Carotid artery disease in post-stroke survivors and effects of enriched environment on stroke pathology in a mouse model of carotid artery stenosis.

AIMS: Carotid artery disease (CAD) is an important risk factor for stroke. We first evaluated CAD and stroke pathology in elderly post-stroke survivors. To simulate CAD, we assessed long-term consequences of bilateral common carotid artery stenosis (BCAS) in mice and exposed them to environmental enrichment (EE). METHODS: Histopathological methods were used to determine degrees of CAD (% area stenosis), brain infarct types, sizes and distribution in post-stroke survivors and BCAS mice. Adult male C57BL/6J mice after BCAS or sham surgery were randomly assigned to standard housing (Std) or limited (3 h) or full-time (Full) exposure to EE per day for 12 weeks. RESULTS: High frequencies of moderate carotid artery stenosis (51-75%) were evident in post-stroke survivors whereas those with severe CAD (>75% stenosis) exhibited greater numbers of cortical rather than subcortical infarcts and, were at higher risk of developing dementia. BCAS in mice reduced cerebral blood flow by 52% (P < 0.01) and thickened carotid artery walls, regardless of EE duration. Remarkably, the total and cortical infarcts declined by >50% in BCAS mice exposed to EE compared with BCAS-Std (P < 0.01). Frontal lobe and cortical strokes were associated with worsening working memory tested in a radial maze paradigm. Proteomic analysis revealed EE, both BCAS-3 h and BCAS-Full attenuated coagulation cascade factors including fibrinogen and von Willebrand factor, markers of blood-brain barrier damage. CONCLUSION: Small cortical and subcortical infarcts were evident in both post-stroke survivors with CAD and BCAS mice. Experimental evidence suggested that moderate exposure to EE is sufficient to reduce subsequent stroke lesions.

Morphometry of the hippocampal microvasculature in post-stroke and age-related dementias.

BACKGROUND: Optimal vascular function is vital for prevention of dementia. We hypothesized that elderly post-stroke survivors who preserve cognitive function show unperturbed cerebral microvasculature compared with those who develop dementia. METHODS: Using stereological spherical probe software, we compared the length density (Lv, cumulative vessel length per unit tissue volume) of hippocampal microvessels in post mortem brain tissue from post-stroke survivors, Alzheimer's disease (AD), vascular dementia (VaD) and normal ageing control subjects. We also assessed microvessel diameters in the same subjects. Microvessels were identified by markers of endothelial cells (glucose transporter 1; GLUT1), basement membrane (collagen IV; COL4) and smooth muscle cell α-actin (SMA). RESULTS: We found increased Lv of both GLUT1 and COL4 immunostained microvessels (P < 0.05) in the hippocampal CA1 region of post-stroke demented (PSD) and AD cases compared with post-stroke nondemented (PSND), control and VaD subjects. However, no changes were apparent in the CA2 region. We also noted significant increase in Lv in the entorhinal cortex of AD compared with PSND and PSD subjects. The mean diameter of microvessels was decreased in PSD, compared with PSND, as well as in AD and VaD compared with controls. Cumulative frequency analysis showed PSND subjects to have significantly greater proportion of microvessels with diameters, ranging from 7 to 12 µm. CONCLUSIONS: An increase in microvascular Lv in AD and PSD suggests either an increase in angiogenesis or the formation of newer microvessel loops in response to cerebral hypoperfusion. The decreased vessel diameters found in AD and VaD suggests increased vasoconstriction in dementia.

Review: cerebral amyloid angiopathy, prion angiopathy, CADASIL and the spectrum of protein elimination failure angiopathies (PEFA) in neurodegenerative disease with a focus on therapy.

