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.

In normal human aging the remaining neurons of two areas of the hippocampal region have been found to compensate for age-related neuronal loss by proliferating new dendrites. In Alzheimer's disease (AD) the layer II pyramidal neurons of the parahippocampal gyrus fail to show this compensatory response, in spite of a probable, exaggerated disease-related loss of neurons. In AD the dentate gyrus granule cells of the hippocampus also show a reduced amount of the compensatory response. This failure of the AD brain to show the normal compensatory plastic response, seen in normal aging as dendritic growth, may be viewed as one of the pathophysiological processes of the disease.

This paper describes the comparability of counts in the locus coeruleus made from serial sections and those made from a single section at the point of greatest density of neurons. Samples of the locus coeruleus neuronal population derived from single section counts though not exactly comparable, are of comparable utility to those obtained from more laborious total neuronal counts. The simpler method was used to examine the hypothesis that there are subtypes of senile dementia of the Alzheimer type. Separation into two groups was achieved when independent variables of cortical neuronal counts and tangle estimates were used. This finding adds to the growing evidence that Alzheimer's disease of the senile type is not a unitary disorder.

The brains of most demented patients show at autopsy the lesions of Alzheimer's disease (AD). However, the brains of other demented patients show either no morphological changes or lesions distinct from those of AD. We report clinicopathological studies on two diseases in this latter group. The study of these diseases can improve our understanding of AD.

Pick's disease is characterized by dementia, lobar cerebral atrophy, and neuronal cytoplasmic inclusions. Most cases, which we have called “classical”, show inclusions made up of straight fibrils that are immunologically cross-reactive with the paired helical filaments of AD. In other “generalized” cases, similar fibrils are coated by granular material and are less reactive with anticytoskeletal antibodies.

In contrast to the cytoplasmic localization of the lesions in Pick's disease, it is the cell nucleus that shows abnormalities in neuronal intranuclear hyaline inclusion disease. This disease can present clinically as dementia of adult onset. Thus, either nuclear or cytoplasmic lesions can produce a pattern of neuronal dysfunction resulting in dementia.

Three patients with clinical Alzheimer's disease were found at postmortem examination to have Lewy-bodies and Lewy-like bodies in the cerebral cortex and the pigmented brainstem nuclei. Neuritic plaques were found in neocortical areas but no neurofibrillary tangles. The distribution of cortical neuronal inclusions correlated with the proposed projection of dopamine terminals. Neuronal cell loss was marked in the ventral tegmental area (paranigral nucleus) and the basal nucleus of Meynert, suggesting a defect in dopaminergic and cholinergic innervation of the cerebral cortex. Immunohistochemical investigations revealed positive staining of cortical Lewy- and Lewy-like bodies for monoclonal antibodies to phosphorylated neurofilaments (03-44, 06-17, 04-7). Also cerebral neurons containing no inclusions showed positivity, suggesting an early neurofilament abnormality, preceding the formation of Lewy-type inclusions.

The effects of bilateral ibotenic acid-induced lesions of the nucleus basalis magnocellularis (nBM) on the acquisition and retention of several spatial memory tasks were studied in the rat. Maintenance of spatial memory in a food search task was impaired following nBM lesions. Acquisition of spontaneous alternation and reinforced alternation in a T-maze was also significantly impaired in animals with these lesions. In contrast, the animals with nBM lesions were not impaired in the acquisition of a position habit in a T-maze. In several of the tasks there was evidence of some learning in the lesioned animals after substantial training, although they were significantly deficient when compared with the controls. Administration of the cholinergic agonists physostigmine sulfate or pilocarpine nitrate prior to behavioral testing resulted in a rapid and significant improvement in the performance of the lesion animals. The ibotenate-induced lesions significantly reduced the activity of choline acetyltransferase (CAT) in the anterior and the posterior neocortex. Hippocampal CAT activity was not changed. The results indicate that the cholinergic projections originating in the nBM are involved in the learning and memory of spatial tasks. They also suggest that degeneration of cholinergic neurons in the basal forebrain contributes significantly to the learning and memory deficits observed in Alzheimer's disease.

Selective neuronal degeneration with concomitant changes in neurotransmitter systems are features of both normal ageing and Alzheimer's disease. There are, however, important neurochemical differences in cerebral cortex. Choline acetyltransferase declines with age in frontal cortex in contrast to the prominent change in the temporal cortex in Alzheimer's disease. The loss of somatostatin, and the recently reported reciprocal change in corticotropin-releasing factor and receptors are not seen with ageing. However, age itself may have an important influence on the neurochemical deficits in Alzheimer's disease which are restricted in the older patients. The problems of post-mortem studies in the analysis of ageing and possible approaches to this are discussed.

