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Sleep and neurodegenerative diseases
Masud Husain
doi : 10.1093/brain/awab031
Brain, Volume 144, Issue 3, March 2021, Pages 695–696
The biological need for sleep is intriguing. To date, it is a puzzle that has escaped definitive explanation, though difficult to brush aside. We all sleep. In fact it seems we all have to. If we don’t the pressure to sleep becomes compelling, and yet we understand so little about why there is such a universal need for sleep—or why it takes up so much of our time. As Matthew Walker puts it in his Essay in this issue: sleep appears to be obligate, non-negotiable and essential.1 Conversely, lack of sleep is considered to be an abnormal state, with insomnia often leading people to...
Sleep essentialism
Matthew P Walker
doi : 10.1093/brain/awab026
Brain, Volume 144, Issue 3, March 2021, Pages 697–699
Sleep is the most idiotic of all behaviours. When you are asleep, you cannot forage for food or eat. You cannot find a mate. You cannot reproduce. You cannot care for your offspring. Worse still, you are vulnerable to predation. On any one of these grounds, but especially all of them as a collective, there ought to have been a powerful evolutionary pressure to block the emergence of sleep or anything remotely like it. But sleep did emerge. And it persisted. Indeed, it has been said that if sleep does not serve an absolutely vital function, then it is the biggest mistake the evolutionary process...
A step forward in understanding the role of sleep and its link to neurodegeneration
Ambra Stefani, Birgit H?gl
doi : 10.1093/brain/awab047
Brain, Volume 144, Issue 3, March 2021, Pages 700–702
Humans spend one-third of their time asleep. Despite this, little is known about the biological functions of sleep. Historically, research on sleep physiology has focused mainly on describing and understanding the different sleep stages and the brain areas involved in their generation and control. With the exception of studies investigating the role of sleep in cognition, with a particular focus on memory formation and brain plasticity, there has been relatively little work on why sleep is necessary.
DBS for refractory epilepsy: is closed-loop stimulation of the medial septum the way forward?
Vincent Magloire, Gabriele Lignani
doi : 10.1093/brain/awab051
Brain, Volume 144, Issue 3, March 2021, Pages 702–705
Epilepsy affects ?1% of the population worldwide, and 30% of patients develop uncontrolled drug-resistant epilepsy despite optimal medication. This refractory form of the disease is associated with high comorbidity rates and increased mortality, and represents an enormous burden to society (?$10 billion per year).1 In the vast majority of cases, it is characterized by recurrent seizures that arise in a single brain region...
Co-pathologies in Alzheimer’s disease: just multiple pathologies or partners in crime?
Sandra O Tomé, Dietmar Rudolf Thal
doi : 10.1093/brain/awab027
Brain, Volume 144, Issue 3, March 2021, Pages 706–708
Increasing evidence suggests that dementia in the elderly may be the result of multiple neuropathologies rather than a single strictly defined disease. While tau neurofibrillary tangles (NFTs) and amyloid-?-containing plaques are the two major neuropathological hallmarks of Alzheimer’s disease, a number of other pathologies often occur alongside them. In fact, pure Alzheimer’s disease is relatively rare. Cerebral amyloid angiopathy (CAA), limbic-predominant, age-related TDP-43 encephalopathy neuropathological changes (LATE-NC) and Lewy body disease (LBD)-related pathology are also seen in Alzheimer’s disease brains. The distribution of...
Progression in Parkinson’s disease: a potpourri of plots and probabilities
Campbell Le Heron, Daniel Myall, Tim Anderson
doi : 10.1093/brain/awab060
Brain, Volume 144, Issue 3, March 2021, Pages 708–711
An almost ubiquitous question raised by patients newly diagnosed with Parkinson’s disease is what the future may hold for them. Whilst much is now understood about the spectrum of changes that can occur over time, for the most part applying group level descriptions to the individual in front of us remains beyond clinical reach. Although this difficulty in predicting disease trajectory is evident in most branches of medicine, Parkinson’s disease presents particular challenges. It is widely heterogeneous, with clinically relevant manifestations varying...
Deep brain stimulation of the brainstem
Gavin J B Elias, Aaron Loh, Dave Gwun, Aditya Pancholi, Alexandre Boutet ...
doi : 10.1093/brain/awaa374
Brain, Volume 144, Issue 3, March 2021, Pages 712–723
Deep brain stimulation (DBS) of the subthalamic nucleus, pallidum, and thalamus is an established therapy for various movement disorders. Limbic targets have also been increasingly explored for their application to neuropsychiatric and cognitive disorders. The brainstem constitutes another DBS substrate, although the existing literature on the indications for and the effects of brainstem stimulation remains comparatively sparse. The objective of this review was to provide a comprehensive overview of the pertinent anatomy, indications, and reported stimulation-induced acute and long-term effects of existing white and grey matter brainstem DBS targets. We systematically searched the published literature, reviewing clinical trial articles pertaining to DBS brainstem targets. Overall, 164 studies describing brainstem DBS were identified. These studies encompassed 10 discrete structures: periaqueductal/periventricular grey (n?=?63), pedunculopontine nucleus (n?=?48), ventral tegmental area (n?=?22), substantia nigra (n?=?9), mesencephalic reticular formation (n?=?7), medial forebrain bundle (n?=?8), superior cerebellar peduncles (n?=?3), red nucleus (n?=?3), parabrachial complex (n?=?2), and locus coeruleus (n?=?1). Indications for brainstem DBS varied widely and included central neuropathic pain, axial symptoms of movement disorders, headache, depression, and vegetative state. The most promising results for brainstem DBS have come from targeting the pedunculopontine nucleus for relief of axial motor deficits, periaqueductal/periventricular grey for the management of central neuropathic pain, and ventral tegmental area for treatment of cluster headaches. Brainstem DBS has also acutely elicited numerous motor, limbic, and autonomic effects. Further work involving larger, controlled trials is necessary to better establish the therapeutic potential of DBS in this complex area.
Glial cells and adaptive immunity in frontotemporal dementia with tau pathology
Iain J Hartnell, David Blum, James A R Nicoll, Guillaume Dorothee, Delphine Boche
doi : 10.1093/brain/awaa457
Brain, Volume 144, Issue 3, March 2021, Pages 724–745
Neuroinflammation is involved in the aetiology of many neurodegenerative disorders including Alzheimer’s disease, Parkinson’s disease and motor neuron disease. Whether neuroinflammation also plays an important role in the pathophysiology of frontotemporal dementia is less well known. Frontotemporal dementia is a heterogeneous classification that covers many subtypes, with the main pathology known as frontotemporal lobar degeneration. The disease can be categorized with respect to the identity of the protein that causes the frontotemporal lobar degeneration in the brain. The most common subgroup describes diseases caused by frontotemporal lobar degeneration associated with tau aggregation, also known as primary tauopathies. Evidence suggests that neuroinflammation may play a role in primary tauopathies with genome-wide association studies finding enrichment of genetic variants associated with specific inflammation-related gene loci. These loci are related to both the innate immune system, including brain resident microglia, and the adaptive immune system through possible peripheral T-cell involvement. This review discusses the genetic evidence and relates it to findings in animal models expressing pathogenic tau as well as to post-mortem and PET studies in human disease. Across experimental paradigms, there seems to be a consensus regarding the involvement of innate immunity in primary tauopathies, with increased microglia and astrocyte density and/or activation, as well as increases in pro-inflammatory markers. Whilst it is less clear as to whether inflammation precedes tau aggregation or vice versa; there is strong evidence to support a microglial contribution to the propagation of hyperphosphorylated in tau frontotemporal lobar degeneration associated with tau aggregation. Experimental evidence—albeit limited—also corroborates genetic data pointing to the involvement of cellular adaptive immunity in primary tauopathies. However, it is still unclear whether brain recruitment of peripheral immune cells is an aberrant result of pathological changes or a physiological aspect of the neuroinflammatory response to the tau pathology.
