The role of capillary pericytes in cerebral blood flow changes during ischaemia and in Alzheimer’s disease

Recently, it was found that brain capillary pericytes play a significant role in controlling cerebral blood flow. Pericytes may therefore also play an important pathological role when cerebral blood flow is compromised, both acutely, as occurs during ischaemic stroke, and chronically, as occurs in Alzheimer’s disease. In this thesis I have investigated the role of brain capillary pericytes as follows. (1) Ischaemia: Pericytes have been suggested to constrict capillaries and subsequently die in rigor during ischaemia, making them a therapeutic target after acute stroke when a long-lasting decrease of cerebral blood flow occurs despite re-opening of the occluded artery. I confirmed that pericytes constrict and die in rigor during ischaemia and demonstrated that the L-type Ca2+ channel blocker nimodipine inhibits ischaemia-induced pericyte constriction. (2) Alzheimer’s disease (AD): Vascular compromise occurs early in AD and amyloid β (Aβ) has been shown to reduce cerebral blood flow. In the cerebral vasculature most resistance is in capillaries, so Aβ might primarily act on contractile capillary pericytes. I used live and fixed human tissue to establish disease-relevance, and rodent experiments to define mechanism, to show that Aβ constricts brain capillaries at pericyte locations. Applying soluble Aβ oligomers to live human cortical tissue constricted capillaries by 25%. Using rat cortical slices this was shown to reflect Aβ evoking capillary pericyte contraction, with an EC50 of 4.7 nM, by generating reactive oxygen species and activating endothelin ET-A receptors. In freshly-fixed diagnostic biopsies from human patients investigated for cognitive decline, mean capillary diameters were 8.1% less in patients showing Aβ deposition than in patients without Aβ deposition. For patients with Aβ deposition, capillary diameter was 31% less at pericyte somata than away from the somata, predicting a halving of blood flow. Constriction of capillaries by Aβ will contribute to the cerebral energy deficit occurring in AD, which promotes further Aβ generation

Control of brain energy supply by astrocytes

Astrocytes form an anatomical bridge between the vasculature and neuronal synapses. Recent work suggests that they play a key role in regulating brain energy supply by increasing blood flow to regions where neurons are active, and setting the baseline level of blood flow. Controversy persists over whether lactate derived from astrocyte glycolysis is used to power oxidative phosphorylation in neurons, but astrocytes sustain neuronal ATP production by recycling neurotransmitter glutamate that would otherwise need to be resynthesised from glucose, and by providing a short-term energy store in the form of glycogen that can be mobilised when neurons are active

Targeting pericytes for therapeutic approaches to neurological disorders

Many central nervous system diseases currently lack effective treatment and are often associated with defects in microvascular function, including a failure to match the energy supplied by the blood to the energy used on neuronal computation, or a breakdown of the blood-brain barrier. Pericytes, an under-studied cell type located on capillaries, are of crucial importance in regulating diverse microvascular functions, such as angiogenesis, the blood-brain barrier, capillary blood flow and the movement of immune cells into the brain. They also form part of the "glial" scar isolating damaged parts of the CNS, and may have stem cell-like properties. Recent studies have suggested that pericytes play a crucial role in neurological diseases, and are thus a therapeutic target in disorders as diverse as stroke, traumatic brain injury, migraine, epilepsy, spinal cord injury, diabetes, Huntington's disease, Alzheimer's disease, diabetes, multiple sclerosis, glioma, radiation necrosis and amyotrophic lateral sclerosis. Here we report recent advances in our understanding of pericyte biology and discuss how pericytes could be targeted to develop novel therapeutic approaches to neurological disorders, by increasing blood flow, preserving blood-brain barrier function, regulating immune cell entry to the CNS, and modulating formation of blood vessels in, and the glial scar around, damaged regions

Comprehension of acoustically degraded speech in Alzheimer's disease and primary progressive aphasia

Successful communication in daily life depends on accurate decoding of speech signals that are acoustically degraded by challenging listening conditions. This process presents the brain with a demanding computational task that is vulnerable to neurodegenerative pathologies. However, despite recent intense interest in the link between hearing impairment and dementia, comprehension of acoustically degraded speech in these diseases has been little studied. Here we addressed this issue in a cohort of 19 patients with typical Alzheimer's disease and 30 patients representing the three canonical syndromes of primary progressive aphasia (nonfluent/agrammatic variant primary progressive aphasia; semantic variant primary progressive aphasia; logopenic variant primary progressive aphasia), compared to 25 healthy age-matched controls. As a paradigm for the acoustically degraded speech signals of daily life, we used noise-vocoding: synthetic division of the speech signal into frequency channels constituted from amplitude-modulated white noise, such that fewer channels convey less spectrotemporal detail thereby reducing intelligibility. We investigated the impact of noise-vocoding on recognition of spoken three-digit numbers and used psychometric modelling to ascertain the threshold number of noise-vocoding channels required for 50% intelligibility by each participant. Associations of noise-vocoded speech intelligibility threshold with general demographic, clinical and neuropsychological characteristics and regional grey matter volume (defined by voxel-based morphometry of patients' brain images) were also assessed. Mean noise-vocoded speech intelligibility threshold was significantly higher in all patient groups than healthy controls, and significantly higher in Alzheimer's disease and logopenic variant primary progressive aphasia than semantic variant primary progressive aphasia (all p < 0.05). In a receiver-operating-characteristic analysis, vocoded intelligibility threshold discriminated Alzheimer's disease, non-fluent variant and logopenic variant primary progressive aphasia patients very well from healthy controls. Further, this central hearing measure correlated with overall disease severity but not with peripheral hearing or clear speech perception. Neuroanatomically, after correcting for multiple voxel-wise comparisons in pre-defined regions of interest, impaired noise-vocoded speech comprehension across syndromes was significantly associated (p < 0.05) with atrophy of left planum temporale, angular gyrus and anterior cingulate gyrus: a cortical network that has previously been widely implicated in processing degraded speech signals. Our findings suggest that the comprehension of acoustically altered speech captures an auditory brain process relevant to daily hearing and communication in major dementia syndromes, with novel diagnostic and therapeutic implications

