Melvyn J. Ball

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease

The Neuropathology Task Force of the Consortium to Establish a Registry for Alzheimers Disease (CERAD) has developed a practical and standardized neuropathology protocol for the postmortem assessment of dementia and control subjects. The protocol provides neuropathologic definitions of such terms as “definite Alzheimers disease” (AD), “probable AD,” “possible AD,” and “normal brain” to indicate levels of diagnostic certainty, reduce subjective interpretation, and assure common language. To pretest the protocol, neuropathologists from 15 participating centers entered information on autopsy brains from 142 demented patients clinically diagnosed as probable AD and on eight nondemented patients. Eighty-four percent of the dementia cases fulfilled CERAD neuropathologic criteria for definite AD. As increasingly large numbers of prospectively studied dementia and control subjects are autopsied, the CERAD neuropathology protocol will help to refine diagnostic criteria, assess overlapping pathology, and lead to a better understanding of early subclinical changes of AD and normal aging.

Evidence for high affinity choline transport in synaptosomes prepared from hippocampus and neocortex of patients with Alzheimer's disease

Sodium-dependent, hemicholinium-sensitive choline transport was measured in purified synaptosomes prepared from fresh necropsy brain of patients with senile dementia of the Alzheimer type and from control subjects. Choline transport velocity was standardized in terms of the occluded lactate dehydrogenase activity of the various synaptosomal preparations, rather than in terms of the protein content, since this enzyme is more representative of the synaptosome content of the purified homogenates. A regional difference in high-affinity choline transport was observed in purified synaptosomes prepared from brains of mentally normal controls; the velocities of sodium-dependent and hemicholinium-sensitive choline uptake into synaptosomes from hippocampus were about twice as great as that into synaptosomes from frontal cortex, indicating a greater relative density of cholinergic innervation in the hippocampus. Hippocampal and neocortical cholinergic nerve cell endings, prepared as synaptosomes, from brains of patients with Alzheimers disease, also accumulated choline by a high-affinity mechanism; however, the velocity of uptake into both brain areas was decreased in comparison with controls. Choline transport into synaptosomes from Alzheimer frontal cortex was reduced approximately 50%, while uptake into Alzheimer hippocampal synaptosomes represented only 20% of the control activity. The reduction in synaptosomal high-affinity choline transport in Alzheimers disease could be indicative of degeneration of cholinergic nerve terminal boutons resulting from cholinergic nerve cell death, or could result from an overall decrease in the number of carrier sites per nerve terminal or in the carrier transport velocity.(ABSTRACT TRUNCATED AT 250 WORDS)

Morphometric comparison of hippocampal microvasculature in ageing and demented people: Diameters and densities

SummaryThe diameters and densities of capillaries and arterioles in the hippocampal cortex of normal subjects and patients with Alzheimers dementia were measured in thick celloidin sections stained for alkaline phosphatase. Microvascular diameters in general are affected more by age than by the presence of dementia of the Alzheimer type. The diameter of both capillaries and arterioles increases significantly with age. The density of capillaries decreases whereas that of the arterioles increases significantly. The capillary changes suggest that a reduced exchange potential accompanies ageing.In brains of people with Alzheimers disease the overall capillary diameters and densities do not differ from those of age-matched controls. Regional changes may, however, be important: those hippocampal zones showing the greatest severity of or increment in nerve cell lesions do correspond to those having the highest levels of or increase in capillary density and the greatest decrease in diameter, suggesting a direct association between neuronal susceptibility to Alzheimer changes and degree of regional blood supply. Capillary surface areas, volumes, and area/capillary volume ratios support the possibility of this relationship.Neurofibrillary tangles and granulovacuolar degeneration do not correlate equally with the degree of capillary “irrigation” tangles are more closely related to these morphological vascular parameters.

Nicotinic binding sites in cerebral cortex and hippocampus in Alzheimer's dementia

Postmortem cerebral neocortical and hippocampal samples were taken from patients who died with dementia of the Alzheimer type (DAT) and individuals without diagnoses of neurological or psychiatric disease (control). Nicotinic binding was assayed with 20 nM [3H]acetylcholine ([3H]ACh) in the presence of atropine, or with 4 nM (-)-[3H]Nic). Binding of both ligands was lower in the following regions from DAT vs. control brains (P≤0.05): superior, middle and inferior temproal gyri, orbital frontal gyrus, middle frontal gyrus, pre- and postcentral gyri, inferior parietal lobule, and hippocampal endplate. Values of the correlation coefficient (rs) for binding of the nicotinic cholinergic ligands in these regions ranged from 0.70 to 0.93 (Ps<0.05), suggesting that [3H]ACh and (-)-[3H]Nic labeled the same sites in human brain. There was no difference in nicotinic binding in the presubiculum, comparing DAT and control samples (P>0.05). Here too, correlations between binding of the two ligands were statistically significant in control and DAT groups (rs=0.92,Ps<0.05). Nicotinic binding measured with [3H]ACh, but not (-)-[3H]Nic, was significantly lower in the H2 (field of Rose) and H1-subiculum areas of DAT samples compared to control. Correlations between binding of the two ligands in these regions ranged from 0.21 to 0.34 for the two groups (Ps>0.05). The findings support a loss of neocortical and hippocampal nicotininc cholinergic binding sites in DAT. Further study is necessary to better characterize the regional losses of nicotinic binding in DAT and to resolve the differences in binding measured by [3H]ACh and (-)-[3H]Nic in the H1-subiculum and H2 (field of Rose) regions.