Depression, dementia and immune dysregulation
Shawn Hayley, Antoine M Hakim, Paul R Albert
doi : 10.1093/brain/awaa405
Brain, Volume 144, Issue 3, March 2021, Pages 746–760
Major depression is a prevalent illness that increases the risk of several neurological conditions. These include stroke, cardiovascular disease, and dementia including Alzheimer’s disease. In this review we ask whether certain types of depression and associated loneliness may be a harbinger of cognitive decline and possibly even dementia. We propose that chronic stress and inflammation combine to compromise vascular and brain function. The resulting increases in proinflammatory cytokines and microglial activation drive brain pathology leading to depression and mild cognitive impairment, which may progress to dementia. We present evidence that by treating the inflammatory changes, depression can be reversed in many cases. Importantly, there is evidence that anti-inflammatory and antidepressant treatments may reduce or prevent dementia in people with depression. Thus, we propose a model in which chronic stress and inflammation combine to increase brain permeability and cytokine production. This leads to microglial activation, white matter damage, neuronal and glial cell loss. This is first manifest as depression and mild cognitive impairment, but can eventually evolve into dementia. Further research may identify clinical subgroups with inflammatory depression at risk for dementia. It would then be possible to address in clinical trials whether effective treatment of the depression can delay the onset of dementia.
Neurofilament light predicts neurological outcome after subarachnoid haemorrhage
Patrick Garland, Matt Morton, Ardalan Zolnourian, Andrew Durnford, Ben Gaastra ...
doi : 10.1093/brain/awaa451
Brain, Volume 144, Issue 3, March 2021, Pages 761–768
To improve outcome prediction following subarachnoid haemorrhage (SAH), we sought a biomarker integrating early brain injury and multiple secondary pathological processes in a prospective study of 42 non-traumatic SAH patients and 19 control individuals. Neurofilament light (NF-L) was elevated in CSF and serum following SAH. CSF and serum NF-L on Days 1–3 post-SAH strongly predicted modified Rankin score at 6 months, independent of World Federation of Neurosurgical Societies (WFNS) score. NF-L from Day 4 onwards also had a profound impact on outcome. To link NF-L to a SAH-specific pathological process, we investigated NF-L’s relationship with extracellular haemoglobin. Most CSF haemoglobin was not complexed with haptoglobin, yet was able to be bound by exogenous haptoglobin i.e. haemoglobin was scavengeable. CSF scavengeable haemoglobin was strongly predictive of subsequent CSF NF-L. Next, we investigated NF-L efflux from the brain after SAH. Serum and CSF NF-L correlated positively. The serum/CSF NF-L ratio was lower in SAH versus control subjects, in keeping with glymphatic efflux dysfunction after SAH. CSF/serum albumin ratio was increased following SAH versus controls. The serum/CSF NF-L ratio correlated negatively with the CSF/serum albumin ratio, indicating that transfer of the two proteins across the blood–brain interface is dissociated. In summary, NF-L is a strong predictive marker for SAH clinical outcome, adding value to the WFNS score, and is a promising surrogate end point in clinical trials.
Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking
Leslie E Sanderson, Kristina Lanko, Maysoon Alsagob, Rawan Almass, Nada Al-Ahmadi ...
doi : 10.1093/brain/awaa459
Brain, Volume 144, Issue 3, March 2021, Pages 769–780
Membrane trafficking is a complex, essential process in eukaryotic cells responsible for protein transport and processing. Deficiencies in vacuolar protein sorting (VPS) proteins, key regulators of trafficking, cause abnormal intracellular segregation of macromolecules and organelles and are linked to human disease. VPS proteins function as part of complexes such as the homotypic fusion and vacuole protein sorting (HOPS) tethering complex, composed of VPS11, VPS16, VPS18, VPS33A, VPS39 and VPS41. The HOPS-specific subunit VPS41 has been reported to promote viability of dopaminergic neurons in Parkinson’s disease but to date has not been linked to human disease. Here, we describe five unrelated families with nine affected individuals, all carrying homozygous variants in VPS41 that we show impact protein function. All affected individuals presented with a progressive neurodevelopmental disorder consisting of cognitive impairment, cerebellar atrophy/hypoplasia, motor dysfunction with ataxia and dystonia, and nystagmus. Zebrafish disease modelling supports the involvement of VPS41 dysfunction in the disorder, indicating lysosomal dysregulation throughout the brain and providing support for cerebellar and microglial abnormalities when vps41 was mutated. This provides the first example of human disease linked to the HOPS-specific subunit VPS41 and suggests the importance of HOPS complex activity for cerebellar function.
Cortical connectivity of the nucleus basalis of Meynert in Parkinson’s disease and Lewy body dementias
Ashwini Oswal, James Gratwicke, Harith Akram, Marjan Jahanshahi, Laszlo Zaborszky ...
doi : 10.1093/brain/awaa411
Brain, Volume 144, Issue 3, March 2021, Pages 781–788
Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB) are related conditions that are associated with cholinergic system dysfunction. Dysfunction of the nucleus basalis of Meynert (NBM), a basal forebrain structure that provides the dominant source of cortical cholinergic innervation, has been implicated in the pathogenesis of both PDD and DLB. Here we leverage the temporal resolution of magnetoencephalography with the spatial resolution of MRI tractography to explore the intersection of functional and structural connectivity of the NBM in a unique cohort of PDD and DLB patients undergoing deep brain stimulation of this structure. We observe that NBM-cortical structural and functional connectivity correlate within spatially and spectrally segregated networks including: (i) a beta band network to supplementary motor area, where activity in this region was found to drive activity in the NBM; (ii) a delta/theta band network to medial temporal lobe structures encompassing the parahippocampal gyrus; and (iii) a delta/theta band network to visual areas including lingual gyrus. These findings reveal functional networks of the NBM that are likely to subserve important roles in motor control, memory and visual function, respectively. Furthermore, they motivate future studies aimed at disentangling network contribution to disease phenotype.