Failure of elimination of proteins from the brain is a major feature in many neurodegenerative diseases. Insoluble proteins accumulate in brain parenchyma and in walls of cerebral capillaries and arteries. Cerebral amyloid angiopathy (CAA) is a descriptive term for amyloid in vessel walls. Here, we adopt the term protein elimination failure angiopathy (PEFA) to focus on mechanisms involved in the pathogenesis of a spectrum of disorders that exhibit both unique and common features of protein accumulation in blood vessel walls. We review (a) normal pathways and mechanisms by which proteins and other soluble metabolites are eliminated from the brain along 100- to 150-nm-thick basement membranes in walls of cerebral capillaries and arteries that serve as routes for lymphatic drainage of the brain; (b) a spectrum of proteins involved in PEFA; and (c) changes that occur in artery walls and contribute to failure of protein elimination. We use accumulation of amyloid beta (Aß), prion protein and granular osmiophilic material (GOM) in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) as examples of different factors involved in the aetiology and pathogenesis of PEFA. Finally, we discuss how knowledge of factors involved in PEFA may help to focus on new therapies for neurodegenerative diseases. When Aß (following immunotherapy) and prion protein are released from brain parenchyma they deposit in walls of cerebral capillaries and arteries; GOM in CADASIL accumulates primarily in artery walls. Therefore, the focus of therapy for protein clearance in neurodegenerative disease should perhaps be on facilitating perivascular elimination of proteins and reducing PEFA.

Increased neural progenitors in individuals with cerebral small vessel disease.

AIMS: Recent work has highlighted a significant increase of neural stem/progenitor cells after stroke in humans. In this study, we examined neurogenesis in small vessel disease, a key concurrent pathology in Alzheimer's disease. METHODS: We assayed autopsy tissue from 13 vascular dementia patients with small vessel disease and 12 age-matched subjects without cerebrovascular pathology, undertaking immunohistochemistry in the affected brain area and the subventricular zone with a well-characterized battery of antibodies to detect neural stem cells/progenitors and immature neurones, as well as choline acetyltransferase immunoreactivity. RESULTS: We showed significant increases ranging from 33% to 92% (P < 0.05) in neural progenitor cells around the areas of microvascular pathology and in the subventricular zone in patients with small vessel disease compared to individuals without cerebrovascular changes, even in patients with severe cerebrovascular disease, as defined by neuropathological assessment. Some of the progenitor cells give rise to immature neurones in the affected areas. These alterations were associated with vascular changes, but were unrelated to the cholinergic deficit observed in the cortex and subventricular zone in these patients, in contrast to other dementias examined such as dementia with Lewy bodies. CONCLUSIONS: This study provides evidence for neurogenesis in small vessel disease and may have important implications for the development of new therapies for neurodegenerative diseases.

Cerebral amyloid ß(42) deposits and microvascular pathology in ageing baboons.

BACKGROUND: Previous studies have extensively reported the deposition of amyloid ß (Aß) peptide with carboxyl- and amino-terminal heterogeneity in cortical and cerebrovascular deposits in Alzheimer's disease (AD) and in non-human primates except baboons. METHODS: We examined the immunocytochemical distribution of Aß peptides and Aß oligomers in brain tissue from three subspecies of 18- to 28-year-old baboons (Papio) and in other monkeys including the squirrel (Saimiri sciureus) and rhesus (Macaca mulatta) for comparison. RESULTS: A general preponderance of Aß(42) in parenchymal deposits and many vascular deposits in all cortical lobes was evident in the baboons. Aß oligomeric immunoreactivity was also apparent like to amyloid plaques. We found that the amino acid sequence of the Aß domain of the baboon amyloid precursor protein is similar to that of man. In contrast to Aß, immunoreactivity to hyperphosphorylated tau protein was largely intracellular and rare in these baboons. Brain tissues from squirrel and rhesus monkeys examined in parallel exhibited mostly vascular and parenchymal deposits containing Aß(42) peptides. Our results were comparable to AD, but showed that even in younger monkeys exhibiting few deposits, Aß(42) was evident in both parenchymal deposits and cerebral amyloid angiopathy. Perivascular amyloid deposits were frequent and often accompanied by microvascular abnormalities in the form of collapsed degenerated capillaries. CONCLUSIONS: Similar to other primates above and below in the phylogenetic order, our observations and evaluation of the literature implicate pathogenicity of Aß(42) peptide associated with microvascular degeneration in baboons. We suggest baboons are useful animals to investigate the dynamics of AD-related pathology.

Review: molecular genetics and pathology of hereditary small vessel diseases of the brain.

