Chris Zarow

Neuropathological basis of magnetic resonance images in aging and dementia

Magnetic resonance (MR) imaging is used widely for assessment of patients with cognitive impairment, but the pathological correlates are unclear, especially when multiple pathologies are present.

Cognitive impact of subcortical vascular and Alzheimer's disease pathology

To assess the interactions among three types of pathology (ie, cerebrovascular disease, hippocampal sclerosis [HS], and Alzheimers disease [AD]), cognitive status, and apolipoprotein E genotype.

Correlates of hippocampal neuron number in Alzheimer's disease and ischemic vascular dementia

The cornu ammonis 1 region of the hippocampus (CA1) sector of hippocampus is vulnerable to both Alzheimers disease (AD)‐type neurofibrillary degeneration and anoxia–ischemia. The objective of this article is to compare number and size of neurons in CA1 in AD versus ischemic vascular dementia. Unbiased stereological methods were used to estimate the number and volume of neurons in 28 autopsy‐derived brain samples. For each case, the entire hippocampus from one cerebral hemisphere was sliced into 5mm slabs (5–7 slabs/case), cut into 50μm sections, and stained with gallocyanine. Using the optical dissector, we systematically sampled the number and size of neurons throughout the extent of CA1 and CA2. The total number of neurons was significantly less in AD compared with ischemic vascular dementia (p < 0.02), but there was no significant difference in neuron size. The greatest loss of neurons was observed in two cases with combined AD and hippocampal sclerosis. Regardless of causative diagnosis, the number of CA1 neurons correlates with magnetic resonance imaging–derived hippocampal volume (r = 0.72; p < 0.001) and memory score (r = 0.62; p < 0.01). We conclude that although CA1 neuron loss is more consistently observed in AD than ischemic vascular dementia, severity of loss shows the expected correlation with structure and function across causative subtype. Reductions in magnetic resonance imaging–derived hippocampal volume reflect loss, rather than shrinkage, of CA1 neurons. Ann Neurol 2005;57:896–903

Neuron loss in key cholinergic and aminergic nuclei in Alzheimer disease: a meta-analysis

Cell counts in the cholinergic nucleus basalis (NB), noradrenergic locus coeruleus (LC), dopaminergic substantia nigra (SN), and the serotonergic dorsal raphe nucleus (DRN) were assessed from primary-level reports in patients with Alzheimer disease (AD) and in controls. Sixty-seven studies that covered about 20 years were included in the meta-analysis. Effect sizes were computed as a standardized mean difference (d) in cell counts between AD and controls. Effect sizes were largest in magnitude for the NB (mean d=2.48, 33 studies, N=585), and the LC (d=2.28, 24 studies, N=545), then the DRN (d=1.79, 11 studies, N=234), and were smallest for the SN (d=0.61, 14 studies, N=440). In general, the overall effect size estimates for the four cell areas were reliable. Using effect size magnitude in the SN as a referent, cell loss was about three times greater in the DRN and four times greater in the NB and LC. Symptomatic drug treatment for AD might be beneficially directed toward ameliorating multiple neurotransmitter deficiencies, particularly cholinergic and noradrenergic.

Stability of neuronal number in the human nucleus basalis of Meynert with age

Numbers of neurons in the nucleus basalis of Meynert were estimated in seventeen non-demented patients who died of chronic hepatic or cardiopulmonary disease. Neurons were counted at the site of maximal neuronal density (SMND). This site was chosen by reviewing serial sections around the decussation of the anterior commissure and appeared to be comparable in different individuals. No correlation between numbers of neurons and age could be found. It appears that no uniform neuronal loss occurs in the nucleus basalis with age. Taken together with biochemical studies of cerebral cortical choline acetyltransferase activity, these findings suggest that there is no overall change in cholinergic input to cerebral cortex with age.

Sulfated glycoprotein-2 is increased in rat hippocampus following entorhinal cortex lesioning

Thios study showed responses of sulfated glycoprotein-2 (SGP-2) in the rat hippocampus after deafferenting lesion. SGP-2 is a plasma protein that also occurs in many peripheral tissues. In some circumstances, elevations of SGP-2 mRNA are associated with cell degeneration and responses to injury. This study used entorhinal cortex lesions (ECL) to partially deafferent the hippocampus by damaging the perforant path and to induce synaptic remodeling. SGP-2 mRNA is increased in hippocampal astrocytes after ECL. Western blot analysis of soluble hippocampal proteins identified 3 major forms of rat SGP-2 protein: a precursor (61 kDa) and 2 reduced subunits at 39.5 and 35 kDa. These forms increased at 4 days post ECL ipsilaterally to the lesion. By immunocytochemistry (ICC), SGP-2 showed an increased immunoreactivity on the lesioned side by 2 days post ECL that continued through 14 days post ECL. Besides immunopositive astrocytes, punctate immunochemical reaction products occurred among the degenerating fibers of the perforant path. We conclude that changes of SGP-2 protein in the hippocampus after ECL occur roughly in parallel with increases of SGP-2 mRNA. The punctate immuno-deposits could represent secreted SGP-2 and may be useful as a marker for degenerating pathways.