Randomized trial of granulocyte colony-stimulating factor for spinal cord injury
Masao Koda, Hideki Hanaoka, Yasuhisa Fujii, Michiko Hanawa, Yohei Kawasaki ...
doi : 10.1093/brain/awaa466
Brain, Volume 144, Issue 3, March 2021, Pages 789–799
Attenuation of the secondary injury of spinal cord injury (SCI) can suppress the spread of spinal cord tissue damage, possibly resulting in spinal cord sparing that can improve functional prognoses. Granulocyte colony-stimulating factor (G-CSF) is a haematological cytokine commonly used to treat neutropenia. Previous reports have shown that G-CSF promotes functional recovery in rodent models of SCI. Based on preclinical results, we conducted early phase clinical trials, showing safety/feasibility and suggestive efficacy. These lines of evidence demonstrate that G-CSF might have therapeutic benefits for acute SCI in humans. To confirm this efficacy and to obtain strong evidence for pharmaceutical approval of G-CSF therapy for SCI, we conducted a phase 3 clinical trial designed as a prospective, randomized, double-blinded and placebo-controlled comparative trial. The current trial included cervical SCI [severity of American Spinal Injury Association (ASIA) Impairment Scale (AIS) B or C] within 48 h after injury. Patients are randomly assigned to G-CSF and placebo groups. The G-CSF group was administered 400 ?g/m2/day × 5 days of G-CSF in normal saline via intravenous infusion for five consecutive days. The placebo group was similarly administered a placebo. Allocation was concealed between blinded evaluators of efficacy/safety and those for laboratory data, as G-CSF markedly increases white blood cell counts that can reveal patient treatment. Efficacy and safety were evaluated by blinded observer. Our primary end point was changes in ASIA motor scores from baseline to 3 months after drug administration. Each group includes 44 patients (88 total patients). Our protocol was approved by the Pharmaceuticals and Medical Device Agency in Japan and this trial is funded by the Center for Clinical Trials, Japan Medical Association. There was no significant difference in the primary end point between the G-CSF and the placebo control groups. In contrast, one of the secondary end points showed that the ASIA motor score 6 months (P?=?0.062) and 1 year (P?=?0.073) after drug administration tend to be higher in the G-CSF group compared with the placebo control group. Moreover, in patients aged over 65 years old, motor recovery 6 months after drug administration showed a strong trend towards a better recovery in the G-CSF treated group (P?=?0.056) compared with the control group. The present trial failed to show a significant effect of G-CSF in primary end point although the subanalyses of the present trial suggested potential G-CSF benefits for specific population.
Diffuse axonal injury has a characteristic multidimensional MRI signature in the human brain
Dan Benjamini, Diego Iacono, Michal E Komlosh, Daniel P Perl, David L Brody ...
doi : 10.1093/brain/awaa447
Brain, Volume 144, Issue 3, March 2021, Pages 800–816
Axonal injury is a major contributor to the clinical symptomatology in patients with traumatic brain injury. Conventional neuroradiological tools, such as CT and MRI, are insensitive to diffuse axonal injury (DAI) caused by trauma. Diffusion tensor MRI parameters may change in DAI lesions; however, the nature of these changes is inconsistent. Multidimensional MRI is an emerging approach that combines T1, T2, and diffusion, and replaces voxel-averaged values with distributions, which allows selective isolation of specific potential abnormal components. By performing a combined post-mortem multidimensional MRI and histopathology study, we aimed to investigate T1-T2-diffusion changes linked to DAI and to define their histopathological correlates. Corpora callosa derived from eight subjects who had sustained traumatic brain injury, and three control brain donors underwent post-mortem ex vivo MRI at 7 T. Multidimensional, diffusion tensor, and quantitative T1 and T2 MRI data were acquired and processed. Following MRI acquisition, slices from the same tissue were tested for amyloid precursor protein (APP) immunoreactivity to define DAI severity. A robust image co-registration method was applied to accurately match MRI-derived parameters and histopathology, after which 12 regions of interest per tissue block were selected based on APP density, but blind to MRI. We identified abnormal multidimensional T1-T2, diffusion-T2, and diffusion-T1 components that are strongly associated with DAI and used them to generate axonal injury images. We found that compared to control white matter, mild and severe DAI lesions contained significantly larger abnormal T1-T2 component (P?=?0.005 and P?<?0.001, respectively), and significantly larger abnormal diffusion-T2 component (P?=?0.005 and P?<?0.001, respectively). Furthermore, within patients with traumatic brain injury the multidimensional MRI biomarkers differentiated normal-appearing white matter from mild and severe DAI lesions, with significantly larger abnormal T1-T2 and diffusion-T2 components (P?=?0.003 and P?<?0.001, respectively, for T1-T2; P?=?0.022 and P?<?0.001, respectively, for diffusion-T2). Conversely, none of the conventional quantitative MRI parameters were able to differentiate lesions and normal-appearing white matter. Lastly, we found that the abnormal T1-T2, diffusion-T1, and diffusion-T2 components and their axonal damage images were strongly correlated with quantitative APP staining (r?=?0.876, P?<?0.001; r?=?0.727, P?<?0.001; and r?=?0.743, P?<?0.001, respectively), while producing negligible intensities in grey matter and in normal-appearing white matter. These results suggest that multidimensional MRI may provide non-invasive biomarkers for detection of DAI, which is the pathological substrate for neurological disorders ranging from concussion to severe traumatic brain injury.
Damage to Broca’s area does not contribute to long-term speech production outcome after stroke
Andrea Gajardo-Vidal, Diego L Lorca-Puls, PLORAS team, Holly Warner, Bawan Pshdary ...
doi : 10.1093/brain/awaa460
Brain, Volume 144, Issue 3, March 2021, Pages 817–832
Broca’s area in the posterior half of the left inferior frontal gyrus has long been thought to be critical for speech production. The current view is that long-term speech production outcome in patients with Broca’s area damage is best explained by the combination of damage to Broca’s area and neighbouring regions including the underlying white matter, which was also damaged in Paul Broca’s two historic cases. Here, we dissociate the effect of damage to Broca’s area from the effect of damage to surrounding areas by studying long-term speech production outcome in 134 stroke survivors with relatively circumscribed left frontal lobe lesions that spared posterior speech production areas in lateral inferior parietal and superior temporal association cortices. Collectively, these patients had varying degrees of damage to one or more of nine atlas-based grey or white matter regions: Brodmann areas 44 and 45 (together known as Broca’s area), ventral premotor cortex, primary motor cortex, insula, putamen, the anterior segment of the arcuate fasciculus, uncinate fasciculus and frontal aslant tract. Spoken picture description scores from the Comprehensive Aphasia Test were used as the outcome measure. Multiple regression analyses allowed us to tease apart the contribution of other variables influencing speech production abilities such as total lesion volume and time post-stroke. We found that, in our sample of patients with left frontal damage, long-term speech production impairments (lasting beyond 3 months post-stroke) were solely predicted by the degree of damage to white matter, directly above the insula, in the vicinity of the anterior part of the arcuate fasciculus, with no contribution from the degree of damage to Broca’s area (as confirmed with Bayesian statistics). The effect of white matter damage cannot be explained by a disconnection of Broca’s area, because speech production scores were worse after damage to the anterior arcuate fasciculus with relative sparing of Broca’s area than after damage to Broca’s area with relative sparing of the anterior arcuate fasciculus. Our findings provide evidence for three novel conclusions: (i) Broca’s area damage does not contribute to long-term speech production outcome after left frontal lobe strokes; (ii) persistent speech production impairments after damage to the anterior arcuate fasciculus cannot be explained by a disconnection of Broca’s area; and (iii) the prior association between persistent speech production impairments and Broca’s area damage can be explained by co-occurring white matter damage, above the insula, in the vicinity of the anterior part of the arcuate fasciculus.
