The close cooperation of clinical and laboratory research has helped to clarify the etiology of some of the dementing processes of the senium. However, the necessary investigations are complicated, laborious, expensive and can be carried out only in well equipped centres in larger cities. This restricts the number of patients who eventually may benefit from these investigations to a small number. What is needed for the psychogeriatric practice particularly in rural areas and smaller cities are simple diagnostic guidelines for the psychiatrist to answer the question whether the patient suffers from a dementia and if so whether the dementia is in all probability due to a primary degenerative process of the brain parenchyma or of the cerebral vasculature or is it due to another cause.

If degeneration of the brain parenchyma seems the prevalent pathogenetic mechanism one would like to establish in a given case which of the known degenerative processes is most probably present in order to avoid mistakes in clinical judgement with their often life threatening consequences.

As part of a prospective clinicopathological study a cohort of “normal” elderly volunteers (n = 110) has been investigated with CT scans, psychometric testing (Extended Scale for Dementia) and neurological examination. CT scans were evaluated by a neuroradiologist for the presence or absence of white matter lucencies (WML). WML were defined as patchy or diffuse areas of decreased attenuation involving only white matter and with no change in adjacent ventricles or sulci.

The 12 subjects with WML had lower scores on the ESD than the 98 subjects without WML (mean ESD with WML 229.5± 14; without WML 236.7±8.6, t-test p<.01) and the difference remains significant even after adjusting for the possible confounding effects of age (ANCOVA, P<.043).

Physostigmine, oxotremorine, RS-86, and a combination of piracetam and lecithin, have all been studied in patients with Alzheimer's disease. Intravenous physostigmine produced a significant improvement in patients' ability to recognize words and particularly to distinguish words they had never seen before from words previously presented. A subgroup of Alzheimer's patients had a clinically meaningful improvement to treatment with oral physostigmine, with the degree of improvement correlating with the ability of oral physostigmine to increase the nocturnal secretion of Cortisol. No statistically significant differences of piracetam or piracetam and lecithin, compared to placebo were noted, however, the ratio of red cell to plasma choline might be associated with treatment responsivity. The potential therapeutic efficacy of oxotremorine proved all but impossible to assess due to concomitant adverse effects, particularly dysphoria. Results with another cholinergic agonist, RS-86, will be reported. This drug appeared to be better tolerated than oxotremorine.

Animals with a kianic acid induced cortical depletion of choline acetyltransferase were found to have a significant impairment in retention of a passive avoidance task, an abnormality that was readily reversible by physostigmine, oxotremorine and 4-amino-pyridine. Cysteamine, a depletor of somatostatin, also produced a comparable deficit.

Neurotransmitter replacement therapy in Alzheimer's Disease is currently being attempted using bethanechol chloride (Urecholine) infused intracerebroventricularly with an Infusaid continuous infusion pump. The rationale of this therapy is based on the severe cortical pre-synaptic cholinergic deficit in the presence of relatively normal post-synaptic muscarinic receptor density. Patients are selected on the basis of strict clinical criteria at a functional stage 4 or 5 of Reisberg. A cortical biopsy at the time of pump and catheter implantation confirms the diagnosis by histological and biochemical examination. Pre-operative, post-operative and serial mental status assessments combined with functional ADL assessments monitor changes in behavior. A 6 months double-blind treatment period is done in every patient, who is then free to continue if he has improved on active treatment. This specific study is part of a multi-centre trial. Other therapeutic trials using somatostatin analogs, such as Sandostatin, could then be done. The biological effects of the latter compound are being studied currently in adult Green Vervet monkeys, prior to its use in Alzheimer patients. Furthermore autoradiography of bethanechol and peptides labeled with 14C administered in these animals by intracerebroventricular infusion will allow a better knowledge of their pharmacological site of action.

Abnormal findings on neurological examination were evaluated in 165 patients with a clinical diagnosis of Alzheimer's disease who attended a memory disorders clinic. Severity of dementia was measured by the Blessed Dementia Scale, and associations of abnormalities with dementia severity were evaluated using logistic regression. Presence of aphasia, apraxia, and primitive reflexes on neurological examination were strongly associated with severity, and weak associations were observed for abnormalities of muscle tone and gait. Among these associated neurological features, only aphasia and apraxia were present in mildly demented cases with sufficient frequency to suggest utility as diagnostic signs early in the course of the disease.

This paper reports neuropsychologic and pathologic data for eleven patients with a clinical diagnosis of probable Alzheimer disease (AD) according to recently proposed NINCDS criteria. In all cases, the clinical diagnoses were verified by cortical biopsy using histopathologic criteria for definite AD. Similar tissue samples from nine non-demented autopsied patients were also evaluated and none received an histopathologic diagnosis of AD. Correlations between cortical plaque counts and neuropsychologic test scores are also presented. These data have important implications for 1) the accuracy of clinical diagnosis in AD; 2) the validity of NINCDS criteria for the clinical and pathologic diagnosis of AD; and 3) the utility of cognitive test scores as indicators of disease severity.