Epidemiological and cohort study finds no association between COVID-19 and Guillain-Barré syndrome

Reports of Guillain-Barré syndrome (GBS) have emerged during the Coronavirus disease 2019 (COVID-19) pandemic. This epidemiological and cohort study sought to investigate any causative association between COVID-19 infection and GBS. The epidemiology of GBS cases reported to the UK National Immunoglobulin Database was studied from 2016 to 2019 and compared to cases reported during the COVID-19 pandemic. Data were stratified by hospital trust and region, with numbers of reported cases per month. UK population data for COVID-19 infection were collated from UK public health bodies. In parallel, but separately, members of the British Peripheral Nerve Society prospectively reported incident cases of GBS during the pandemic at their hospitals to a central register. The clinical features, investigation findings and outcomes of COVID-19 (definite or probable) and non-COVID-19 associated GBS cases in this cohort were compared. The incidence of GBS treated in UK hospitals from 2016 to 2019 was 1.65–1.88 per 100 000 individuals per year. GBS incidence fell between March and May 2020 compared to the same months of 2016–19. GBS and COVID-19 incidences during the pandemic also varied between regions and did not correlate with one another (r = 0.06, 95% confidence interval: −0.56 to 0.63, P = 0.86). In the independent cohort study, 47 GBS cases were reported (COVID-19 status: 13 definite, 12 probable, 22 non-COVID-19). There were no significant differences in the pattern of weakness, time to nadir, neurophysiology, CSF findings or outcome between these groups. Intubation was more frequent in the COVID-19 affected cohort (7/13, 54% versus 5/22, 23% in COVID-19-negative) attributed to COVID-19 pulmonary involvement. Although it is not possible to entirely rule out the possibility of a link, this study finds no epidemiological or phenotypic clues of SARS-CoV-2 being causative of GBS. GBS incidence has fallen during the pandemic, which may be the influence of lockdown measures reducing transmission of GBS inducing pathogens such as Campylobacter jejuni and respiratory viruses

First, tau causes NO problem

Pathological tau disrupts the association between nitric oxide (NO) synthase and PSD95, impairing NO signaling and neurovascular coupling before causing neurodegeneration. Stopping production of pathological tau rescues NO signaling, neurovascular coupling and neuronal function, but doesn’t remove tangles, suggesting that (like amyloid-β) soluble tau is an important driver of early neurovascular dysfunction and subsequent neuronal damage

Amyloid β oligomers constrict human capillaries in Alzheimer's disease via signaling to pericytes

Cerebral blood flow is reduced early in Alzheimer’s disease (AD). Because most of the vascular resistance within the brain is in capillaries, this could reflect dysfunction of contractile pericytes on capillary walls. Here we used live and rapidly-fixed biopsied human tissue to establish disease-relevance, and rodent experiments to define mechanism. We found that, in humans with cognitive decline, amyloid β (Aβ) constricts brain capillaries at pericyte locations. This was caused by Aβ generating reactive oxygen species, which evoked the release of endothelin-1 (ET) that activated pericyte ETA receptors. Capillary, but not arteriole, constriction also occurred in vivo in a mouse model of AD. Thus, inhibiting the capillary constriction caused by Aβ could potentially reduce energy lack and neurodegeneration in AD

Prognostic indicators and outcomes of hospitalised COVID-19 patients with neurological disease: An individual patient data meta-analysis

BACKGROUND: Neurological COVID-19 disease has been reported widely, but published studies often lack information on neurological outcomes and prognostic risk factors. We aimed to describe the spectrum of neurological disease in hospitalised COVID-19 patients; characterise clinical outcomes; and investigate factors associated with a poor outcome. METHODS: We conducted an individual patient data (IPD) meta-analysis of hospitalised patients with neurological COVID-19 disease, using standard case definitions. We invited authors of studies from the first pandemic wave, plus clinicians in the Global COVID-Neuro Network with unpublished data, to contribute. We analysed features associated with poor outcome (moderate to severe disability or death, 3 to 6 on the modified Rankin Scale) using multivariable models. RESULTS: We included 83 studies (31 unpublished) providing IPD for 1979 patients with COVID-19 and acute new-onset neurological disease. Encephalopathy (978 [49%] patients) and cerebrovascular events (506 [26%]) were the most common diagnoses. Respiratory and systemic symptoms preceded neurological features in 93% of patients; one third developed neurological disease after hospital admission. A poor outcome was more common in patients with cerebrovascular events (76% [95% CI 67-82]), than encephalopathy (54% [42-65]). Intensive care use was high (38% [35-41]) overall, and also greater in the cerebrovascular patients. In the cerebrovascular, but not encephalopathic patients, risk factors for poor outcome included breathlessness on admission and elevated D-dimer. Overall, 30-day mortality was 30% [27-32]. The hazard of death was comparatively lower for patients in the WHO European region. INTERPRETATION: Neurological COVID-19 disease poses a considerable burden in terms of disease outcomes and use of hospital resources from prolonged intensive care and inpatient admission; preliminary data suggest these may differ according to WHO regions and country income levels. The different risk factors for encephalopathy and stroke suggest different disease mechanisms which may be amenable to intervention, especially in those who develop neurological symptoms after hospital admission