Long-term evolution of multiple sclerosis iron rim lesions in 7 T MRI
Assunta Dal-Bianco, Günther Grabner, Claudia Kronnerwetter, Michael Weber, Barbara Kornek ...
doi : 10.1093/brain/awaa436
Brain, Volume 144, Issue 3, March 2021, Pages 833–847
Recent data suggest that multiple sclerosis white matter lesions surrounded by a rim of iron containing microglia, termed iron rim lesions, signify patients with more severe disease course and a propensity to develop progressive multiple sclerosis. So far, however, little is known regarding the dynamics of iron rim lesions over long-time follow-up. In a prospective longitudinal cohort study in 33 patients (17 females; 30 relapsing-remitting, three secondary progressive multiple sclerosis; median age 36.6 years (18.6–62.6), we characterized the evolution of iron rim lesions by MRI at 7 T with annual scanning. The longest follow-up was 7 years in a subgroup of eight patients. Median and mean observation period were 1 (0–7) and 2.9 (±2.6) years, respectively. Images were acquired using a fluid-attenuated inversion recovery sequence fused with iron-sensitive MRI phase data, termed FLAIR-SWI, as well as a magnetization prepared two rapid acquisition gradient echoes, termed MP2RAGE. Volumes and T1 relaxation times of lesions with and without iron rims were assessed by manual segmentation. The pathological substrates of periplaque signal changes outside the iron rims were corroborated by targeted histological analysis on 17 post-mortem cases (10 females; two relapsing-remitting, 13 secondary progressive and two primary progressive multiple sclerosis; median age 66 years (34–88), four of them with available post-mortem 7 T MRI data. We observed 16 nascent iron rim lesions, which mainly formed in relapsing-remitting multiple sclerosis. Iron rim lesion fraction was significantly higher in relapsing-remitting than progressive disease (17.8 versus 7.2%; P?<?0.001). In secondary progressive multiple sclerosis only, iron rim lesions showed significantly different volume dynamics (P?<?0.034) compared with non-rim lesions, which significantly shrank with time in both relapsing-remitting (P?<?0.001) and secondary progressive multiple sclerosis (P?<?0.004). The iron rims themselves gradually diminished with time (P?<?0.008). Compared with relapsing-remitting multiple sclerosis, iron rim lesions in secondary progressive multiple sclerosis were significantly more destructive than non-iron rim lesions (P?<?0.001), reflected by prolonged lesional T1 relaxation times and by progressively increasing changes ascribed to secondary axonal degeneration in the periplaque white matter. Our study for the first time shows that chronic active lesions in multiple sclerosis patients evolve over many years after their initial formation. The dynamics of iron rim lesions thus provide one explanation for progressive brain damage and disability accrual in patients. Their systematic recording might become useful as a tool for predicting disease progression and monitoring treatment in progressive multiple sclerosis.
Subclinical anterior optic pathway involvement in early multiple sclerosis and clinically isolated syndromes
Marco Pisa, Tommaso Croese, Gloria Dalla Costa, Simone Guerrieri, Su-Chun Huang ...
doi : 10.1093/brain/awaa458
Brain, Volume 144, Issue 3, March 2021, Pages 848–862
Optical coherence tomography (OCT) is gaining increasing relevance in the assessment of patients with multiple sclerosis. Converging evidence point to the view that neuro-retinal changes, in eyes without acute optic neuritis, reflect inflammatory and neurodegenerative processes taking place throughout the CNS. The present study aims at exploring the usefulness of OCT as a marker of inflammation and disease burden in the earliest phases of the disease. Thus, a cohort of 150 consecutive patients underwent clinical, neurophysiological and brain MRI assessment as well as lumbar puncture as part of their diagnostic workup for a neurological episode suggestive of inflammatory CNS disorder; among those 32 patients had another previous misdiagnosed episode. For the present study, patients also received a visual pathway assessment (OCT, visual evoked potentials, visual acuity), measurement of CSF inflammatory markers (17 cytokines-chemokines, extracellular vesicles of myeloid origin), and dosage of plasma neurofilaments. Subclinical optic nerve involvement is frequently found in clinically isolated syndromes by visual evoked potentials (19.2%). OCT reveals ganglion cell layer asymmetries in 6.8% of patients; retinal fibre layer asymmetries, despite being more frequent (17.8%), display poor specificity. The presence of subclinical involvement is associated with a greater disease burden. Second, ganglion cell layer thinning reflects the severity of disease involvement even beyond the anterior optic pathway. In fact, the ganglion cell layer in eyes without evidence of subclinical optic involvement is correlated with Expanded Disability Status Scale, low contrast visual acuity, disease duration, brain lesion load, presence of gadolinium enhancing lesions, abnormalities along motor and somatosensory evoked potentials, and frequency of CSF-specific oligoclonal bands. Third, the inner nuclear layer thickens in a post-acute (1.1–3.7 months) phase after a relapse, and this phenomenon is counteracted by steroid treatment. Likewise, a longitudinal analysis on 65 patients shows that this swelling is transient and returns to normal values after 1 year follow-up. Notwithstanding, the clinical, MRI, serological and CSF markers of disease activity considered in the study are strictly associated with one another, but none of them are associated with the inner nuclear layer. Our findings challenge the current hypothesis that the inner nuclear layer is an acute phase marker of inflammatory activity. The present study suggests that instrumental evidence of subclinical optic nerve involvement is associated with a greater disease burden in clinically isolated syndrome. Neuro-retinal changes are present since the earliest phases of the disease and yield important information regarding the neurodegenerative and inflammatory processes occurring in the CNS.
Sleep deprivation impairs molecular clearance from the human brain
Per Kristian Eide, Vegard Vinje, Are Hugo Pripp, Kent-Andre Mardal, Geir Ringstad
doi : 10.1093/brain/awaa443
Brain, Volume 144, Issue 3, March 2021, Pages 863–874
It remains an enigma why human beings spend one-third of their life asleep. Experimental data suggest that sleep is required for clearance of waste products from brain metabolism. This has, however, never been verified in humans. The primary aim of the present study was to examine in vivo whether one night of total sleep deprivation affects molecular clearance from the human brain. Secondarily, we examined whether clearance was affected by subsequent sleep. Multiphase MRI with standardized T1 sequences was performed up to 48 h after intrathecal administration of the contrast agent gadobutrol (0.5 ml of 1 mmol/ml), which served as a tracer molecule. Using FreeSurfer software, we quantified tracer enrichment within 85 brain regions as percentage change from baseline of normalized T1 signals. The cerebral tracer enrichment was compared between two cohorts of individuals; one cohort (n?=?7) underwent total sleep deprivation from Day 1 to Day 2 (sleep deprivation group) while an age and gender-matched control group (n?=?17; sleep group) was allowed free sleep from Day 1 to Day 2. From Day 2 to 3 all individuals were allowed free sleep. The tracer enriched the brains of the two groups similarly. Sleep deprivation was the sole intervention. One night of sleep deprivation impaired clearance of the tracer substance from most brain regions, including the cerebral cortex, white matter and limbic structures, as demonstrated on the morning of Day 2 after intervention (sleep deprivation/sleep). Moreover, the impaired cerebral clearance in the sleep deprivation group was not compensated by subsequent sleep from Day 2 to 3. The present results provide in vivo evidence that one night of total sleep deprivation impairs molecular clearance from the human brain, and that humans do not catch up on lost sleep.
