Cholinergic innervation in neuritic plaques.

Although several studies of Alzheimer's disease suggest that the frequency of neuritic plaques in the cerebral cortex is correlated with the severity of dementia and with reduction in presynaptic cholinergic markers in the cortex, the relationship between cholinergic cortical innervation and the pathogenesis of plaques is unknown. The hypothesis was tested that the neurites in the plaque consist, in part, of presynaptic cholinergic axons, many of which arise from neurons in the basal forebrain. This hypothesis was tested by analyzing the character and distribution of plaques in monkeys, aged 4 to 31 years, with staining for acetylcholin-esterase and also with Congo red and silver stains. Immature and mature plaques were rich in acetylcholinesterase. As the plaques matured, the amount of amyloid increased, and the number of neurites and the activity of acetylcholinesterase decreased. End-stage amyloid-rich plaques lacked acetylcholinesterase. These observations indicate that changes in cortical cholinergic innervation are an important feature in the pathogenesis and evolution of the neuritic plaque.

Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain.

Recent evidence indicates that the nucleus basalis of Meynert, a distinct population of basal forebrain neurons, is a major source of cholinergic innervation of the cerebral cortex. Postmortem studies have previously demonstrated profound reduction in the presynaptic markers for cholinergic neurons in the cortex of patients with Alzheimer's disease and senile dementia of the Alzheimer's type. The results of this study show that neurons of the nucleus basalis of Meynert undergo a profound (greater than 75 percent) and selective degeneration in these patients and provide a pathological substrate of the cholinergic deficiency in their brains. Demonstration of selective degeneration of such neurons represents the first documentation of a loss of a transmitter-specific neuronal population in a major disorder of higher cortical function and, as such, points to a critical subcortical lesion in Alzheimer's patients.

The role of nutrients in the prevention and treatment of Alzheimer's disease: methodology for a systematic review.

There is a large body of existing data on nutrition in Alzheimer's disease (AD). We are conducting a systematic review of published scientific literature to determine the role of specific nutrients, both individually and in combination, in the prevention and treatment of AD. This will contribute towards a structured evidence base to help inform the clinical management of AD. The objective of the systematic review is to evaluate the strength of evidence from both observational cohort studies and randomized controlled trials on the role of fats, vitamins, antioxidants and other nutrients in the prevention and treatment of AD. We present here the methodology of our systematic review.

Topography of the magnocellular basal forebrain system in human brain.

In primates, the large neurons in the nucleus basalis of Meynert (nbM), nucleus of the diagonal band of Broca (dbB), and medial septum are part of a cholinergic system with direct projections to amygdala, hippocampus, and cortex. Recent evidence indicates that neurons of this system selectively degenerate in individuals with Alzheimer's disease (AD) and suggests that degeneration of these cells contributes to the loss of presynaptic cortical cholinergic markers which occurs in these patients. The present report describes the topographical distribution of these large intensely basophilic, basal forebrain neurons in human brain. Rostrally, neurons of this magnocellular system are present in the medial septum and the dorsal and ventral parts of the nucleus of the dbB. The largest number occur in the nbM, which is situated in the substantia innominata below the globus pallidus. Caudally, large nbM-type neurons are found along the ventral and lateral edges of the globus pallidus. Neurons of this type are also encountered in the white matter below the putamen and nucleus accumbens, at the edges of the anterio commissure, in the white matter laminae of the globus pallidus and within and at the medial edge of the genu of the interal capsule. Directions for dissection of this system in human brain are given in an Appendix.

Cholinergic therapy in dementia.

After reviewing the evidence for cholinergic pathology in Alzheimer's disease and related disorders, this paper reviews strategies for treating dementia using cholinomimetic drugs. Special attention is paid to cholinesterase inhibitors, particularly tacrine, the drug recently approved by the FDA. New studies suggesting that muscarinic and nicotinic cholinergic receptor active drugs may be more effective will be reviewed. Brief mention will be made of strategies to slow the progression of Alzheimer's disease.

Future prospects for Alzheimer's disease therapy: ethical and policy issues for the international community.