Advances in molecular genetics have enabled identification of several monogenic conditions involving small vessels predisposing to ischaemic and haemorrhagic strokes and diffuse white matter disease. With emphasis on cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), we review the molecular pathogenesis of recently characterized disorders including cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), retinal vasculopathy with cerebral leukodystrophy (RVCL) and the Collagen type IV, alpha 1 (COL4A1)-related disorders. CADASIL remains the most common hereditary small vessel disease (SVD) caused by >190 different mutations in the NOTCH3 gene, which encodes a cell-signalling receptor. Mutant NOTCH3 instigates degeneration of vascular smooth muscle cells in small arteries and arterioles leading to recurrent lacunar infarcts. Mutations in the serine protease HTRA1 gene are associated with CARASIL. Aberrant HTRA1 activity results in increased transforming growth factor-ß signalling provoking multiple actions including vascular fibrosis and extracellular matrix synthesis. The RVCL disorders characterized by profound retinopathy are associated with mutations in TREX1, which encodes an abundant 3'-5' DNA-specific exonuclease. TREX1 mutations lead to detrimental gain-of-function or insufficient quantities of enzyme. The COL4A1-related disorders are highly variable comprising four major phenotypes with overlapping systemic and central nervous system features including SVD with cerebral haemorrhages in children and adults. Mutant COL4A1 likely disrupts the extracellular matrix resulting in fragile vessel walls. The hereditary SVDs albeit with variable phenotypes demonstrate how effects of different defective genes converge to produce the characteristic arteriopathy and microvascular disintegration leading to vascular cognitive impairment.

Medial temporal lobe atrophy on MRI differentiates Alzheimer's disease from dementia with Lewy bodies and vascular cognitive impairment: a prospective study with pathological verification of diagnosis.

The purpose of this study was to determine the diagnostic accuracy of medial temporal lobe atrophy (MTA) on MRI for distinguishing Alzheimer's disease from other dementias in autopsy confirmed cases, and to determine pathological correlates of MTA in Alzheimer's disease, dementia with Lewy bodies (DLB) and vascular cognitive impairment (VCI). We studied 46 individuals who had both antemortem MRI and an autopsy. Subjects were clinicopathologically classified as having Alzheimer's disease (n = 11), DLB (n = 23) or VCI (n = 12). MTA was rated visually using a standardized (Scheltens) scale blind to clinical or autopsy diagnosis. Neuropathological analysis included Braak staging as well as quantitative analysis of plaques, tangles and alpha-synuclein Lewy body-associated pathology in the hippocampus. Correlations between MTA and pathological measures were carried out using Spearman's rho, linear regression to assess the contributions of local pathologic changes to MTA. Receiver operator curve analysis was used to assess the diagnostic specificity of MTA for Alzheimer's disease among individuals with Alzheimer's disease, DLB and VCI. MTA was a highly accurate diagnostic marker for autopsy confirmed Alzheimer's disease (sensitivity of 91% and specificity of 94%) compared with DLB and VCI. Across the entire sample, correlations were observed between MTA and Braak stage (rho = 0.50, P < 0.001), per cent area of plaques in the hippocampus (rho = 0.37, P = 0.014) and per cent area of tangles in the hippocampus (rho = 0.49, P = 0.001). Linear regression showed Braak stage (P = 0.022) to be a significant predictor of MTA but not percent area of plaques (P = 0.375), percent area of tangles (P = 0.330) or percent area of Lewy bodies (P = 0.086). MTA on MRI had robust discriminatory power for distinguishing Alzheimer's disease from DLB and VCI in pathologically confirmed cases. Pathologically, it is more strongly related to tangle rather than plaque or Lewy body pathology in the temporal lobe. It may have utility as a means for stratifying samples in vivo on the basis of putative differences in pathology.

Knowledge and perception of stroke amongst hospital workers in an African community.