Repeated traumatic brain injury and risk of epilepsy: a Danish nationwide cohort study
Kasper Lolk, Julie W Dreier, Jakob Christensen
doi : 10.1093/brain/awaa448
Brain, Volume 144, Issue 3, March 2021, Pages 875–884
Traumatic brain injury is associated with increased risk of epilepsy, but the importance of repeated traumatic brain injuries has not yet been established. We performed a nationwide population-based cohort study of 2?476?905 individuals born in Denmark between 1977 and 2016. We estimated hazard ratios (HRs) and the cumulative incidence of epilepsy following traumatic brain injury using Cox and competing risk regression, respectively. To estimate the cumulative incidence of epilepsy in the population without traumatic brain injury, we matched 10 controls for each subject with traumatic brain injury on year of birth, sex, and date of brain insult in the index person. In the cohort, traumatic brain injury was sustained by 167?051 subjects (71?162 females and 95?889 males), and 37?200 individuals developed epilepsy (17?905 females and 19?295 males). Compared with subjects without traumatic brain injury, the relative risk of epilepsy increased after a first traumatic brain injury [HR 2.04, 95% confidence interval (CI) 1.96–2.13] and even more after a second traumatic brain injury (HR 4.45, 95% CI 4.09–4.84). The risk increased with the severity of the first and the second traumatic brain injury, most notably after severe traumatic brain injuries. Females were more likely than males to develop epilepsy after mild traumatic brain injury (HR 2.13, 95% CI 2.00–2.28 versus HR 1.77, 95% CI 1.66–1.88; P?<?0.0001); in contrast, males were more likely than females to develop epilepsy after severe traumatic brain injury (HR 5.00, 95% CI 4.31–5.80 versus 3.21, 95% CI 2.56–4.03; P?=?0.0012). The risk remained increased for decades after the traumatic brain injury. This knowledge may inform efforts to prevent the development of post-traumatic epilepsy.
Closed-loop stimulation of the medial septum terminates epileptic seizures
Yuichi Takeuchi, M?rk Harangoz?, Lizeth Pedraza, Tam?s F?ldi, G?bor Koz?k ...
doi : 10.1093/brain/awaa450
Brain, Volume 144, Issue 3, March 2021, Pages 885–908
Temporal lobe epilepsy with distributed hippocampal seizure foci is often intractable and its secondary generalization might lead to sudden death. Early termination through spatially extensive hippocampal intervention is not feasible directly, because of the large size and irregular shape of the hippocampus. In contrast, the medial septum is a promising target to govern hippocampal oscillations through its divergent connections to both hippocampi. Combining this ‘proxy intervention’ concept and precisely timed stimulation, we report here that closed-loop medial septum electrical stimulation can quickly terminate intrahippocampal seizures and suppress secondary generalization in a rat kindling model. Precise stimulus timing governed by internal seizure rhythms was essential. Cell type-specific stimulation revealed that the precisely timed activation of medial septum GABAergic neurons underlaid the effects. Our concept of time-targeted proxy stimulation for intervening pathological oscillations can be extrapolated to other neurological and psychiatric disorders, and has potential for clinical translation.
Striatal and cerebellar vesicular acetylcholine transporter expression is disrupted in human DYT1 dystonia
Joachim Mazere, Bixente Dilharreguy, Gwenaëlle Catheline, Marie Vidailhet, Marc Deffains ...
doi : 10.1093/brain/awaa465
Brain, Volume 144, Issue 3, March 2021, Pages 909–923
Early-onset torsion dystonia (TOR1A/DYT1) is a devastating hereditary motor disorder whose pathophysiology remains unclear. Studies in transgenic mice suggested abnormal cholinergic transmission in the putamen, but this has not yet been demonstrated in humans. The role of the cerebellum in the pathophysiology of the disease has also been highlighted but the involvement of the intrinsic cerebellar cholinergic system is unknown. In this study, cholinergic neurons were imaged using PET with 18F-fluoroethoxybenzovesamicol, a radioligand of the vesicular acetylcholine transporter (VAChT). Here, we found an age-related decrease in VAChT expression in the posterior putamen and caudate nucleus of DYT1 patients versus matched controls, with low expression in young but not in older patients. In the cerebellar vermis, VAChT expression was also significantly decreased in patients versus controls, but independently of age. Functional connectivity within the motor network studied in MRI and the interregional correlation of VAChT expression studied in PET were also altered in patients. These results show that the cholinergic system is disrupted in the brain of DYT1 patients and is modulated over time through plasticity or compensatory mechanisms.
Prediction of Alzheimer's disease using multi-variants from a Chinese genome-wide association study
Longfei Jia, Fangyu Li, Cuibai Wei, Min Zhu, Qiumin Qu ...
doi : 10.1093/brain/awaa364
Brain, Volume 144, Issue 3, March 2021, Pages 924–937
Previous genome-wide association studies have identified dozens of susceptibility loci for sporadic Alzheimer’s disease, but few of these loci have been validated in longitudinal cohorts. Establishing predictive models of Alzheimer’s disease based on these novel variants is clinically important for verifying whether they have pathological functions and provide a useful tool for screening of disease risk. In the current study, we performed a two-stage genome-wide association study of 3913 patients with Alzheimer’s disease and 7593 controls and identified four novel variants (rs3777215, rs6859823, rs234434, and rs2255835; Pcombined = 3.07?×?10?19, 2.49?×?10?23, 1.35?×?10?67, and 4.81?×?10?9, respectively) as well as nine variants in the apolipoprotein E region with genome-wide significance (P?<?5.0?×?10?8). Literature mining suggested that these novel single nucleotide polymorphisms are related to amyloid precursor protein transport and metabolism, antioxidation, and neurogenesis. Based on their possible roles in the development of Alzheimer’s disease, we used different combinations of these variants and the apolipoprotein E status and successively built 11 predictive models. The predictive models include relatively few single nucleotide polymorphisms useful for clinical practice, in which the maximum number was 13 and the minimum was only four. These predictive models were all significant and their peak of area under the curve reached 0.73 both in the first and second stages. Finally, these models were validated using a separate longitudinal cohort of 5474 individuals. The results showed that individuals carrying risk variants included in the models had a shorter latency and higher incidence of Alzheimer’s disease, suggesting that our models can predict Alzheimer’s disease onset in a population with genetic susceptibility. The effectiveness of the models for predicting Alzheimer’s disease onset confirmed the contributions of these identified variants to disease pathogenesis. In conclusion, this is the first study to validate genome-wide association study-based predictive models for evaluating the risk of Alzheimer’s disease onset in a large Chinese population. The clinical application of these models will be beneficial for individuals harbouring these risk variants, and particularly for young individuals seeking genetic consultation.