In addition to being driven by basic scientific research and the preclinical and clinical evaluation of promising new compounds, the development of drugs for patients with Alzheimer's disease (AD) must also be guided by public policy and ethical considerations. More carefully coordinated efforts should be devoted to reducing caregiver burden and providing community-based health care services for patients with chronic as opposed to acute diseases. Important ethical issues include the appropriate duration of double-blind, placebo-controlled clinical trials, the determination of the meaning of "informed consent" when dealing with patients with dementia, the establishment of outcome goals for various stages of the disease process, and the provision of appropriate hospice-type care. The establishment of the International Working Group on Harmonization of Dementia Drug Guidelines is an important step in the process of achieving an international approach toward the development and evaluation of drugs for patients with AD.

Specific neurochemical systems and memory.

This commentary addresses issues raised in common by the various authors of papers in this section: the role of different chemical systems in memory, new approaches for assessing the effects of drugs, and issues for the future in evaluating animal models of human disorders of memory.

New approaches to quantitative neuropathology: multivariate analysis of morphologic and neurochemical measures.

The excellent review by Coleman and Flood on neuropathological changes in normal aging and Alzheimer's disease highlights the need for development and application of computer-assisted image analysis to the study of neurons in these conditions. The morphological and neurochemical changes in normal and pathological aging require quantitation and statistical analysis that can be best performed with the assistance of the image and data processing capabilities of the computer. Advanced image processing systems are being developed to identify and classify neurons according to several intelligently chosen visual features, apply discriminant analysis and population statistics to this data, and correlate this information to other neurochemical measurements as well as the clinical history of the patient. Techniques such as immunocytochemistry, receptor autoradiography and in situ hybridization produce information-rich images of the distribution of proteins and nucleic acids in tissue slices that can be analyzed by this approach.

Is the placebo control obsolete in a world after donepezil and vitamin E?

Recent clinical trials of donepezil and vitamin E have produced active therapeutic drugs for the treatment of patients with Alzheimer disease (AD). The AD research community is now in a gray zone between the absence of accepted therapies and the presence of completely effective therapies. How should these therapies guide the choice of the proper control for future AD clinical trials? The community equipoise principle can guide a process to answer this question. The principle is that a clinical trial should answer clinical questions that are valued by the community who will use the results of that trial. This means that the choice of the proper control for future AD clinical trials ought to be guided by the values of a community who will experience the results of those trials: physicians and patients or their representatives such as caregivers. The values of patients can be included by giving them a voice in the design and review of clinical trials. Community dialogue should be the norm for the design and review of AD clinical trials. We conclude with suggestions to foster this dialogue and issues that should be addressed.

Personality changes in Alzheimer's disease.

How personality changes in Alzheimer's disease is not well understood. Accentuations of premorbid personality, systematic shifts in personality traits, and specific personality changes affecting subtypes of patients have been postulated. To investigate which of these alternatives occurs in Alzheimer's disease, caregivers were given a comprehensive personality inventory standardized for use by informants. Caregivers observed more neurotic, less extroverted, and less conscientious behavior. To a smaller extent, patients with Alzheimer's disease were reported as becoming less agreeable and less open. The changes in reports of neuroticism, extroversion, agreeableness, and openness suggested consistent systematic shifts across all patients. Patients with depressive features were reported to have been more neurotic; those with paranoid delusions were reported as having been more hostile. Premorbid personality traits may predispose to subsequent psychiatric symptoms in Alzheimer's disease.

Memory evaluation in Alzheimer's disease. Caregivers' appraisals and objective testing.