BACKGROUND AND PURPOSE: Stroke is a growing public health problem worldwide. Hospital workers are sources of knowledge on health issues including stroke. The present study aimed at assessing the knowledge and perception of a sample of Nigerian hospital workers about stroke. METHODS: Hospital-based, cross-sectional survey. Respondents selected by systematic random sampling were interviewed using a 29-item pre-tested, structured, semi-closed questionnaire. RESULTS: There were 370 respondents (63% female, mean age: 34.4 +/- 7.5 years; 61% non-clinical workers). Twenty-nine per cent of respondents did not recognize the brain as the organ affected. Hypertension (88.6%) was the commonest risk factor identified; 13.8% identified evil spirit/witchcraft as a cause of stroke, whilst one-sided body weakness (61.9%) was most commonly identified as warning symptom. Hospital treatment was most preferred by 61.1% of respondents whilst spiritual healing was most preferred by 13.0%. In the bivariate analysis, higher level of education and being a clinical worker correlated with better stroke knowledge (P < 0.001). CONCLUSION: This study demonstrates gaps in the knowledge of these hospital workers about stroke, and treatment choice influenced by cultural and religious beliefs. Health education is still important, even, amongst health workers and stroke awareness campaigns may need to involve faith-based organizations.

Medullary autonomic pathology in carotid sinus hypersensitivity.

AIMS: Carotid sinus hypersensitivity (CSH) is an ageing-related autonomic disorder, rarely occurring before the age of 50 years but increasing in incidence thereafter. Clinical symptoms of CSH include falls and dizziness, thought to be precipitated by dysfunctional baroreflex responses. CSH is highly prevalent in Alzheimer's disease (AD), Parkinson's disease (PD) and dementia with Lewy bodies (DLB); diseases that are associated with variable degeneration of medullary autonomic nuclei which regulate baroreflex responses. Currently, there are no descriptions of the integrity of medullary autonomic nuclei in CSH. We hypothesized medullary autonomic degeneration is found in elderly patients with CSH. METHODS: Using in vitro digital imaging, we quantified the burden of tau, amyloid beta and alpha-synuclein in autonomic nuclei of 12 patients prospectively assessed with CSH (age 83 years) compared with 14 (80 years) control subjects. RESULTS: We found increased tau (P < 0.000) accumulation in baroreflex associated nuclei, but not the hypoglossal or raphe in the CSH patients. Medullary tau accumulation was not related to the development of AD in the CSH patients. Tau was colocalized to catecholaminergic neurones and occurred in the absence of neuronal loss. We found no difference in alpha-synuclein, amyloid beta or microglial numbers between the CSH cases and controls. CONCLUSIONS: We suggest that hyperphosphorylated tau accumulation particularly in tyrosine hydroxylase containing neurones may impair central regulation of baroreflex responses in patients with CSH. Future clinic-pathological investigations should reveal whether medullary degeneration is the cause of CSH symptoms.

Hereditary multi-infarct dementia of the Swedish type is a novel disorder different from NOTCH3 causing CADASIL.

Several hereditary small vessel diseases (SVDs) of the brain have been reported in recent years. In 1977, Sourander and Wålinder described hereditary multi-infarct dementia (MID) in a Swedish family. In the same year, Stevens and colleagues reported chronic familial vascular encephalopathy in an English family bearing a similar phenotype. These disorders have invariably been suggested to be cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) but their genetic identities remain unknown. We used molecular, radiological and neuropathological methods to characterize these disorders. Direct DNA sequencing unexpectedly confirmed that affected members of the English family carried the R141C mutation in the NOTCH3 gene diagnostic of CADASIL. However, we did not detect any pathogenic mutations in the entire 8091 bp reading frame of NOTCH3 or find clear evidence for NOTCH3 gene linkage in the Swedish DNA. This was consistent with the lack of hyperintense signals in the anterior temporal pole and external capsule in Swedish subjects upon magnetic resonance imaging. We further found no evidence for granular osmiophilic material in skin biopsy or post-mortem brain samples of affected members in the Swedish family. In addition, there was distinct lack of NOTCH3 N-terminal fragments in the cerebral microvasculature of the Swedish hereditary MID subjects compared to the intense accumulation in the English family afflicted with CADASIL. Several differences in arteriosclerotic changes in both the grey and white matter were also noted between the disorders. The sclerotic index values, density of collagen IV immunoreactivity in the microvasculature and number of perivascular macrophages were greater in the English CADASIL samples compared to those from the Swedish brains. Multiple approaches suggest that the Swedish family with hereditary MID suspected to be CADASIL has a different novel disorder with dissimilar pathological features and belongs to the growing number of genetically uncharacterized familial SVDs.

Advances in molecular genetics and pathology of cerebrovascular disorders.