The interplay of emotional and social conceptual processes during moral reasoning in frontotemporal dementia
Cherie Strikwerda-Brown, Siddharth Ramanan, Zoë-Lee Goldberg, Annu Mothakunnel, John R Hodges ...
doi : 10.1093/brain/awaa435
Brain, Volume 144, Issue 3, March 2021, Pages 938–952
Cooperative social behaviour in humans hinges upon our unique ability to make appropriate moral decisions in accordance with our ethical values. The complexity of the neurocognitive mechanisms underlying moral reasoning is revealed when this capacity breaks down. Patients with the behavioural variant of frontotemporal dementia (bvFTD) display striking moral transgressions in the context of atrophy to frontotemporal regions supporting affective and social conceptual processing. Developmental studies have highlighted the importance of social knowledge to moral decision making in children, yet the role of social knowledge in relation to moral reasoning impairments in neurodegeneration has largely been overlooked. Here, we sought to examine the role of affective and social conceptual processes in personal moral reasoning in bvFTD, and their relationship to the integrity and structural connectivity of frontotemporal brain regions. Personal moral reasoning across varying degrees of conflict was assessed in 26 bvFTD patients and compared with demographically matched Alzheimer’s disease patients (n?=?14), and healthy older adults (n?=?22). Following each moral decision, we directly probed participants’ subjective emotional experience as an index of their affective response, while social norm knowledge was assessed via an independent task. While groups did not differ significantly in terms of their moral decisions, bvFTD patients reported feeling ‘better’ about their decisions than healthy control subjects. In other words, although bvFTD patients could adjudicate between different courses of action in the moral scenarios, their affective responses to these decisions were highly irregular. This blunted emotional reaction was exclusive to the personal high-conflict condition, with 61.5% of bvFTD patients reporting feeling ‘extremely good’ about their decisions, and was correlated with reduced knowledge of socially acceptable behaviour. Voxel-based morphometry analyses revealed a distributed network of frontal, subcortical, and lateral temporal grey matter regions involved in the attenuated affective response to moral conflict in bvFTD. Crucially, diffusion-tensor imaging implicated the uncinate fasciculus as the pathway by which social conceptual knowledge may influence emotional reactions to personal high-conflict moral dilemmas in bvFTD. Our findings suggest that altered moral behaviour in bvFTD reflects the dynamic interplay between degraded social conceptual knowledge and blunted affective responsiveness, attributable to atrophy of, and impaired information transfer between, frontal and temporal cortices. Delineating the mechanisms of impaired morality in bvFTD provides crucial clinical information for understanding and treating this challenging symptom, which may help pave the way for targeted behavioural interventions.
The development and convergence of co-pathologies in Alzheimer’s disease
John L Robinson, Hayley Richardson, Sharon X Xie, EunRan Suh, Vivianna M Van Deerlin ...
doi : 10.1093/brain/awaa438
Brain, Volume 144, Issue 3, March 2021, Pages 953–962
Cerebral amyloid angiopathy (CAA), limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) and Lewy bodies occur in the absence of clinical and neuropathological Alzheimer’s disease, but their prevalence and severity dramatically increase in Alzheimer’s disease. To investigate how plaques, tangles, age and apolipoprotein E ?4 (APOE ?4) interact with co-pathologies in Alzheimer’s disease, we analysed 522 participants ?50 years of age with and without dementia from the Center for Neurodegenerative Disease Research (CNDR) autopsy program and 1340 participants in the National Alzheimer's Coordinating Center (NACC) database. Consensus criteria were applied for Alzheimer’s disease using amyloid phase and Braak stage. Co-pathology was staged for CAA (neocortical, allocortical, and subcortical), LATE-NC (amygdala, hippocampal, and cortical), and Lewy bodies (brainstem, limbic, neocortical, and amygdala predominant). APOE genotype was determined for all CNDR participants. Ordinal logistic regression was performed to quantify the effect of independent variables on the odds of having a higher stage after checking the proportional odds assumption. We found that without dementia, increasing age associated with all pathologies including CAA (odds ratio 1.63, 95% confidence interval 1.38–1.94, P?<?0.01), LATE-NC (1.48, 1.16–1.88, P?<?0.01), and Lewy bodies (1.45, 1.15–1.83, P?<?0.01), but APOE ?4 only associated with CAA (4.80, 2.16–10.68, P?<?0.01). With dementia, increasing age associated with LATE-NC (1.30, 1.15–1.46, P?<?0.01), while Lewy bodies associated with younger ages (0.90, 0.81–1.00, P?=?0.04), and APOE ?4 only associated with CAA (2.36, 1.52–3.65, P?<?0.01). A longer disease course only associated with LATE-NC (1.06, 1.01–1.11, P?=?0.01). Dementia in the NACC cohort associated with the second and third stages of CAA (2.23, 1.50–3.30, P?<?0.01), LATE-NC (5.24, 3.11–8.83, P?<?0.01), and Lewy bodies (2.41, 1.51–3.84, P?<?0.01). Pathologically, increased Braak stage associated with CAA (5.07, 2.77–9.28, P?<?0.01), LATE-NC (5.54, 2.33–13.15, P?<?0.01), and Lewy bodies (4.76, 2.07–10.95, P?<?0.01). Increased amyloid phase associated with CAA (2.27, 1.07–4.80, P?=?0.03) and Lewy bodies (6.09, 1.66–22.33, P?=?0.01). In summary, we describe widespread distributions of CAA, LATE-NC and Lewy bodies that progressively accumulate alongside plaques and tangles in Alzheimer’s disease dementia. CAA interacted with plaques and tangles especially in APOE ?4 positive individuals; LATE-NC associated with tangles later in the disease course; most Lewy bodies associated with moderate to severe plaques and tangles.
Severe oligomeric tau toxicity can be reversed without long-term sequelae
Alfonso Martinisi, Martin Flach, Frederik Sprenger, Stephan Frank, Markus Tolnay ...
doi : 10.1093/brain/awaa445
Brain, Volume 144, Issue 3, March 2021, Pages 963–974
Tau is a microtubule stabilizing protein that forms abnormal aggregates in many neurodegenerative disorders, including Alzheimer’s disease. We have previously shown that co-expression of fragmented and full-length tau in P301SxTAU62on tau transgenic mice results in the formation of oligomeric tau species and causes severe paralysis. This paralysis is fully reversible once expression of the tau fragment is halted, even though P301S tau expression is maintained. Whereas various strategies to target tau aggregation have been developed, little is known about the long-term consequences of reverted tau toxicity. Therefore, we studied the long-term motor fitness of recovered, formerly paralysed P301SxTAU62on-off mice. To assess the seeding competence of oligomeric toxic tau species, we also inoculated ALZ17 mice with brainstem homogenates from paralysed P301SxTAU62on mice. Counter-intuitively, after recovery from paralysis due to oligomeric tau species expression, ageing P301SxTAU62on-off mice did not develop more motor impairment or tau pathology when compared to heterozygous P301S tau transgenic littermates. Thus, toxic tau species causing extensive neuronal dysfunction can be cleared without inducing seeding effects. Moreover, these toxic tau species also lack long-term tau seeding effects upon intrahippocampal inoculation into ALZ17 mice. In conclusion, tau species can be neurotoxic in the absence of seeding-competent tau aggregates, and mice can clear these tau forms permanently without tau seeding or spreading effects. These observations suggest that early targeting of non-fibrillar tau species may represent a therapeutically effective intervention in tauopathies. On the other hand, the absent seeding competence of early toxic tau species also warrants caution when using seeding-based tests for preclinical tauopathy diagnostics.
