Charles Flicker

Mild cognitive impairment in the elderly: Predictors of dementia

We conducted full diagnostic evaluations, including a comprehensive cognitive assessment battery, of a group of 32 elderly subjects with a clinically identified mild cognitive impairment and a group of 32 age-matched and education-matched normal subjects. The mildly impaired subjects performed significantly more poorly than the controls on tests of recent memory, remote memory, language function, concept formation, and visuospatial praxis. Follow-up evaluations of cognitive status 2 years later revealed clinically detectable cognitive decline relative to baseline in 23 (72%) of the mildly impaired subjects. Several of the objective psychological tests accurately discriminated at baseline between the decliners and nondecliners in the mildly impaired group. Among the 20 mildly impaired subjects with no complicating conditions, 16 exhibited cognitive deterioration between baseline and follow-up. These results suggest that most elderly subjects with mild cognitive deficits, as determined by clinical evaluation and objective psychological testing, will manifest the progressive mental deterioration characteristic of dementia and that psychometric predictors can be used to distinguish between benign and more significant underlying disorders in mildly impaired elderly subjects.

The Cholinergic Hypothesis: A Historical Overview, Current Perspective, and Future Directions

When one considers that Alzheimer’s disease was initially characterized in the first decade of this century,’ it seems remarkable that the disease remains such a mystery. The relative etiologic roles played by various genetic, toxic, viral, and immunologic influences remain ill-defined, and the origin and direct functional implications of its most characteristic neuropathological markers, neurofibrillary tangles and amyloid plaques, likewise are unknown. Although it has been shown that inadequate blood supply to the brain does not provide a tenable explanation for the primary symptoms of Alzheimer’s disease: the final neurological pathways that are responsible remain obscure. One possible exception to this is the recent accumulation of evidence suggesting that a breakdown of central cholinergic transmission plays an important role in the earliest and primary symptoms of the disease, manifested as a severe and progressive cognitive disturbance highlighted by an inability to remember recent With normal aging, a similar, though less severe, memory loss has been documented6*’ (sometimes referred to as benign senescent forgetfulness*) with similar evidence for a parallel role of cholinergic dys f~nc t ion .~*~*~*’~ The logic and empirical support for this line of thinking have collectively become known as the “cholinergic hypothesis of geriatric memory dysf~nction.”~-~ Stated in its most simple and direct terms, the cholinergic hypothesis asserts that significant, functional disturbances in cholinergic activity occur in the brains of aged and especially demented patients, these disturbances play an important role in the memory loss and related cognitive problems associated with old age and dementia, and proper enhancement or restoration of cholinergic function may significantly reduce the severity of the cognitive loss. One should note that the cholinergic hypothesis states nothing about etiological factors responsible for aging or dementia. Rather, it attempts to explain only the most direct, cause-effect relationship associated with the primary symptoms (i.e., memory loss). Likewise, the hypothesis does not address the additional roles that cholinergic dysfunction may play in other neurobehavioral disturbances of aging or dementia. Finally, no exclusive or solitary involvement of the cholinergic system in age-related

Selective memory loss following nucleus basalis lesions: Long term behavioral recovery despite persistent cholinergic deficiencies

Rats were trained for several months to perform a radial arm maze task and then given either sham or ibotenic acid lesions of the nucleus basalis magnocellularis (NBM), the primary cholinergic projection to the neocortex. The lesion produced a profound and apparently selective disturbance in memory for recent events. Further testing revealed that although the memory deficit persisted for several weeks, a gradual but complete recovery eventually occurred. Moreover, when these functionally recovered rats were later tested on a passive avoidance task that is normally sensitive to lesions of the NBM, no deficit was found. Thus, the post-lesion recovery of function generalized to a different memory test, upon which no post-lesion practice had been given. Post-mortem determinations revealed that the lesions caused marked neurodegeneration of the NBM, and decreases in both cortical choline acetyltransferase activity and high affinity choline uptake, but had no effect on density of muscarinic receptors. No evidence of neuronal recovery or neurochemical compensatory changes in the cholinergic system was found in the cortical projection areas, lesion site, or in parallel cholinergic systems terminating in the hippocampus or olfactory bulb. These results support the idea that the cortically-projecting cholinergic cells of the NBM normally play an important role in mediating recent memory. However, they also demonstrate that any simple relationship between the function of this brain region and the mediation of recent memory is unlikely. Finally, the results of this study direct attention toward issues related to the mechanisms involved with the recovery of function, and the extent to which degeneration of this brain area may contribute directly to the severe disturbance of cognitive function associated with certain neurodegenerative diseases (e.g., Alzheimers, Picks and Parkinsons disease).

A Longitudinal Study of Cognitive Function in Elderly Persons with Subjective Memory Complaints

Objective: To assess change in cognitive function in elderly individuals with subjective memory loss over a follow‐up interval of more than 3 years.

Implications of memory and language dysfunction in the naming deficit of senile dementia

Young normals, elderly normals, and patients with either mild-to-moderate or severe senile dementia of the Alzheimer type (SDAT) were administered several tests of language function and remote memory. On all of the language tests examined, elderly normals exhibited a mild, nonsignificant performance decrement relative to the young normals. Advanced SDAT patients were markedly impaired on all of the tests. Early dementia patients were most impaired, relative to aged normals, on tests of object naming, category instance fluency, and remote memory. The deficit was smaller on the WAIS vocabulary subtest, on selecting the name of a visually presented object, and on recalling the function of an object. Early SDAT patients were least impaired in selecting the picture of an object after its name had been provided and in selecting objects that belong to a specified functional category. The results are consistent with the notion that the language dysfunction in early SDAT is due to a deficit in semantic memory function in which general, categorical information remains available whereas information about specific attributes becomes less accessible. The object naming test might be useful in the assessment of treatment effects upon SDAT because of its sensitivity and specificity to dementia, its high face validity, and its independence of recent memory.