OBJECTIVES: To evaluate if caregivers are reliable informants concerning memory deficits in patients with Alzheimer's disease (AD). DESIGN: Responses of caregivers of patients with probable AD and responses of healthy control subjects on a standardized memory questionnaire were compared with objective measures of cognition (Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery) and with clinical estimates of activities of daily living, depression, and psychopathology (Consortium to Establish a Registry for Alzheimer's Disease [CERAD] clinical assessment battery) using the Self-report Memory Questionnaire. SETTING: A federally funded AD research center. SUBJECTS: The referred sample included 117 patients with probable AD, their informants, and 41 healthy control subjects age-matched to the patients. Patients and control subjects were between the ages of 58 and 85 years, had between 9 and 19 years of education, and were in good health. EXCLUSIONS: Patients who did not meet NINCDS-ADRDA criteria of probable AD. MAIN OUTCOME MEASURE: The optimal number of questionnaire items yielding the best combination of sensitivity and specificity. RESULTS: An abbreviated version of the scale, renamed the Short-Memory Questionnaire, had excellent specificity and sensitivity for identifying dementia. Positive and negative predictive values were 63.5% and near 100%, respectively. The Short-Memory Questionnaire showed good reliability, internal consistency, and external validity. Caregiver appraisals of memory deficits significantly correlated with objective measures of memory and also with generalized cognitive dysfunction. CONCLUSIONS: Caregivers of patients with AD are reliable informants of their relatives' deficits. The Short-Memory Questionnaire is an easily administered, informant-based scale that may be useful in clinical settings or epidemiologic studies to screen out persons with memory difficulties.

Reductions in acetylcholine and nicotine binding in several degenerative diseases.

Alzheimer's disease, Parkinson's disease, and progressive supranuclear palsy are all characterized by loss of neurons in the basal forebrain cholinergic system and by associated reductions in cortical presynaptic cholinergic markers, such as choline acetyltransferase. In this report, we identify that a major cortical receptor alteration in these disorders is a reduction in nicotinic receptors measured using both tritiated acetylcholine and levorotatory tritiated nicotine binding.

Theodor Meynert: foreshadowing modern concepts of neuropsychiatric pathophysiology.

Theodor Meynert's neuroanatomic studies contributed to the development of the nineteenth-century "brain psychiatry" movement. His speculations--that certain cognitive impairments resulted from an imbalance in blood flow between cortical and subcortical structures--parallel modern controversies concerning the role of these brain regions in the pathophysiology of dementia. Meynert described a subcortical nucleus in the basal forebrain, the nucleus basalis of Meynert, which has recently been shown to provide cholinergic innervation to the cortex. Loss of cells in this structure in Alzheimer's disease, a so-called "cortical" dementia, and in the dementia of Parkinson's disease, a so-called "subcortical" dementia, probably accounts for the loss of cortical cholinergic markers in these diseases. An understanding of Meynert's contributions may avoid unproductive speculation in attempts to study the interactions between cortical and subcortical structures in neuropsychiatric diseases.

Genesis of Alzheimer's disease.

Our understanding of the pathogenesis of Alzheimer's disease (AD) had advanced rapidly, particularly in the area of genetics. Clinical trials of agents that offer the promise of going beyond symptomatic treatment to actually slowing the progression of disease, perhaps by enhancing the viability of neurons, are under way. Most of the ideas for therapeutic approaches that may slow progression of disease have come from a combination of epidemiologic and basic science observations. Anti-inflammatory agents, nicotine, estrogens, and free radical scavengers are major areas of inquiry. In addition to being a biological condition of considerable complexity, AD is also challenging from a social and cultural perspective. An appreciation of the changes occurring in our scientific and clinical environments may lead to building more effective bridges between science and society and to better diagnostic and therapeutic approaches to AD.

Differential diagnosis of Alzheimer's disease.

Accurate diagnosis of dementia is essential to provide appropriate treatment as well as patient and family counseling. It may be difficult to differentiate dementia from delirium. In addition, several features distinguish dementia from depression, but the two can coexist and the distinction may be uncertain. Dementias can be grouped into two categories: dementia that presents without prominent motor signs and dementia that presents with prominent motor signs. Dementias without prominent motor signs include Alzheimer's disease, frontotemporal dementia, and Creutzfeld-Jakob and other prion diseases. Dementias characterized at onset by prominent motor signs include dementias with Lewy bodies, idiopathic Parkinson's disease, progressive supranuclear palsy, cortico-basal ganglionic degeneration, hydrocephalus, Huntington's disease, and vascular dementia. Routine diagnostic steps include a careful history, mental status screening, laboratory and imaging studies, and neuropsychologic testing. Genetic testing is available, but its use is controversial and raises complex ethical questions.

Neurotransmitter receptors in olivopontocerebellar atrophy: an autoradiographic study.

