Pyramidal neurons of the prefrontal cortex in post-stroke, vascular and other ageing-related dementias.

Dementia associated with cerebrovascular disease is common. It has been reported that ∼30% of elderly patients who survive stroke develop delayed dementia (post-stroke dementia), with most cases being diagnosed as vascular dementia. The pathological substrates associated with post-stroke or vascular dementia are poorly understood, particularly those associated with executive dysfunction. Three separate yet interconnecting circuits control executive function within the frontal lobe involving the dorsolateral prefrontal cortex, anterior cingulate cortex and the orbitofrontal cortex. We used stereological methods, along with immunohistological and related cell morphometric analysis, to examine densities and volumes of pyramidal neurons of the dorsolateral prefrontal cortex, anterior cingulate cortex and orbitofrontal cortex in the frontal lobe from a total of 90 elderly subjects (age range 71-98 years). Post-mortem brain tissues from post-stroke dementia and post-stroke patients with no dementia were derived from our prospective Cognitive Function After Stroke study. We also examined, in parallel, samples from ageing controls and similar age subjects pathologically diagnosed with Alzheimer's disease, mixed Alzheimer's disease and vascular dementia, and vascular dementia. We found pyramidal cell volumes in layers III and V in the dorsolateral prefrontal cortex of post-stroke and vascular dementia and, of mixed and Alzheimer's disease subjects to be reduced by 30-40% compared to post-stroke patients with no dementia and controls. There were no significant changes in neuronal volumes in either the anterior cingulate or orbitofrontal cortices. Remarkably, pyramidal neurons within the orbitofrontal cortex were also found to be smaller in size when compared to those in the other two neocortical regions. To relate the cell changes to cognitive function, we noted significant correlations between neuronal volumes and total CAMCOG, orientation and memory scores and clinical dementia ratings. Total estimated neuronal densities were not significantly changed between patients with post-stroke dementia and post-stroke patients with no dementia groups or ageing controls in any of the three frontal regions. In further morphometric analysis of the dorsolateral prefrontal cortex, we showed that neither diffuse cerebral atrophy nor neocortical thickness explained the selective neuronal volume effects. We also noted that neurofilament protein SMI31 immunoreactivity was increased in post-stroke and vascular dementia compared with post-stroke patients with no dementia and correlated with decreased neuronal volumes in subjects with post-stroke dementia and vascular dementia. Our findings suggest selective regional pyramidal cell atrophy in the dorsolateral prefrontal cortex-rather than neuronal density changes per se-are associated with dementia and executive dysfunction in post-stroke dementia and vascular dementia. The changes in dorsolateral prefrontal cortex pyramidal cells were not associated with neurofibrillary pathology suggesting there is a vascular basis for the observed highly selective neuronal atrophy.

Hippocampal neuronal atrophy and cognitive function in delayed poststroke and aging-related dementias.

BACKGROUND AND PURPOSE: We have previously shown delayed poststroke dementia in elderly (≥75 years old) stroke survivors is associated with medial temporal lobe atrophy; however, the basis of the structural and functional changes is unknown. METHODS: Using 3-dimensional stereological methods, we quantified hippocampal pyramidal neuronal volumes and densities in a total of 95 postmortem samples from demented and nondemented poststroke survivors within our prospective Cognitive Function after Stroke study and subjects pathologically diagnosed with vascular dementia, Alzheimer disease, and mixed Alzheimer disease and vascular dementia syndrome. RESULTS: Hippocampal CA1 but not CA2 subfield neuron density was affected in poststroke, Alzheimer disease, vascular dementia, and mixed dementia groups relative to control subjects (P<0.05). Neuronal volume was reduced in the poststroke dementia relative to poststroke nondemented group in both CA1 and CA2, although there were no apparent differences in neuronal density. Poststroke nondemented neuronal volumes were similar to control subjects but greater than in all dementias (P<0.05). Neuronal volumes positively correlated with global cognitive function and memory function in both CA1 and CA2 in poststroke subjects (P<0.01). Degrees of neuronal atrophy and loss were similar in the poststroke dementia and vascular dementia groups. However, in the entorhinal cortex layer V, neuronal volumes were only impaired in the mixed and Alzheimer disease groups (P<0.05). CONCLUSIONS: Our results suggest hippocampal neuronal atrophy is an important substrate for dementia in both cerebrovascular and neurodegenerative disease.

Neuron volumes in hippocampal subfields in delayed poststroke and aging-related dementias.

Hippocampal atrophy is widely recognized in Alzheimer disease (AD). Whether neurons within hippocampal subfields are similarly affected in other aging-related dementias, particularly after stroke, remains an open question. We investigated hippocampal CA3 and CA4 pyramidal neuron volumes and densities using 3-dimensional stereologic techniques in postmortem samples from a total of 67 subjects: poststoke demented (PSD; n = 11), nondemented stroke survivors (PSND) and PSD patients from the CogFAST (Cognitive Function After Stroke) cohort (n = 13), elderly controls (n = 12), and subjects diagnosed as having vascular dementia (n = 11), AD (n = 10), and mixed AD and vascular dementia (n = 10). We found that CA3 and CA4 neuron volumes were reduced in PSD samples compared with those in PSND samples. The CA3 and CA4 neuron volumes were positively correlated with poststroke global cognitive function but were not associated with the burden of AD pathology. There were no differences in total neuron densities in either subfield in any of the groups studied. Our results indicate that selective reductions in CA4 and to a lesser extent CA3 neuron volumes may be related to post stroke cognitive impairment and aging-related dementias. These data suggest that CA4 neurons are vulnerable to disease processes and support our previous finding that a reduction in hippocampal neuron volume predominantly reflects vascular mechanisms as contributing to dementia after stroke.

Quantitative vascular pathology and phenotyping familial and sporadic cerebral small vessel diseases.

We quantified vascular changes in the frontal lobe and basal ganglia of four inherited small vessel diseases (SVDs) including cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), pontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL), hereditary multi-infarct dementia of Swedish type (Swedish hMID), and hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS). Vascular pathology was most severe in CADASIL, and varied with marginally greater severity in the basal ganglia compared to the frontal lobe. The overall sclerotic index values in frontal lobe were in the order CADASIL ≥ HERNS > PADMAL > Swedish hMID > sporadic SVD, and in basal ganglia CADASIL > HERNS > Swedish hMID > PADMAL> sporadic SVD. The subcortical white matter was almost always more affected than any gray matter. We observed glucose transporter-1 (GLUT-1) protein immunoreactivities were most affected in the white matter indicating capillary degeneration whereas collagen IV (COL4) immunostaining was increased in PADMAL cases in all regions and tissue types. Overall, GLUT-1 : COL4 ratios were higher in the basal ganglia indicating modifications in capillary density compared to the frontal lobe. Our study shows that the extent of microvascular degeneration varies in these genetic disorders exhibiting common end-stage pathologies but is the most aggressive in CADASIL.