After organizational involvement in a clinicopathological investigation of Alzheimer's Disease for a decade, the present appears an appropriate time to reflect upon both the major challenges encountered as well as the exciting opportunities presented by such a longitudinal study.

Problematic areas have included: (a) brevity of research grant intervals (generally one- or two-year); (b) turnover of support personnel, as a consequence; (c) limited biostatistical and data management expertise dedicated to the Study objectives; (d) limited neuropsychological manpower in this specialized sphere; (e) “distillate” effect of postmortem retrieval, by which only some of the many clinical cases expire during any grant period, only some of those receive autopsy permission, only some of those demonstrate (pure) Alzheimer's Disease neuropathologically, and only some are harvested quickly enough for specialized (e.g. biochemical) analyses; (f) ensuring the scientific optimization of available tissue samples; and (g) paucity of cases dying in the early stages of the illness.

Significant achievements include: (a) demonstration of the opportunities for young researchers committed to careers in behavioral neurology, psychogeriatrics or neurodegenerative pathology; (b) development of improved testing protocols for psychometric, electroencephalographic and neuroradiological evaluation of the demented elderly; (c) ethical enrolment both of a large cohort of Alzheimer patients and a sizeable normative (control) population; (d) public cooperation permitting a postmortem compliance rate exceeding 75%; (e) rapid autopsy retrieval times (50% < 6 hours); (f) utilization of human postmortem synaptosomal preparations for neurochemical investigations; (g) availability of fresh autopsy tissues for other specialized techniques (e.g. magnetic resonance spectroscopy, in situ hybridization); and (h) a collegial forum for the regular exchange of scientific data.

While the challenges to be met are certainly not unique to our Study, the interdisciplinary and longitudinal nature of this approach could magnify their potentially retardatory effect upon research quality. By contrast, however, surmounting these hurdles enables the participant scientists to share in an incomparable opportunity for observational insights into the cellular and pathogenetic mechanisms underlying the cognitive decline of Alzheimer patients. The vigour with which my numerous collaborators at the University of Western Ontario meet such challenges may serve as a model for other Alzheimer centres where a similar research system is likewise expected to justify the anticipation of its supportive funding agencies, and of the patients whom we are pledged to comfort.

Hippocampal capillary and arteriolar measurements showed a significant reduction in capacity with normal aging. Alzheimer's dementia was not associated with any further reduction; in fact regional variations suggested that the zones of Amnion's horn most severely affected by tangles and granulovacuoles retained the best vascular capacity.

The arterial system supplying the hippocampus, from the posterior cerebral artery to the series of small hippocampal arteries, was also assessed. Its capacity, as judged by arterial diameters, was similarly found to decrease significantly with age; the arterial diameters of Alzheimer cases were (insignificantly) greater than those of the normal old.

Calcarine capillary and arteriolar measurements also indicated a marked reduction of capacity with normal aging, and, as before, in Alzheimer's dementia there was no further significant change. All three phases of the study thus suggest that cerebrovascular capacity in Alzheimer's dementia is at least as good as in the normal old, if not better.

Senile (neuritic) plaques with amyloid cores and their relationship to the microvasculature were examined in the calcarine cortex. In both normal old and Alzheimer cases the plaques tended to congregate where capillaries were densest. Their correlation with capillary density was however better in the normal old, raising the question of whether their pathogenesis might differ in the two conditions.

To define the pathology in cases of non-Alzheimer primary degenerative dementia (non-AD PDD), we have studied autopsies from four medical centres accessioned in consecutive years since 1976. Neurochemical studies of the basal forebrain-cortical (BF-C) cholinergic system have been conducted in cases from which frozen tissue was available. Twenty-two cases (mean age 70 years, range 47-86) in which the history was consistent with PDD, but which did not meet anatomic criteria for AD, were selected. Approximately 70 cases of PDD, which were accessioned in the same years and met the anatomic criteria for AD, were excluded. The pathologic findings permitted a classification into six groups: Lewy body disease (LBD), 4 cases; Pick's disease, 6 cases; cortical degeneration with motor neuron disease (CDmnd), 2 cases; hippocampal and temporal lobe sclerosis, 3 cases; few or nonspecific abnormalities, 5 cases; other disorders, 2 cases. Our findings suggest that LBD and Pick's disease account for a large proportion of cases of non-AD PDD in the presenile age group, but that a large number of other disorders occasionally present as PDD. Careful examination of the motor systems, as well as cerebral structures relate' to cognitive function, is important in the neuropathologic evaluation. Lesions of the BF-C cholinergic system have been most consistent and severe in LBD, and have not been identified in CDmnd.

A potential relationship between Alzheimer's Disease (AD) and insulin gene expression was suggested by the observation that patients with AD have altered levels of fasting blood sugar and insulin. Since polymorphisms in the region 5' to the insulin gene have been associated with blood glucose levels, we have studied this polymorphism in AD patients. Subjects were 19 nondiabetic AD patients with symptoms of aphasia and apraxia and a family history of AD; and 20 age and sex-matched nondiabetic controls without family history of AD. The 5' polymorphic region of the insulin gene was analyzed by restriction enzyme digestion of DNA extracted from whole venous blood. We did not observe a correlation between the size of the 5' polymorphic region and AD.