Our findings dispel the commonly held belief that the EEG always worsens progressively in dementia of the Alzheimer's type. In a continuing cohort analytical study of dementia, 139 patients with Alzheimer's disease and 148 controls were studied for EEG abnormalities and progression. EEGs were read without knowledge of the previous EEGs or clinical condition, and classified according to the presence of diffuse delta or theta, bisynchronousspikes, projected activity, and focal activity. EEGs were significantly different in the two groups. EEG scores generally worsened over 1-4 years, but most of the subjects showed no alteration in their EEG scores. A few patients with Alzheimer's disease showed improvement of EEG findings.

The terms “cortical” and “subcortical” dementia are controversial; however, the clinical distinction between them is real. For example, although Alzheimer's and Parkinson's disease (prototypical of cortical and subcortical dementia, respectively) share clinical features, they differ in the presence of aphasia, apraxia, and agnosia in Alzheimer's disease but not in Parkinson's dementia. We review our studies aimed at clarifying the mechanisms underlying the differences between these neurological disorders. Experimental paradigms adopted from animal models were used to study the functional anatomy and neuropsychological characteristics of Alzheimer's and Parkinson's disease. The tasks administered include delayed alternation (DA) and delayed response (DR), which are sensitive to frontal system damage, and tactile discrimination learning (TOL) and reversal (TRL) paradigms sensitive to parietal system damage. Alzheimer's patients were significantly impaired on all tasks whereas Parkinsonians with dementia were impaired only on DR and TRL. Consideration of neuroanatomical and neuropsychological mechanisms involved in DA, DR, TOL, and TRL appears to have sharpened the distinction between Alzheimer's and Parkinson's dementia. Dementia in Alzheimer's disease may involve dorsolateral frontal, orbitofrontal and parietal systems. In contrast, dementia in Parkinson's disease may involve prominent dorsolateral frontal system damage.

Language impairment in Alzheimer's disease has become an important clinical issue. It has been recognized for some time that the disease may begin with aphasia and even before frank aphasia develops, some of the earliest changes in a large number of individuals consist of impairment of word fluency and semantic access manifesting itself in word finding difficulty. The second major issue concerning language in Alzheimer's disease is that the cases which have early severe language impairment may represent a more progressive familial variety of disease as it has been suggested in the literature. This is still subject to controversy. Finally, it will be documented that the later stage of the disease shows language invariably impaired and goes through stages of dissolution that resemble anomic, transcortical sensory, Wernicke's and global aphasias. Accurate assessment of language may turn out to be one of the most reliable predictors of the stages of Alzheimer's disease and provides important insights into the cerebral organization of language, semantic access, relationship of semantic and episodic memory and the pathophysiology of the disease.

Currently the diagnosis of progressive organic dementia is one of exclusion offered only after cognitive decline is well advanced. Early in the disease process, memory complaints most often bring elderly people to the attention of their family physician .This behaviour represents the first step in the process of giving a patient the medical diagnosis of organic dementia, yet no systematic method has been developed to gather such subjective information and evaluate its medical significance. We are developing a memory complaints questionnaire and a brief non-threatening memory screening instrument to help identify organic dementia in its earliest stages. The screening device will be related to more sophisticated neuropsychological measures of dementia and it should be sensitive to mental deterioration over short periods of time. The instruments will document perceived and objective changes in memory and will help the physician attribute their findings to normal aging, depression and/or degenerative CNS disease.

This paper describes select results of a longitudinal study of 62 mild to moderate Alzheimer's disease (AD) patients, in comparison to 60 age-matched healthy controls. Initial neurologic, radiologic, psychiatric, laboratory and cognitive examinations, required two full days, followed by one-day examinations at annual intervals. Of the total original sample, 31 AD patients and 39 controls could actually be followed for three annual examinations. Cognitive examination data confirmed cross-sectional (group discriminative) validity of memory and language measures, and showed the expected longitudinal deterioration in the AD sample, with controls maintaining consistent performance over the three years. However, those measures showing largest group differences at initial examination were not the best for tracking patient deterioration over time. Implications of these results for the selection of cognitive assessment measures are discussed.

The study of Alzheimer's disease is hampered by insufficient knowledge of its cause. It can best be described as a syndrome whose clinical and pathological features, and their associations over time, need to be more carefully examined. Issues which impede our understanding of this syndrome include the lack of: (a) a singular “gold standard” for its identification; (b) longitudinal studies with appropriate comparison groups and neuropathological follow-up; and (c) standardized multifaceted clinical assessment procedures. Our awareness of the significance of these issues has led us to undertake a large-scale prospective, longitudinal investigation of 399 dementing and normal individuals at Sunnybrook Medical Centre. As a result of problems identified, it is proposed that research efforts across various Canadian centres be coordinated to best utilize available resources and expertise.