Hypersensitivity to scopolamine in the elderly

Scopolamine hydrobromide, 0.43 mg/70 kg, was administered by subcutaneous injection to ten young and ten elderly subjects. A comprehensive neuropsychological test battery was used to assess the effects of scopolamine, as compared to placebo, on cognitive function. As previously reported for this group of young subjects, scopolamine significantly impaired performance on tests of recent memory and visuospatial praxis. The same effects were observed in the elderly subjects, but the magnitude of the effects was much larger. The scopolamine injections produced significant psychomotor slowing in the elderly, whereas higher doses of the drug are required to produce this effect in young subjects. In both young and old subjects scopolamine failed to affect immediate memory, language function, object sorting, and the frequency of intrusion errors (although trends toward an effect were more apparent in the elderly). Remote memory, tested in the elderly only, was also unaffected. The results suggest that scopolamines cognitive effects are quantitatively more pronounced in elderly subjects than young subjects, but that they are qualitatively similar and do not constitute a valid model for the cognitive dysfunction associated with Alzheimers disease.

A Two-Year Longitudinal Study of Cognitive Function in Normal Aging and Alzheimer's Disease

A group of 136 elderly subjects were administered a comprehensive neuropsychological test battery, which was readministered 2 years later. Among the 136 elderly subjects, 86 were assigned a diagnosis of probable Alzheimers disease. An additional 33 young subjects were administered the assessment battery at baseline only. The normal elderly group exhibited no decline in cognitive test performance over the 2-year follow-up interval. Subjects with mild cognitive impairment, however, were as likely to deteriorate between baseline and follow-up as the more severely impaired subjects. The tests that exhibited longitudinal decline in the Alzheimers disease patients constituted a subset of the tests that revealed cross-sectional deficits relative to the normal elderly. Differences in baseline cognitive test performance and in rate of cognitive deterioration were examined in relatively young versus relatively old Alzheimers disease patients. Potential psychometric predictors of cognitive decline in the normal elderly were identified.

Scopolamine effects on memory, language, visuospatial praxis and psychomotor speed

Scopolamine hydrobromide was administered by subcutaneous injection to 30 young subjects in a dose of 0.22 mg/70 kg, 0.43 mg/70 kg, or 0.65 mg/70 kg. Treatment effects were compared to placebo on an extensive cognitive assessment battery. Almost all tests in the battery had been previously administered to Alzheimers disease patients and nondemented elderly subjects. Scopolamine produced deficits on tests of verbal recall, visuospatial recall, visual recognition memory, visuospatial praxis, visuoperceptual function, and psychomotor speed. Immediate memory, language function, object sorting, and frequency of intrusion errors were unaffected. The low dose of scopolamine produced some peripheral anticholinergic signs but did not affect the cognitive measures. The results support the conclusion reached in previous studies that the cognitive profile of scopolamine-injected young subjects is more similar to that of the nondemented elderly than to that of Alzheimers disease patients.

Behavioral recovery following bilateral lesions of the nucleus basalis does not occur spontaneously

Recent studies have shown that rats given bilateral ibotenic acid lesions of the nucleus basalis (NBM) exhibit significant impairments on tasks requiring recent or trial-specific memory. However, despite the persistence of cholinergic deficiencies in the cortical projection area, the memory impairments gradually recover over a period of several months of training. Moreover, in one study, the behavioral recovery on a radial arm maze retention task was shown to generalize to a completely different behavior paradigm (passive avoidance) on which the animals had received no prior experience. The present study was performed to determine the extent to which this generalized recovery of performance on memory tasks is dependent upon extensive post-lesion training. Rats were given ibotenic acid lesions of the NBM and were then passively detained in their home cages for six months. Contrary to animals which had received post-surgical radial arm maze experience, the animals detained in their home cages displayed a significant retention impairment when tested on the passive avoidance task, suggesting that the experience the animals receive is an important factor for whether post-lesion functional recovery occurs. This study also confirms that the loss of cholinergic markers following bilateral, NBM lesions persists for at least several months, or longer.

Behavioral and biochemical effects of nucleus basalis magnocellularis lesions: implications and possible relevance to understanding or treating Alzheimer's disease.

Publisher Summary Alzheimers disease is an age-related neurodegenerative disorder, which is clinically characterized by its deleterious effects on higher cognitive function. Although issues regarding the nature, etiology, and treatment of Alzheimers disease are interrelated, they often require different types of experiments at different levels of analysis. This chapter presents data from a series of studies that addresses several separate, but inter-related issues. The first involves the question of the functional role of the nucleus basalis magnocellularis (NBM) in mediating memory. The second issue concerns the role that cell loss in the nucleus basalis may play in the early symptoms of Alzheimers and other neurodegenerative diseases. Certainly, the profound and specific loss of memory following damage to the basal forebrain-cortical cholinergic system provides a strong argument for a possible role. Moreover, the operational similarities between the artificially induced deficit and the memory loss found to occur spontaneously in aged rodents, primates, humans, and early-stage Alzheimer patients make the argument for an important role even more compelling.