We used in vitro receptor autoradiography to study four cases of olivopontocerebellar atrophy (OPCA) and three age- and postmortem delay-matched controls. In OPCA, benzodiazepine receptors were unchanged in cerebellar cortex but increased in the dentate nucleus, perhaps related to loss of Purkinje cell or brainstem afferents. Muscimol binding was reduced primarily in the granule cell layer. The density of muscarinic cholinergic receptors was reduced in molecular and granule cell layers, but appeared increased in the dentate.

Complex visual disturbances in Alzheimer's disease.

Although Alzheimer's disease (AD) involves visual association cortex, previous studies have not systematically investigated complex visual disturbances in AD. We examined 30 community-based AD patients, 13 (43%) of whom had complex visual complaints, and compared them with 30 controls on 7 types of complex visual tasks. Despite preserved visual acuity and color recognition, the AD patients were impaired in the visual evaluation of common objects, famous faces, spatial locations, and complex figures. In the AD patients, we found that all 30 had disturbances in figure-ground analysis; 17 (57%) had difficulties visually recognizing actual objects ("agnosia"); those with worse dementia disability had the most complex visual disturbances; and a subgroup (6) with Balint's syndrome performed the most poorly on the complex visual tasks. This study demonstrates that a range of complex visual disturbances are common in AD and suggests that they may result from the known neuropathology in the visual association cortex.

Alzheimer's disease: low levels of peptide alpha-amidation activity in brain and CSF.

Carboxyl terminal alpha-amidation confers biologic activity to many neuropeptides. Levels of alpha-amidating activity, peptidyl-glycine alpha-amidating monooxygenase (PAM), were reduced in the CSF of patients with dementia of the Alzheimer type (DAT) compared with healthy, age-matched controls. Repeat lumbar puncture data revealed a decline in CSF PAM activity of approximately 16% per year in DAT patients. Of the cerebral cortical regions examined, only the temporal pole showed reduced PAM activity in patients with Alzheimer's disease (AD) compared with controls. These studies may indicate selective dysfunction of neurons which normally synthesize biologically active, alpha-amidated peptides in the CNS of AD patients.

Huntington's disease: increased number and altered regulation of benzodiazepine receptor complexes in frontal cerebral cortex.

The properties of benzodiazepine receptors in samples of six areas of cerebral cortex from patients and controls matched with respect to age, sex, and postmortem delay have been studied by in vitro radioligand binding techniques. A statistically significant 30 to 40% increase in the number of benzodiazepine and allosterically linked GABA-A receptors is observed in the midfrontal cortex (A9/A10), but in no other cortical region examined. The degree of enhancement of [3H]diazepam binding by a given dose of GABA or pentobarbital is significantly reduced in Huntington's disease midfrontal cortex. As in the case of receptor number changes, other cortical regions examined show less prominent changes in regulation of benzodiazepine binding by GABA or pentobarbital. Direct identification of the benzodiazepine binding subunit by photoaffinity labeling with [3H]flunitrazepam reveals a single species of apparent molecular weight 51 kD in patients and controls, suggesting that gross changes in structure of the benzodiazepine binding subunit do not account for the observed alterations in benzodiazepine receptor regulation.

Gender differences in language of AD patients: a longitudinal study.

We examined gender differences in probable Alzheimer's disease (AD) patients on language measures at four data collections (entry, 6, 12, and 18 months) and a normal elderly (NE) comparison group at entry and 18 months. Comparison of gender differences in language abilities of 60 (29 men, 31 women) early (Clinical Dementia Ratings I and II) AD subjects at entry revealed significant effects for gender on the Boston Naming Test (BNT) and Peabody Picture Vocabulary Test-Revised (PPVT-R) but not on the Word Fluency Test, shortened Token Test, or modified Reporter's Test. The 37 subjects (18 men, 19 women) who completed less than four data collection sessions compared with the 23 subjects (11 men, 12 women) who completed all four sessions differed on education and Reporter's Test scores. Longitudinal analysis of measures showed that gender differences persisted for the BNT and PPVT-R and that time differences were found on all measures. Gender differences remained after correcting for age, education, duration of illness, and mental status. We found no differences for the NE comparison group for gender or time. All AD subject trends were downward, suggesting that (1) language is affected over time in AD, (2) both men and women decline at similar rates, and (3) language abilities of women are more severely impaired at all time points.