Sequence of clinical and neurodegeneration events in Parkinson’s disease progression
Neil P Oxtoby, Louise-Ann Leyland, Leon M Aksman, George E C Thomas, Emma L Bunting ...
doi : 10.1093/brain/awaa461
Brain, Volume 144, Issue 3, March 2021, Pages 975–988
Dementia is one of the most debilitating aspects of Parkinson’s disease. There are no validated biomarkers that can track Parkinson’s disease progression, nor accurately identify patients who will develop dementia and when. Understanding the sequence of observable changes in Parkinson’s disease in people at elevated risk for developing dementia could provide an integrated biomarker for identifying and managing individuals who will develop Parkinson’s dementia. We aimed to estimate the sequence of clinical and neurodegeneration events, and variability in this sequence, using data-driven statistical modelling in two separate Parkinson’s cohorts, focusing on patients at elevated risk for dementia due to their age at symptom onset. We updated a novel version of an event-based model that has only recently been extended to cope naturally with clinical data, enabling its application in Parkinson’s disease for the first time. The observational cohorts included healthy control subjects and patients with Parkinson’s disease, of whom those diagnosed at age 65 or older were classified as having high risk of dementia. The model estimates that Parkinson’s progression in patients at elevated risk for dementia starts with classic prodromal features of Parkinson’s disease (olfaction, sleep), followed by early deficits in visual cognition and increased brain iron content, followed later by a less certain ordering of neurodegeneration in the substantia nigra and cortex, neuropsychological cognitive deficits, retinal thinning in dopamine layers, and further deficits in visual cognition. Importantly, we also characterize variation in the sequence. We found consistent, cross-validated results within cohorts, and agreement between cohorts on the subset of features available in both cohorts. Our sequencing results add powerful support to the increasing body of evidence suggesting that visual processing specifically is affected early in patients with Parkinson’s disease at elevated risk of dementia. This opens a route to earlier and more precise detection, as well as a more detailed understanding of the pathological mechanisms underpinning Parkinson’s dementia.
Cognitive decline heralds onset of symptomatic inherited prion disease
Joseph Mole, Simon Mead, Peter Rudge, Akin Nihat, Tzehow Mok ...
doi : 10.1093/brain/awaa409
Brain, Volume 144, Issue 3, March 2021, Pages 989–998
The clinical effectiveness of any disease-modifying treatment for prion disease, as for other neurodegenerative disorders, will depend on early treatment before damage to neural tissue is irrevocable. Thus, there is a need to identify markers that predict disease onset in healthy at-risk individuals. Whilst imaging and neurophysiological biomarkers have shown limited use in this regard, we recently reported progressive neurophysiological changes in individuals with the inherited prion disease mutation P102L. We have also previously demonstrated a signature pattern of fronto-parietal dysfunction in mild prion disease. Here we address whether these cognitive features anticipate the onset of symptoms in a unique sample of patients with inherited prion disease. In the cross-sectional analysis, we analysed the performance of patients at three time points in the course of disease onset: prior to symptoms (n?=?27), onset of subjective symptoms without positive clinical findings (n?=?8) and symptomatic with positive clinical findings (n?=?24). In the longitudinal analysis, we analysed data from 24 patients who were presymptomatic at the time of recruitment and were followed up over a period of up to 17 years, of whom 16 remained healthy and eight converted to become symptomatic. In the cross-sectional analysis, the key finding was that, relative to a group of 25 healthy non-gene carrier controls, patients with subjective symptoms but without positive clinical findings were impaired on a smaller but similar set of tests (Trail Making Test part A, Stroop test, Performance IQ, gesture repetition, figure recall) to those previously found to be impaired in mild prion disease. In the longitudinal analysis, Trail Making Test parts A and B, Stroop test and Performance IQ scores significantly discriminated between patients who remained presymptomatic and those who converted, even before the converters reached criteria for formal diagnosis. Notably, performance on the Stroop test significantly discriminated between presymptomatic patients and converters before the onset of clinical symptoms [area under the curve = 0.83 (95% confidence interval, 0.62–1.00), P?=?0.009]. Thus, we report here, for the first time, neuropsychological abnormalities in healthy patients prior to either symptom onset or clinical diagnosis of inherited prion disease. This constitutes an important component of an evolving profile of clinical and biomarker abnormalities in this crucial group for preventive medicine.
Psychosis in neurodegenerative disease: differential patterns of hallucination and delusion symptoms
Georges Naasan, Suzanne M Shdo, Estrella Morenas Rodriguez, Salvatore Spina, Lea Grinberg ...
doi : 10.1093/brain/awaa413
Brain, Volume 144, Issue 3, March 2021, Pages 999–1012
Although psychosis is a defining feature of Lewy body disease, psychotic symptoms occur in a subset of patients with every major neurodegenerative disease. Few studies, however, have compared disease-related rates of psychosis prevalence in a large autopsy-based cohort, and it remains unclear how diseases differ with respect to the nature or content of the psychosis. We conducted a retrospective chart review of 372 patients with autopsy-confirmed neurodegenerative pathology: 111 with Alzheimer’s disease, 59 with Lewy body disease and concomitant Alzheimer’s disease, 133 with frontotemporal lobar degeneration (FTLD) with tau inclusions (including progressive supranuclear palsy, corticobasal degeneration or Pick’s disease), and 69 with FTLD and TDP inclusions (FTLD-TDP, including types A–C). Psychosis content was classified by subtype, and the frequency of each subtype was compared among pathological diagnoses using logistic regression. A total of 111 of 372 patients had psychosis. Compared to other groups, patients with Lewy body disease/Alzheimer’s disease pathology were significantly more likely to have hallucinations and were more likely to have more than one subtype of hallucination. Patients with Braak Parkinson stage 5–6 Lewy body disease were significantly more likely than those with no Lewy body disease to have visual hallucinations of misperception, peripheral hallucinations, hallucinations that moved, hallucinations of people/animals/objects, as well as delusions regarding a place and delusions of misidentification. The feeling of a presence occurred significantly more frequently in patients with Lewy body disease/Alzheimer’s disease than all other pathologies. Patients with FTLD-TDP were significantly more likely to have delusions, and for the delusions to occur in the first 3 years of the disease, when compared to patients with Alzheimer’s disease and FTLD-tau, though rates were not significantly greater than patients with Lewy body disease/Alzheimer’s disease. Paranoia occurred more frequently in the FTLD-TDP and Lewy body disease/Alzheimer’s disease categories compared to patients with Alzheimer’s disease or FTLD-tau. Patients with FTLD-TDP pathology had delusions of misidentification as frequently as patients with Lewy body disease/Alzheimer’s disease, and were significantly more likely to have self-elevating delusions such as grandiosity and erotomania compared to patients with other pathologies including FTLD-tau. These data show that the nature and content of psychosis can provide meaningful information about the underlying neurodegenerative pathology, emphasizing the importance of characterizing patients’ psychoses for prediction of the neuropathological diagnosis, regardless of a patient’s clinical syndrome.
All or nothing belief updating in patients with schizophrenia reduces precision and flexibility of beliefs
Matthew R Nassar, James A Waltz, Matthew A Albrecht, James M Gold, Michael J Frank
doi : 10.1093/brain/awaa453
Brain, Volume 144, Issue 3, March 2021, Pages 1013–1029
Schizophrenia is characterized by abnormal perceptions and beliefs, but the computational mechanisms through which these abnormalities emerge remain unclear. One prominent hypothesis asserts that such abnormalities result from overly precise representations of prior knowledge, which in turn lead beliefs to become insensitive to feedback. In contrast, another prominent hypothesis asserts that such abnormalities result from a tendency to interpret prediction errors as indicating meaningful change, leading to the assignment of aberrant salience to noisy or misleading information. Here we examine behaviour of patients and control subjects in a behavioural paradigm capable of adjudicating between these competing hypotheses and characterizing belief updates directly on individual trials. We show that patients are more prone to completely ignoring new information and perseverating on previous responses, but when they do update, tend to do so completely. This updating strategy limits the integration of information over time, reducing both the flexibility and precision of beliefs and provides a potential explanation for how patients could simultaneously show over-sensitivity and under-sensitivity to feedback in different paradigms.