Progress in molecular genetics has enabled the dissection of several autosomal dominantly inherited forms of cerebrovascular disorders. Mutations in diverse genes might induce pathological changes in intracranial vessels, resulting in cerebral haemorrhages and ischaemic strokes. Such pathologies, however, might also result from systemic vascular disease caused by mutations or polymorphisms in genes that regulate cardiovascular physiology, blood coagulation, lipid metabolism and metabolic functions. Interestingly, several mutations that directly affect CNS vasculature involve genes that control inter- or intracellular signalling functions. Although highly variable phenotypes make it difficult to pinpoint the genotypes, genetic characterization of cerebrovascular disorders is valuable for understanding the pathogenesis and management of sporadic disease.

Carotid sinus hypersensitivity associated with focal alpha-synucleinopathy of the autonomic nervous system.

A case of an 82-year-old woman who experienced repeated falls is described. She exhibited a cardioinhibitory carotid sinus hypersensitivity after right carotid sinus massage (CSM), but without evidence of orthostatic hypotension. After a pacemaker was implanted, she did not experience any falls, dizziness or syncope. Her balance eventually deteriorated, but she remained cognitively intact and died from lung cancer at the age of 89 years. Neuropathological examination showed only age-related Alzheimer's disease pathology and a few alpha-synuclein-positive granular deposits and neurites in the dorsal nucleus of the vagus and solitary tract nucleus in the medulla, but a marked alpha-synuclein pathology in the stellate ganglia. The cardioinhibitory element of her CSM was possibly because of the alpha-synuclein pathology in the ganglion, which impaired sympathetic transmission. This case shows another phenotype among patients with alpha-synucleinopathy.

Effects of NOS inhibition on the cardiopulmonary system and brain microvascular markers after intermittent hypoxia in rats.

We previously demonstrated that rats subjected to intermittent hypoxia (IH) by exposure to 10% O(2) for 4 h daily for 56 days in a normobaric chamber, developed pulmonary hypertension, right ventricular hypertrophy and wall-thickening in pulmonary arterioles, compared with normoxic (N) controls. These changes were greater in rats subjected to continuous hypoxia (CH breathing 10% O(2) for 56 days). Cerebral angiogenesis was demonstrated by immunostaining with glucose transporter 1 (GLUT1) antibody, in viable vessels, in CH and to a lesser degree in IH. In this study, adult Wistar rats were subjected to the same hypoxic regimes and given the nitric oxide synthase (NOS) inhibitor N(6)-nitro-L-arginine methyl ester (L-NAME) in drinking water (NLN, IHLN and CHLN regimes) to induce hypertension. There was significant systemic hypertension in NLN and IHLN rats, compared with N and IH, but surprisingly not in CHLN compared with CH. Hematocrit rose in all hypoxic groups (up to 79% in CHLN). There was no significant pulmonary hypertension in IHLN versus NLN rats, although there was asymmetric wall thickening in pulmonary arterioles. Cerebral GLUT1 immunoreactivity increased with L-NAME, with or without hypoxia, especially in CHLN rats, but conspicuously there was no evidence of angiogenesis in brains of IHLN compared with NLN rats. NOS blockade may attenuate the cerebral and pulmonary vascular changes of IH while augmenting cerebral angiogenesis in continuous hypoxia. However, whether cerebral effects are due to systemic hypertension or changes in cerebral nitric oxide production needs to be evaluated.

Impact of hypertension and apolipoprotein E4 on poststroke cognition in subjects >75 years of age.

BACKGROUND AND PURPOSE: The apolipoprotein E4 allele (APOE4) associates with increased dementia risk, and hypertension may associate with mild cognitive deficits. We examined whether nondemented stroke patients with (1) a prestroke history of hypertension and (2) APOE4 were more cognitively impaired at 3 months after stroke. METHODS: A total of 257 participants were genotyped and outcomes from neuropsychological evaluations analyzed using regression. RESULTS: Total Cambridge Assessment for Mental Disorders in the Elderly (CAMCOG) and speed of working memory significantly associated with hypertension. No outcomes significantly associated with APOE4. CONCLUSIONS: Subjects with prestroke hypertension had more impaired global cognition and slower access to information held in working memory.

