Severe white matter astrocytopathy in CADASIL.

OBJECTIVES: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by strategic white matter (WM) hyperintensities on MRI. Pathological features include WM degeneration, arteriolosclerosis, lacunar infarcts, and the deposition of granular osmiophilic material. Based on the hypothesis that the gliovascular unit is compromised, we assessed the nature of astrocyte damage in the deep WM of CADASIL subjects. METHODS: We evaluated post-mortem brains from CADASIL, cerebral small vessel disease, similar age cognitively normal and older control subjects. Standard immunohistochemical, immunofluorescent, and unbiased stereological methods were used to evaluate the distribution of astrocytes, microvessels, and autophagy markers in five different brain regions. RESULTS: Compared to the controls, the deep WM of CADASIL subjects overall showed increased numbers of glial fibrillary acidic protein (GFAP)-positive clasmatodendritic astrocytes (P=0.037) and a decrease in the percentage of normal appearing astrocytes (P=0.025). In accord with confluent WM hyperintensities, the anterior temporal pole contained abundant clasmatodendritic astrocytes with displaced aquaporin 4 immunoreactivity. Remarkably, we also found strong evidence for the immunolocalization of autophagy markers including microtubule-associated protein 1, light chain 3 (LC3), and sequestosome 1/p62 and Caspase-3 in GFAP-positive clasmatodendritic cells, particularly within perivascular regions of the deep WM. LC3 was co-localized in more than 90% of the GFAP-positive clasmatodendrocytes. CONCLUSIONS: Our novel findings show astrocytes undergo autophagy-like cell death in CADASIL, with the anterior temporal pole being highly vulnerable. We propose astrocytes transform from normal appearing type A to hypertrophic type B and eventually to clasmatodendritic type C cells. These observations also suggest the gliovascular unit of the deep WM is severely impaired in CADASIL.

A Systematic Review of the Prevalence of Oropharyngeal Dysphagia in Stroke, Parkinson's Disease, Alzheimer's Disease, Head Injury, and Pneumonia.

Oropharyngeal dysphagia is a common condition after stroke, Parkinson's disease (PD), and Alzheimer's disease (AD), and can cause serious complications including malnutrition, aspiration pneumonia, and premature mortality. Despite its high prevalence among the elderly and associated serious complications, dysphagia is often overlooked and under-diagnosed in vulnerable patient populations. This systematic review aimed to improve understanding and awareness of the prevalence of dysphagia in susceptible patient populations. MEDLINE, EMBASE, the Cochrane library, PROSPERO, and disease-specific websites were systematically searched for studies reporting oropharyngeal dysphagia prevalence or incidence in people with stroke, PD, AD, traumatic brain injury, and community-acquired pneumonia, from the USA, Canada, France, Germany, Italy, Spain, UK, Japan, China, and regional studies. The quality of study descriptions were assessed based on STROBE guidelines. A total of 1207 publications were identified and 33 met inclusion criteria: 24 in stroke, six in PD, two in traumatic brain injury, and one in patients with traumatic brain injury. Dysphagia was reported in 8.1-80 % of stroke patients, 11-81 % of PD, 27-30 % of traumatic brain injury patients, and 91.7 % of patients with community-acquired pneumonia. No relevant studies of dysphagia in AD were identified. This review demonstrates that dysphagia is highly prevalent in these populations, and highlights discrepancies between studies, gaps in dysphagia research, and the need for better dysphagia management starting with a reliable, standardized, and validated method for oropharyngeal dysphagia identification.

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.

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.