Neuritic plaques and vessels of visual cortex in aging and Alzheimer's dementia

Changes in microvascular dimensions occurring with normal aging and Alzheimers dementia were measured in thick sections of postmortem human visual cortex stained for alkaline phosphatase. Capillary density was decreased to the same degree in both normal aged and demented aged subjects. The fields selected for analysis in both groups included all cortical laminae and, where possible, amyloid-cored neuritic plaques. The mean density of such plaques in these selected fields was slightly but not significantly higher in the demented group. In both groups plaques were more plentiful in visual laminae with the highest capillary densities (II-IV), but plaques and vessels were closer to each other in the normal aged than in the demented. Plaque distributions differed; in the normal aged, plaques concentrated in lamina IV; in the demented they were more evenly spread throughout the laminae. Plaque cores were larger in the demented. Amyloid angiopathy was more common and more extensive in the demented group; amyloid-cored plaques were not closely associated with affected vessels. Plaque distributions in Alzheimer subjects with and without amyloid angiopathy differed; plaque density was greatest in those without angiopathy. Alzheimers dementia was not associated with any decline in microvascularity. Plaque concentration in well vascularized laminae suggests a pathogenetic role for some blood-borne agent. Differences in plaque distributions imply that the role or the agent differs in normal and demented aging, or perhaps between cases with and without amyloid angiopathy.

Laminar variation in the microvascular architecture of normal human visual cortex (area 17)

Diameters and densities of arterioles and capillaries were measured in thick alkaline phosphatase-stained sections of human visual cortex from normal young adults. Values were compared between laminae. Capillary diameters ranked: IV greater than V-VI greater than II-III greater than I; capillary densities ranked: IV greater than II-III greater than V-VI greater than I. The striking capillary density of lamina IV overlaps the stria Gennarii and, like it, is limited to area 17. The data suggest correlations with similar laminar distributions of some neurotransmitters and of certain common neuropathological lesions.

TOPOGRAPHY OF NEUROFIBRILLARY TANGLES AND GRANULOVACUOLES IN HIPPOCAMPI OF PATIENTS WITH DOWN'S SYNDROME: QUANTITATIVE COMPARISON WITH NORMAL AGEING AND ALZHEIMER'S DISEASE

Ball M. J. & Nuttall, K. (1981) Neuropathology and Applied Neurobiology 7, 13–20

Human herpes virus infections and Alzheimer's disease

Human herpes virus infections and Alzheimers Disease. Herpes viruses cause acute and chronic diseases of the peripheral and central nervous systems and have been implicated in the aetiology of Alzheimers disease (AD). In this investigation the relevance of human herpes virus infection to AD was assessed by in situ hybridization. The abundant latency associated transcript(s) of herpes simplex virus type 1 (HSV‐1) were detected at a significantly higher incidence in the trigeminal ganglia of individuals with AD than in controls. But we could find no evidence of viral RNA in the central nervous system (CNS), looking specifically in the hippo‐campal cortex of demented individuals with extensive neuropathological changes of AD. These studies solve one problem in testing the viral hypothesis of causation, i.e. the sensitivity of the methods used in the search for latent infection. But the central issue remains unresolved because of necessity, only the end stage of a prolonged pathophysiological process has been examined. Our conclusions are qualified accordingly.

Muscarinic binding and choline acetyltransferase in postmortem brains of demented patients.

Postmortem human brain samples were taken from non-neurological controls as well as demented subjects who died with Alzheimers disease (AD), multi-infarct dementia (MID), or a combination of AD and MID dementia (MIXED). Choline acetyltransferase (ChAT) activity was measured radiometrically using [1-14C]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 less than or equal to 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 less than or equal to 0.01) (AD vs. control) and the H1-subiculum region (p less than or equal to 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 less than or equal to 0.05). The results suggest a regionally specific upregulation of cerebral muscarinic receptors in dementia, especially in AD.

Reductions in parietal and temporal cerebral metabolic rates for glucose are not specific for Alzheimer's disease.

Reduction in the regional cerebral metabolic rate for glucose (rCMRglc) in the parietal and temporal regions has been shown in Alzheimers disease (AD). The specificity of these findings for this disease state is uncertain. We repeatedly measured rCMRglc with positron emission tomography and [18F]2-fluoro-2-deoxy-D-glucose in the resting state in a 68 year old man with slowly progressive dementia who, during life, was initially diagnosed as having dementia of the Alzheimer type, then Parkinson disease with dementia, but was found to have only Parkinsons disease at necropsy. Metabolic ratios (rCMRglc/mean grey CMRglc) were significantly (p < 0.05) reduced in parietal and temporal regions, as well as in the prefrontal and premotor areas. This pattern was similar in regional distribution and magnitude of the defect to that seen in patients with probable AD. These results suggest that reductions of glucose metabolism in association neocortex in AD are not specific to the disease process, but may be related to the dementia state.