Vascular Basement Membrane Pathology and Alzheimer's Disease

ABSTRACT: We have previously demonstrated that the capillary vascular basement membrane (VBM) is pathologically altered in Alzheimers disease (AD). This microangiopathy is highlighted by the immunocytochemical localization of the three principal intrinsic VBM components: heparan sulfate proteoglycan, collagen type IV, and laminin. These three VBM components also immunolabel amyloid deposits and senile plaque‐associated glial processes. The present study examines the ultrastructure of the VBM in one brain region severely affected (temporal gyrus) and one relatively spared (cerebellum) from the lesions of AD in both AD and neurological control cases. The cross‐sectional area as well as the width of the VBM were found to be greater in AD cortical capillaries. In addition, we found ultrastructural evidence for the activation of microglial‐related perivascular cells, and their apparent extravasation through the VBM, findings consistent with the hypothesis that these cells are being recruited as part of a disease‐related immune response. The recruitment of these “resting” microglial‐like cells from their intra‐VBM location to plaques and tangles in AD may explain (1) the thickening and vacuolization of the VBM; (2) the specificity of this VBM alteration to brain regions where there are plaques and tangles; and (3) the source of some of the large number of activated microglia in these affected areas. Thus, while VBM alterations may not be specific to AD, these changes appear to be specifically related to the disease process.

Cerebral Atherosclerosis Is Associated With Cystic Infarcts and Microinfarcts but Not Alzheimer Pathologic Changes

Background and Purpose— Some studies have reported associations between intracranial atherosclerosis and Alzheimer disease pathology. We aimed to correlate severity of cerebral atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy with neurofibrillary tangles, neuritic plaques, and cerebral infarcts. Methods— This autopsy study (n=163) was drawn from a longitudinal study of subcortical ischemic vascular disease, Alzheimer disease, and normal aging. Multivariable logistic regression models were used to test associations among the 3 forms of cerebrovascular disease and the presence of ischemic and neurodegenerative brain lesions. Apolipoprotein E genotype was included as a covariate in these multivariable models. Results— Cerebral atherosclerosis was positively associated with microinfarcts (odds ratio [OR], 2.3; 95% confidence interval [CI], 1.2–4.4) and cystic infarcts (OR, 2.0; 95% CI, 1.0–4.2) but not Alzheimer disease pathology. Arteriolosclerosis showed a positive correlation with lacunar infarcts (OR, 2.0; 95% CI, 1.0–4.2) but not Alzheimer disease pathology. Cerebral amyloid angiopathy was inversely associated with lacunar infarcts (OR, 0.6; 95% CI, 0.41–1.1), but positively associated with Braak and Braak stage (OR, 1.5; 95% CI, 1.1–2.1) and Consortium to Establish a Registry for Alzheimer Disease plaque score (OR, 1.5; 95% CI, 1.1–2.2). Conclusions— Microinfarcts, which have been correlated with severity of cognitive impairment, were most strongly associated with atherosclerosis. Possible pathogenetic mechanisms include artery-to-artery emboli, especially microemboli that may include atheroemboli or platelet-fibrin emboli. Arteriolosclerosis was positively, whereas cerebral amyloid angiopathy was negatively correlated with lacunar infarcts, which might prove helpful in clinical differentiation of arteriolosclerotic from cerebral amyloid angiopathy–related vascular brain injury.

Increased apolipoprotein E mRNA in the hippocampus in Alzheimer disease and in rats after entorhinal cortex lesioning.

The distribution of apolipoprotein E (ApoE) mRNA was characterized in the hippocampus of humans with Alzheimer disease (AD) and in rats with experimental lesions (unilateral ablation of the entorhinal cortex) that model selected features of AD. In both AD and the lesion model, we observed a shift in the location of astrocytes containing prevalent ApoE mRNA from the neuropil to regions with densely packed neurons. The increased abundance of ApoE mRNA in astrocytes close to neuron cell bodies could be indicative of lipid uptake in regions where neurons are degenerating or where synaptic remodeling is taking place.

Neuropathologic comorbidity and cognitive impairment in the Nun and Honolulu-Asia Aging Studies

Objective: To examine frequencies and relationships of 5 common neuropathologic abnormalities identified at autopsy with late-life cognitive impairment and dementia in 2 different autopsy panels. Methods: The Nun Study (NS) and the Honolulu-Asia Aging Study (HAAS) are population-based investigations of brain aging that included repeated cognitive assessments and comprehensive brain autopsies. The neuropathologic abnormalities assessed were Alzheimer disease (AD) neuropathologic changes, neocortical Lewy bodies (LBs), hippocampal sclerosis, microinfarcts, and low brain weight. Associations with screening tests for cognitive impairment were examined. Results: Neuropathologic abnormalities occurred at levels ranging from 9.7% to 43%, and were independently associated with cognitive impairment in both studies. Neocortical LBs and AD changes were more frequent among the predominantly Caucasian NS women, while microinfarcts were more common in the Japanese American HAAS men. Comorbidity was usual and very strongly associated with cognitive impairment. Apparent cognitive resilience (no cognitive impairment despite Braak stage V) was strongly associated with minimal or no comorbid abnormalities, with fewer neocortical AD lesions, and weakly with longer interval between final testing and autopsy. Conclusions: Total burden of comorbid neuropathologic abnormalities, rather than any single lesion type, was the most relevant determinant of cognitive impairment in both cohorts, often despite clinical diagnosis of only AD. These findings emphasize challenges to dementia pathogenesis and intervention research and to accurate diagnoses during life.