Scrapie affected brains exhibit a number of pathological features in common with the human neurodegenerative condition, Alzheimer's disease. The present report describes studies on chromatin structure seen in these two disease processes.

Chromatin associated proteins influence transcriptional activity of DNA through an effect upon chromatin structure. We examined chromatin structure by: (1) measuring the capacity of the enzyme micrococcal nuclease to release mono- and dinucleosomes from isolated nuclei and (2) measuring DN A-histone interactions by examining the effect of ambient tonicity upon the release of chromatin proteins.

In two strains of mice infected with two strains of scrapie agent there was reduced accessibility to micrococcal nuclease and an increased content on dinucleosomes of the histone HI and Hl° types. These changes precede clinical signs of scrapie and resemble those found in the human conditions of Alzheimer's and Pick's disease. Scrapie mouse brain differs from Alzheimer brain in that scrapie does not alter histone-DNA interactions as monitored by ionically induced histone release from chromatin. Despite similarities, the scrapie agent appears to operate upon different molecular mechanisms than those found in Alzheimer's disease.

Studies of families located through a proband with dementia of the Alzheimer type have demonstrated transmission of the disorder within families, probably through shared genes. Increasing closeness of genetic relationship and increasing severity of illness are both associated with increasing risk to relatives. Families a.t high risk are especially valuable for studies of the biology of dementing illness including, in particular, their molecular genetics. Associations at several levels between Down's syndrome and Alzheimer's dementia provide important clues for molecular hypotheses.

We examined the degree of neuronal loss from the nucleus basalis of Meynert (nbM) in two groups of Alzheimer patients differing in the degree of intellectual impairment. Significant cell loss from the nbM was found only in the more severely demented group of patients. Mean cell counts (per lOu, paraffin section) were compiled separately for the anterior, intermediate and posterior subdivisions of the human nbM in three groups of subjects: Group 1 (N = 4) was severely demented and was untestable on the Extended Scale for Dementia (ESD) for at least the last two years of life; Group 2 (N = 4) was less demented and had completed at least one ESD test within 12 months of death; Group 3 (five controls) had died of non-neurological causes. In Group 2 there was a small (but insignificant) trend toward cell loss in the anterior subdivision, and a normal complement of neurons in both the intermediate and posterior subdivisions. There was, however, significant cell loss from all subdivisions of Group 1. How these cell counts may relate to the severity of the dementia is discussed.

Alzheimer's disease is a progressive neurodegenerative disease characterized neuropathologically by the development of large numbers of neurofibrillary tangles in certain neuronal populations of affected brains. This paper presents a review of the available evidence which suggests that aluminum is associated with Alzheimer's disease and specifically with the development of the neurofibrillary tangle. Aluminum salts innoculated into experimental animals produce neurofilamentous lesions which are similar, though not identical, to the neurofibrillary tangle of man. Although a few reports have suggested evidence of increased amounts of aluminum in the brains of Alzheimer's disease victims, such bulk analysis studies have been difficult to replicate. Using scanning electron microscopy with x-ray spectrometry, we have identified accumulations of aluminum in neurofibrillary tangle-bearing neurons of Alzheimer's disease. Similar accumulations have been identified in the neurofibrillary tangle-bearing neurons found in the brains of indigenous natives of Guam who suffer from parkinsonism with dementia and amyotrophic lateral sclerosis. This ongoing research still cannot ascribe a causal role of aluminum in the pathogenesis of neurofibrillary tangle formation; however, it does suggest that environmental factors may play an important part in the formation of this abnormality.

The current evidence for and against abnormalities of the blood-brain barrier in “normal” aging and Alzheimer's disease is reviewed. Recent studies of cerebral amyloid angiopathy, a microangiopathy commonly observed in Alzheimer's disease and one suggested to result from blood-brain barrier derangement, are discussed with particular attention to the biochemical nature of the vascular amyloid material, and features it shares with the amyloid found in senile plaque cores and with neurofibrillary tangles. Modern techniques that will probably clarify blood-brain barrier pathophysiology are reviewed.

Unconventional agents and conventional viruses provide model systems to investigate the pathogenesis of Alzheimer's disease (AD). The essay which follows examines the hypothetical role of herpes simplex in AD and presents some generally applicable experimental approaches to detecting genes in brain tissues. The concluding section, on parallels between AD and diseases of the brain caused by unconventional viruses, defines strategies for isolating genes related to pathology.