PSAP variants in Parkinson’s disease: a large cohort study in Chinese mainland population
Yu-wen Zhao, Hong-xu Pan, Qian Zeng, Zheng-huan Fang, Zhen-hua Liu ...
doi : 10.1093/brain/awaa391
Brain, Volume 144, Issue 3, March 2021, Page e25
We read with great interest the article published recently in Brain by Oji et al. (2020b) ‘Variants in saposin D domain of prosaposin gene linked to Parkinson’s disease’, which reported variants in the saposin D domain of the prosaposin (PSAP) gene and their association with Parkinson’s disease. PSAP encodes a prosaposin protein that degrades into four active saposins (A–D) (Ouled Amar Bencheikh et al., 2018). Deficiency of saposin B is a known cause of metachromatic leukodystrophy (MLD); deficiency of saposin C is a known cause of Gaucher disease; whereas deficiency of saposin A may be a cause of...
Reply: PSAP variants in Parkinson’s disease: a large cohort study in Chinese mainland population
Yutaka Oji, Taku Hatano, Manabu Funayama, Nobutaka Hattori
doi : 10.1093/brain/awaa393
Brain, Volume 144, Issue 3, March 2021, Page e26
We thank Zhao et al. (2021) for their interest in our article and their analysis of prosaposin (PSAP) variants using a large Chinese mainland cohort study of sporadic Parkinson’s disease and sex-, age-, and ethnicity-matched healthy control subjects.
Two heterozygous progranulin mutations in progressive supranuclear palsy
Wanlin Yang, Bin Deng, Yu Huang, Jingxing Liu, Zifeng Huang ...
doi : 10.1093/brain/awaa428
Brain, Volume 144, Issue 3, March 2021, Page e27
We read with interest the recent report by Huin et al. (2020) who reported homozygous progranulin (GRN) mutations in six patients, with two distinct presentations comprising a childhood form with neuronal ceroid lipofuscinosis 11 (CLN11) symptoms at an early age, and another group with frontotemporal dementia (FTD) and parkinsonism after 50 years of age. Heterozygous GRN mutations are a well-recognized cause of FTD associated with neuronal cytoplasmic TAR DNA-binding protein 43 (TDP-43) inclusions. The varied phenotypes associated with the underlying allelic state can be a major challenge for genetic counselling. While there have been case reports of GRN mutations presenting with other...
Reply: Two heterozygous progranulin mutations in progressive supranuclear palsy
Vincent Huin, Mathieu Barbier, Alexandra Durr, Isabelle Le Ber
doi : 10.1093/brain/awaa456
Brain, Volume 144, Issue 3, March 2021, Page e28
Thank you for the opportunity to respond to Yang et al. (2021), reporting a patient diagnosed with progressive supranuclear palsy (PSP) who carried two novel heterozygous missense variants in the GRN gene. The authors reported one case, a 65-year-old male who presented with an akinetic-rigid syndrome, postural instability and supranuclear gaze palsy. Clinical signs fulfilled the Movement Disorder Society’s clinical diagnostic criteria for probable PSP (H?glinger et al., 2017). Sequencing of nine genes with pathogenic variants that cause dementia (GRN, MAPT, C9orf72, VCP, TARDBP, CHMP2B, APP, PSEN1 and PSEN2) revealed two heterozygous...
Neurological complications in COVID-19 patients from Latin America
Sonia M D Brucki, Luiza A Corazza, Apolônio P de Queiroz, Maraysa P Barros, Jo?o F S Tatsch ...
doi : 10.1093/brain/awaa440
Brain, Volume 144, Issue 3, March 2021, Page e29
We read the study by Paterson et al. (2020) entitled ‘The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings’ with great interest. They described a cohort of 43 patients, 23.25% of whom had encephalopathy and 18.6% strokes with a high prevalence of inflammatory CNS syndromes (27.9%). Nine of 12 cases demonstrated acute disseminated encephalomyelitis; this is a higher frequency than that found in other studies. We aimed to compare these results to a sample from a Latin American middle-income country.
Defective phosphatidylethanolamine biosynthesis leads to a broad ataxia-spasticity spectrum
Rauan Kaiyrzhanov, Saskia Wortmann, Taryn Reid, Mohammadreza Dehghani, Mohammad Yahya Vahidi Mehrjardi ...
doi : 10.1093/brain/awaa442
Brain, Volume 144, Issue 3, March 2021, Page e30
With great interest, we read the article by Rickman et al. (2020), highlighting the link between defective phosphatidylethanolamine (PE) biosynthesis and hereditary spastic paraplegia (HSP). The cytidine diphosphate (CDP)-ethanolamine pathway is a three-step enzymatic cascade involved in PE biosynthesis. The rate-limiting enzyme in this pathway, ethanolamine-phosphate cytidylyltransferase (ET), is encoded by PCYT2 (OMIM 618770), and biallelic variants in this gene have been associated with a clinical spectrum of HSP (Vaz et al., 2019; Vélez-Santamar?a et al., 2020). Selenoprotein 1 (SELENOI) (OMIM 607915, also known as EPT1), catalyses the final step...
From ‘loose fitting’ to high-performance, uncertainty-aware brain-age modelling
Tim Hahn, Lukas Fisch, Jan Ernsting, Nils R Winter, Ramona Leenings ...
doi : 10.1093/brain/awaa454
Brain, Volume 144, Issue 3, March 2021, Page e31
In brain-age modelling, a machine learning model is trained on a normative, usually healthy group of individuals to predict chronological age from neuroimaging data. This model is then applied to new data and the difference between predicted and chronological age—termed the brain-age gap (BAG)—is taken as a measure of deviation from ‘normal ageing’. This new area of research has generated large interest over the last decade and accelerated ageing has been associated with many different disorders and pathologies (Franke and Gaser, 2019).
Reply: From ‘loose fitting’ to high-performance, uncertainty-aware brain-age modelling
Vishnu Bashyam, Haochang Shou, Christos Davatzikos
doi : 10.1093/brain/awaa455
Brain, Volume 144, Issue 3, March 2021, Page e32
We appreciate the opportunity to defend our original claims and continue the discussion about the effects of regularization on deep learning-based brain age prediction. While we understand that this is a relatively unexplored topic and further inquiry is certainly needed to validate our results, we refute several of the claims presented in the letter from Hahn et al. (2021).
Corrigendum to: Defining the clinical, molecular and imaging spectrum of adaptor protein complex 4-associated hereditary spastic
doi : 10.1093/brain/awaa424
Brain, Volume 144, Issue 3, March 2021, Page e33
Corrigendum to: Loss of supervillin causes myopathy with myofibrillar disorganization and autophagic vacuoles
doi : 10.1093/brain/awaa412
Brain, Volume 144, Issue 3, March 2021, Page e34
