or DAT.)

Imaging studies reveal generalized atrophy, but the degree of atrophy is inconsistently related to the degree of dementia. EEG may show slowing. Various additional possible markers are under study MRI, SPECT, PET, various CSF findings.

--Neuropathology: gross atrophy with widening of the cortical sulci and enlargement of the ventricles. Reduction of cortical neurons. Amyloid containing plaques. Neurofibrillary tangles. Granulovacuolar degeneration of cells in the hippocampus. Some of these findings can be seen in the brains of normal elderly individuals without dementia, further complicating the process of a definitive diagnosis. Cholinergic depletion by 50 to 90% in the neocortex and hippocampus (mechanisms for this are poorly understood).

--Interventions: It is important to keep the general health of the patient in mind, as additional problems can be overlooked in the context of a diagnosis of DAT. Acetylcholinesterase inhibitors such as Aricept, Reminyl and Exelon have been tried with DAT. Do not forget the psychosocial and legal interventions such as support groups, day care, respite care, residential care, establishing Advance Directives, estate planning, issues related to driving. Unfortunately, it is also necessary to be alert to abuse issues. Individuals with DAT can be very frustrating to care for and they have been abused by care providers in various settings.

2. Wernicke-Korsakoff Syndrome

--This is a treatable (possibly reversible) cause of dementia and, on the basis of autopsy studies is under-recognized in life—with possibly four times as many cases recognized on post mortem exam than are recognized in life. Complete recovery can occur in about 20% of patients.

--This is a deficiency disease resulting from the lack of an essential nutrient in the diet or from a factor which increases the need for the nutrient—in this case Thiamine (B1). It is a syndrome with two components the Wernicke component and the Korsakoff component.

--In this country this is seen most commonly in the context of alcoholism. (Of course, many additional medical problems are also associated with alcoholism.) This is the result of the alcoholic’s increasing reliance on ETOH as a primary non-nutrient caloric source. Also seen in gastric plication, hyperemesis, psychiatric patients with dietary restrictions based on delusions, renal dialysis, cancer, HIV, extreme dietary conditions as seen in POWs and third world countries.

n The Wernicke component or Wernicke’s encephalopathy consists of oculomotor signs (weakness or paralysis of abduction, diplopia, internal strabismus, horizontal nystagmus on lateral gaze), ataxia, global confusion. Only one-third of patients have all three of the classic triad. The patients are often withdrawing from alcohol as well. 80% have polyneuropathy. They often have tachycardia, exertional dyspnea and postural hypotension. EEG is diffusely slow. If untreated, there is an elevation in blood pyruvate and reduction of blood transketolase (a Thiamine dependent enzyme). Death occurs in 15-20% of patients usually due to complicating infection or to hepatic failure. For patients who improve with treatment (i.e., Thiamine): the ocular palsies improve in hours to days; the ataxia improves slowly (weeks to months) and usually the patient is left with a wide-based gait; vestibular function improves slowly (weeks to months). Often some residual findings remain. The global confusion recedes and the Korsakoff’s component often remains.

n The Korsakoff’s component or Korsakoff Syndrome comprises a disorder of cognitive function in which memory is deranged out of all proportion to the other components of mentation and behavior. The symptoms include: retrograde amnesia, anterograde amnesia, lack of initiative and spontaneity, relatively intact immediate memory. Confabulation is an interesting finding when present but is only variably present. To identify Korsakoff’s Syndrome the patient must be alert, attentive, responsive and capable of understanding the written and spoken word, capable of making appropriate deductions from given premises and capable of solving problems that can be concluded within his/her forward memory span.

--It is important to emphasize that in the nutritionally deficient patient with Wernicke-Korsakoff Syndrome, the syndrome is not two separate conditions but rather the changing ocular/ataxic/confusional state into an amnestic disorder.

--Neuropathology: Symmetrical lesions are seen in the paraventricular regions of the thalamus and hypothalamus, the mamillary bodies, the periaquiductal region of the midbrain, the floor of the 4^th ventricle and the anterior-superior folia of the cerebellum (particularly of the vermis). Lesions are invariably found in the mamillary bodies and less consistently in the other areas.

--Wernicke’s is a medical emergency. Immediate administration of Thiamine (50 mg IV and 50 mg IM), the latter daily thereafter until resumption of normal nutrition. Beware of IV glucose as such infusions may deplete B vitamin reserves thus possibly precipitating Wernicke’s in a previously unaffected individual or causing a worsening of an already affected patient or causing acute cardiovascular beriberi.

F. NEUROPSYCHOLOGICAL TESTS COMMONLY USED IN ASSESSING COGNITION IN ADULTS

(You will see these tests referenced in reports on your patients. There are literally hundreds of these tests. The following are commonly used.)

See attached model.

(Examples of some of the tests have been discussed in the context of the criteria for the diagnosis of dementia. The following is a further description of some of those measures as well as an overview of this area.)

Special concerns in testing cognitive function in a clinical setting.

1. Accurate history of educational, occupational, avocational activities, i.e., determination of “expectations” for test performance for this particular patient

2. Diversity issues

3. Medications

4. Depression can present with cognitive inefficiencies which can appear to be the onset of dementia. This is a very common issue.

5. Statistical properties of the test and norm group. See attached graph.

6. Malingering.

7. Changes which occur “normally” with increasing age. For example:

Wechsler Adult Intelligence Scale-III (WAIS-III)

Minimum “raw score” points spread evenly across 6 Verbal subtests and 5 Performance subtests for an IQ of 100, i.e., center of the distribution for each age group. Percentages represent the percent of the raw score total at age 30 (for an IQ of 100) that is needed to achieve an IQ of 100 at the various age levels. Age 27 is also included because it is the average age of students graduating from the U of U School of Medicine.

Age = 27 30 40 50 60 70 80 89

Verbal…… 122 129 133 138 124 121 106 102

103% 107% 96% 94% 82% 79%

Perform…...167 165 161 149 134 108 92 81

98% 90% 81% 66% 56% 49%

Full Scale… 289 294 294 287 258 229 198 183

100% 98% 88% 78% 67% 62%

Some examples of commonly used cognitive tests:

1. “Wechsler” IQ Tests

2. “Wechlser” Memory Scales

3. Halstead-Reitan Battery

4. Specialized testing: Trails A and B, Boston Naming Test, Benton Visual Retention Test or Graham-Kendall Memory-for-Designs, Rey-Osterrieth Complex Figure Test, Controlled Oral Word Association Test, tests for left visual neglect, etc.

A basic “mental status exam” such as Folstein’s Mini-Mental State Exam (MMSE) is an essential part of the neurologic exam in a patient with a suspected dementia. I’ll see you in April (after the Olympics) to discuss this further!

References:

1. Diagnostic and Statistical Manual of Mental Disorders III-R and IV. American Psychiatric Association. Washington, D.C., 1987, 1994.

2. Green, J. Neuropsychological Evaluation of the Older Adult. Academic Press: New York, 2000.

3. Lezak, M. Neuropsychological Assessment. Oxford Press: New York, l995.

4. Mesulam, M. Principles of Behavioral and Cognitive Neurology. Oxford Press: New York, 2000.

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