Multiple neurotransmitter systems are affected in senile dementia of the Alzheimer's type (SDAT). Among them, acetylcholine has been most studied. It is now well accepted that the activity of the enzyme, choline acetyltransferase (ChAT) is much decreased in various brain regions including the frontal and temporal cortices, hippocampus and nucleus basalis of Meynert (nbm) in SDAT. Cortical M2-muscarinic and nicotinic cholinergic receptors are also decreased but only in a certain proportion (30-40%) of SDAT patients. For other systems, it appears that cortical serotonin (5-HT)-type 2 receptor binding sites are decreased in SDAT. This diminution in 5-HT2 receptors correlates well with the decreased levels of somatostatin-like immunoreactive materials found in the cortex of SDAT patients. Cortical somatostatin receptor binding sites are decreased in about one third of SDAT patients. Finally, neuropeptide Y and neuropeptide Y receptor binding sites are distributed in areas enriched in cholinergic cell bodies and nerve fiber terminals and it would be of interest to determine possible involvement of this peptide in SDAT. Thus, it appears that multi-drug clinical trials should be considered for the treatment of SDAT.

The local cerebral metabolic rate for glucose (LCMRgl) was determined by positron emission tomography (PET) using the 18F-fluorodeoxyglucose method in a series of Alzheimer patients and normal controls. The LCMRgl declined in the cerebral cortex with age, but the decrement was significantly greater in the clinically diagnosed Alzheimer's cases. Comparison of PET and psychological data indicated that, as the disease progressed clinically, the reduction in cortical LCMRgl and the number of cortical regions involved also increased. Variable regions of cortex were involved in the early stages but the temporal, parietal and frontal regions were most typically affected. One case coming to autopsy showed that the severity of the LCMRgl decline paralleled loss of neurons in the cortex and their replacement with astroglia.

A case of Pick's disease coming to autopsy had shown a different and highly characteristic pattern of cortical metabolic defect. In this case also a poor metabolic rate was associated with extensive gliosis.

Acetylcholinesterase (AChE) staining of the cerebral cortex in elderly normals and Alzheimer's disease cases with a new, highly sensitive method showed that in Alzheimer's disease there was an extensive loss of AChE-positive fibers with senile plaques frequently incorporating AChE-positive fiber debris. AChE staining of the substantia innominata area, where the cells giving rise to these neocortical fibers are presumably located, also showed evidence of degenerating cells and fibers.

Deficiencies in cholinergic nerve function have been clearly documented in patients with Alzheimer's disease. The lack of this neurotransmitter may be responsible for early memory loss in patients with the disease. Choline mustard Az ion has been used in our laboratory to produce cholinergic hypofunction in rat brain. Injections of the compound into the medial septal nucleus and dorsal hippocampus produced tissue lesions. The lesions were dose and time-dependent. Lesions produced in the medial septum resulted in transmitter depression in the hippocampus. These results suggest non-specific tissue damage because 5-HT levels were lower than normal. Other strategies for getting choline mustard Az ion into rat brain are being investigated to circumvent the apparent ability of this compound and other nitrogen mustard analogs of choline to produce non-specific tissue damage when injected directly into brain tissue.

Cholinergic receptors (muscarinic subtypes M1 and M2, and putative nicotinic binding) have been examined in the hippocampus obtained at autopsy from a variety of patients with cognitive disorders (Alzheimer's, Parkinson's, and Huntington's diseases, Down's Syndrome and alcoholic dementia) and compared with neurologically normal controls and cases of Motor Neuron disease. In all of the disorders associated with a pre-synaptic cortical cholinergic deficit reflected by an extensive loss of choline acetyltransferase (Alzheimer's disease, Parkinson's disease and Down's Syndrome) there was a substantial reduction in the binding of (3H) nicotine to the nicotinic receptor. By contrast reductions in both muscarinic subtypes (M1 and M2) were apparent to only a moderate extent in Alzheimer's disease, whereas in Parkinson's disease binding was significantly increased (apparently not in relation to anti-cholinergic drug treatment) in the non-demented but not demented cases. A further abnormality detected in Alzheimer's disease but not the other disorders investigated was a decrease in an endogenous inhibitor of nicotinic binding, the identity of which is as yet unknown but which may be a candidate for a possible endogenous modulator of the nicotinic receptor. These observations suggest that in Alzheimer's disease not only muscarinic but also nicotinic receptor function should be considered in relation both to future therapeutic strategies and, in the search for a clinical marker which might be of diagnostic value, to potential probes of the cortical cholinergic system.

Postmortem human brain samples were taken from non-neurological controls as well as demented subjects who died with Alzheimer's disease (AD), multi-infarct dementia (MID), or a combination of AD and MID dementia (MIXED). Choline acetyltransferase (Ch AT) activity was measured radiometrically using [ 1 -l4C]acetyl-coenzyme A as the substrate, muscarinic binding was assayed with [3H]quinuclidinyl benzilate, and the proportion of binding associated with high affinity agonist sites was measured by carbamylcholine displacement of the radioligand.

