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 (non-fluent/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 predefined 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.

The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings.

Preliminary clinical data indicate that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with neurological and neuropsychiatric illness. Responding to this, a weekly virtual coronavirus disease 19 (COVID-19) neurology multi-disciplinary meeting was established at the National Hospital, Queen Square, in early March 2020 in order to discuss and begin to understand neurological presentations in patients with suspected COVID-19-related neurological disorders. Detailed clinical and paraclinical data were collected from cases where the diagnosis of COVID-19 was confirmed through RNA PCR, or where the diagnosis was probable/possible according to World Health Organization criteria. Of 43 patients, 29 were SARS-CoV-2 PCR positive and definite, eight probable and six possible. Five major categories emerged: (i) encephalopathies (n = 10) with delirium/psychosis and no distinct MRI or CSF abnormalities, and with 9/10 making a full or partial recovery with supportive care only; (ii) inflammatory CNS syndromes (n = 12) including encephalitis (n = 2, para- or post-infectious), acute disseminated encephalomyelitis (n = 9), with haemorrhage in five, necrosis in one, and myelitis in two, and isolated myelitis (n = 1). Of these, 10 were treated with corticosteroids, and three of these patients also received intravenous immunoglobulin; one made a full recovery, 10 of 12 made a partial recovery, and one patient died; (iii) ischaemic strokes (n = 8) associated with a pro-thrombotic state (four with pulmonary thromboembolism), one of whom died; (iv) peripheral neurological disorders (n = 8), seven with Guillain-Barré syndrome, one with brachial plexopathy, six of eight making a partial and ongoing recovery; and (v) five patients with miscellaneous central disorders who did not fit these categories. SARS-CoV-2 infection is associated with a wide spectrum of neurological syndromes affecting the whole neuraxis, including the cerebral vasculature and, in some cases, responding to immunotherapies. The high incidence of acute disseminated encephalomyelitis, particularly with haemorrhagic change, is striking. This complication was not related to the severity of the respiratory COVID-19 disease. Early recognition, investigation and management of COVID-19-related neurological disease is challenging. Further clinical, neuroradiological, biomarker and neuropathological studies are essential to determine the underlying pathobiological mechanisms that will guide treatment. Longitudinal follow-up studies will be necessary to ascertain the long-term neurological and neuropsychological consequences of this pandemic.

Cerebral blood flow decrease as an early pathological mechanism in Alzheimer's disease.

Therapies targeting late events in Alzheimer's disease (AD), including aggregation of amyloid beta (Aß) and hyperphosphorylated tau, have largely failed, probably because they are given after significant neuronal damage has occurred. Biomarkers suggest that the earliest event in AD is a decrease of cerebral blood flow (CBF). This is caused by constriction of capillaries by contractile pericytes, probably evoked by oligomeric Aß. CBF is also reduced by neutrophil trapping in capillaries and clot formation, perhaps secondary to the capillary constriction. The fall in CBF potentiates neurodegeneration by upregulating the BACE1 enzyme that makes Aß and by promoting tau hyperphosphorylation. Surprisingly, therefore, CBF reduction may play a crucial role in driving cognitive decline by initiating the amyloid cascade itself, or being caused by and amplifying Aß production. Here, we review developments in this area that are neglected in current approaches to AD, with the aim of promoting novel mechanism-based therapeutic approaches.

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.

Reversible cerebral vasoconstriction syndrome: a rare cause of postpartum headache.

We describe two women presenting with severe postpartum headache associated with hypertension but with no other signs or investigation results to suggest pre-eclampsia. In one case, the headache was associated with atypical subarachnoid haemorrhage. The variable nature of the headache and the degree of associated hypertension raised the clinical suspicion of reversible cerebral vasoconstriction syndrome, confirmed on MR angiography. Both patients took nimodipine until the cerebral vasoconstriction had resolved radiologically.

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

Cerebral blood flow is reduced early in the onset of 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. 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 ß (Aß) constricts brain capillaries at pericyte locations. This was caused by Aß 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 Aß could potentially reduce energy lack and neurodegeneration in AD.

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.

Psychiatric manifestations of primary Sjögren's syndrome: a case report and literature review.

A 54-year-old woman diagnosed with primary Sjögren's syndrome in 2007 presented with a 1-year history of visual hallucinations requiring admission to a psychiatric unit. The hallucinations resolved while on olanzapine and hydroxychloroquine but recurred when they were stopped. Despite restarting olanzapine, her visual hallucinations persisted. When she started a tapering dose of prednisolone, all the hallucinations resolved. This report adds to the small literature on psychiatric manifestations of Sjögren's syndrome and provides evidence that low-dose corticosteroids may be an effective treatment for this manifestation.