Cerebral vessels in ageing and Alzheimer's disease.

The integrity of the cerebral vasculature is crucial to the maintenance of cognitive functions during ageing. Prevailing evidence suggests that cerebrovascular functions decline during normal ageing, with pronounced effects in Alzheimer's disease (AD). The causes of these changes largely remain unknown. While previous studies recorded ageing-related impairments, such as atherosclerosis and loss of innervation in basal surface arteries of the brain, it only recently has been realized that a number of subtle alterations in both the intracranial resistance vessels and the smaller capillaries is apparent in both ageing animals and humans. The dominant changes include alterations in composition of connective tissues and smooth muscle of large vessel walls, thickening of the vascular basement membrane, thinning of the endothelium in some species, loss of endothelial mitochondria and increased pericytes. Some of these attributes appear more affected in AD. Other abnormalities entail profound irregularities in the course of microvessels, unexplained inclusions in the basement membrane and changes in unique proteins and membrane lipids associated with the blood-brain barrier. Brain imaging and permeability studies show no clear functional evidence to support the structural and biochemical anomalies, but it is plausible that focal and transient breach of the blood-brain barrier in ageing, and more notably in AD, occurs. Thus, circumscribed neuronal populations in certain brain regions could become vulnerable. Furthermore, the characteristic deposition of amyloid in vessels in AD may exacerbate the decline in vascular function and promote chronic hypoperfusion. Although not explicit from current studies, it is likely that the brain vasculature is continually modified by growth and repair mechanisms in attempts to maintain perfusion during ageing and disease.

The prevalence and clinical manifestations of delirium in sub-Saharan Africa: a systematic review with inferences.

BACKGROUND: In high-income countries with ageing populations, delirium is most prevalent in older adults and in palliative and intensive care settings. The prevalence and aetiology of delirium are likely to differ in low income countries, including sub-Saharan Africa (SSA), due to different population demographics, disease burden and exposure to pathogens. We reviewed published literature relating to the prevalence, clinical features and underlying causes of delirium in SSA and compare this with that published in high-income countries in order to identify knowledge and clinical service gaps, and priorities for further research. METHODS: We performed a narrative review by comprehensively searching the following databases: Medline, PsychInfo, Embase and PubMed. Studies published between January 1 1975 and December 31 2013 in all languages, including the terms 'delirium', 'acute brain syndrome', 'organic brain syndrome', or 'acute confusion' originating from SSA were included. In addition, reference lists of included articles and online databases of African medical literature were hand-searched. We also included case series and case reports due to paucity of published studies. RESULTS: We identified a total of 46 relevant studies. Delirium was the main focus of only one cross-sectional study, whereas most included delirium in studies on neuropsychiatric conditions. Only two studies reported prevalence in older adults. Most studies reported very low (<2%) delirium prevalence, whereas delirium in psychiatric inpatient and outpatient settings was higher than expected (18.2%-29.9%). Descriptive studies of 'bouffee delirante' from psychiatry settings were often describing delirium. Infection and HIV seropositivity were common associations of delirium throughout these studies. There were no studies of intensive, critical or surgical care settings or of management strategies. CONCLUSIONS: We currently know very little about the prevalence, presentation and aetiology of delirium in developing countries. This knowledge gap should be tackled with some urgency, in order to address questions of screening, diagnosis, prevention and management in this setting.

Stroke genomics in people of African ancestry: charting new paths.

One in six people worldwide will experience a stroke in his/her lifetime. While people in Africa carry a disproportionately higher burden of poor stroke outcomes, compared to the rest of the world, the exact contribution of genomic factors to this disparity is unknown. Despite noteworthy research into stroke genomics, studies exploring the genetic contribution to stroke among populations of African ancestry in the United States are few. Furthermore, genomics data in populations living in Africa are lacking. The wide genomic variation of African populations offers a unique opportunity to identify genomic variants with causal relationships to stroke across different ethnic groups. The Stroke Investigative Research and Educational Network (SIREN), a component of the Human Health and Heredity in Africa (H3Africa) Consortium, aims to explore genomic and environmental risk factors for stroke in populations of African ancestry in West Africa and the United States. In this article, we review the literature on the genomics of stroke with particular emphasis on populations of African origin.