Relative to control, ChAT activity was significantly reduced (p ≤0.01) in samples taken from the temporal, frontal, and hippocampal areas of demented patients. A small elevation in Bmax was noted in the hippocampal endplate (p ≤0.01) (AD vs. control) and the H1-subiculum region (p ≤0.05) (AD vs. all other groups). In addition, the percentage of binding associated with high affinity agonist sites was greater in the frontal cortex of AD and MID samples (p≤0.05), compared with MIXED and control, and in the temporal cortex of the AD group compared with all other groups (p≤0.05). The results suggest a regionally specific upregulation of cerebral muscarinic receptors in dementia, especially in AD.

Recent research with computerized tomography (CT) and magnetic resonance imaging (MR) of the brain has revealed a type of tissue change for which no fitting term exists. The change appears as areas of decreased density on CT and changed signals of the white matter in MR images. Because neither a definite pathological change nor a specific clinical deficit has been linked with the CT and MR changes, a designation is required that limits itself to describing the changes themselves.

We propose “leuko-araiosis”. The Greek root leuko-, signifying “white”, has found wide usage in modern medical terminology: e.g. leucine, leukocyte, leukorrhoea. Also several precedents exist for its application to the white matter of the central nervous system: e.g. leukoencephalitis, leukomyelitis, leukotomy. Araios is an adjective meaning “rarefied”, and the suffix -osis converts the adjective to a noun meaning “rarefaction, diminution of density”, a word used in the Hippocratic Collection to describe a state of excessive porosity of the lung.

A descriptive term precludes premature presuppositions and encourages the search for causes.

In order to study possible metabolic derangements in Alzheimer's disease (AD), we performed phosphorus 31 nuclear magnetic resonance (31P NMR) spectroscopy on brain samples obtained at autopsy from 7 patients with AD and 9 control subjects. Aqueous solutions of brain tissue contained well-defined peaks of intermediate compounds in phospholipid metabolism, including the phosphomonoesters phosphocholine and phosphoethanolamine, and the phosphodiesters glycerophosphorylcholine and glycerophosphorylethanolamine. 3IP NMR spectra also displayed the inorganic phosphorus signal, which provides an index to the in vivo concentration of high-energy compounds.

We found evidence for altered phospholipid metabolism in that relative levels of phosphomonoesters were decreased, and phosphodiesters increased, in frontal and parietal regions of patients with AD compared to control subjects. The inorganic phosphorus resonance peaks were similar in AD and control subjects, suggesting that energy stores are not diminished in AD. These preliminary data are consistent with the hypothesis that abnormalities in phospholipid metabolism contribute to possible neuronal membrane dysfunction and impaired cholinergic neurotransmission in AD.

Evidence indicates that Alzheimer's disease (AD) causes functional disconnection of neocortical association areas. In mildly demented AD patients without measurable neocortically-mediated cognitive abnormalities, positron emission tomography demonstrates reduced parietal lobe glucose metabolism and left/right metabolic asymmetries in neocortical association areas. Similar metabolic abnormalities occur in moderately demented patients, but are accompanied by appropriate language and visuospatial discrepancies. Left/right metabolic asymmetries correspond with reduced numbers of partial correlations between metabolic rates in homologous right and left regions, and in the frontal and parietal cortices, indicating metabolic uncoupling among these regions. The affected association regions are those which demonstrate Alzheimer-type neuropathology post-mortem.

Of all the movement disorders, Huntington's disease has been most consistently associated with dementia, while it is only over the last decade that intellectual and cognitive decline have been recognized as common features of Parkinson's disease. It is now known that the pathology in these two conditions reflects differential involvement of the striatum. The Huntington lesion is primarily in the caudate, while the Parkinson lesion preferentially affects the putamen. Both conditions have more diffuse pathology, and dementia may also occur in a wide range of other extrapyramidal diseases, such as progressive supranuclear palsy, the parkinsonism-dementia complex of Guam, and certain spinocerebellar degenerations. Clinicopathological correlations will be reviewed in these disorders of primarily subcortical pathology, and comparisons will be made with Alzheimer's disease, a disorder of predominantly cortical pathology.

The clinical course of vascular dementia has been described as a stepwise deterioration over time. We studied the chronologic course of cognitive performance over 1-4 years in seven patients with known ischemic cerebrovascular disease whose dementia subtype was assigned according to the clinical history and the pattern of white matter lesions seen on magnetic resonance imaging (MRI). One patient had the lacunar state, three had subcortical arteriosclerotic encephalopathy and three had multiple cortical and subcortical strokes. All were being treated with an antiplatelet agent and six received antihypertensive therapy. Four of the seven vascular dementia patients improved cognitively over the first year. A fluctuating course was eventually seen in all patients. None showed stepwise deterioration of cognitive function over time. The MRI was useful in subclassifying vascular dementia patients, but the clinical course did not appear to vary as a function of the dementia subtype.