Score: 23.0, Published: 2024-02-12
DOI: 10.1101/2022.09.20.22280086
In the neurodegenerative disease Progressive Supranuclear Palsy (PSP), tau pathology progresses through the brain in a stereotypical spatiotemporal pattern, and where tau pathology appears, synapses are lost. We tested the hypothesis that tau pathology spreads between brain regions in PSP by moving from pre- to post-synapses. Sub-diffraction-limit microscopy of human post-mortem brain samples revealed that oligomeric tau is present in synaptic pairs in PSP, with an 80-fold increased chance of post-synapses containing tau when they oppose a tau-containing pre-synapse. In living human brain slice cultures, PSP-derived oligomeric tau was taken up by post-synapses. Synaptic engulfment by astrocytes was observed in both post-mortem brain and human brain slice cultures challenged with PSP-derived tau. These data indicate that tau pathology spreads via synapses in PSP and that astrocytes contribute to synapse loss. Targeting synaptic tau and astrocyte-mediated phagocytosis of synapses are promising targets for attenuating synaptic loss and pathology propagation in PSP.
Score: 7.3, Published: 2024-02-13
DOI: 10.1101/2024.02.12.24302715
Background and ObjectivesModerate-to-severe traumatic brain injury patients commonly manifest vestibular dysfunction with imbalance and dizziness. Importantly, falls in these patients are linked to long-term unemployment and increased mortality. There are however no objective acute-prospective longitudinal data of vestibular outcomes nor of the mechanisms predicting vestibular recovery. We previously showed that in acute traumatic brain injury, acute imbalance was linked to impaired vestibular perception of self-motion (i.e. vestibular agnosia) via right inferior longitudinal fasciculus disruption. This report importantly could not inform upon the predictors nor neural substrates of vestibular recovery, questions which we focus upon in this first acute-longitudinal study assessing objective vestibular recovery in traumatic brain injury, with detailed clinical, laboratory and neuroimaging measures. MethodsWe screened 918 hospitalized traumatic brain injury patients, recruiting 39 acutely (18 - 65 age) with preserved peripheral vestibular function confirmed via vestibular ocular reflex testing (patients 2.52{degrees}/s versus controls 1.78{degrees}/s; P > 0.05) of which 34 patients (17 with vestibular agnosia) completed the follow-up testing. Common inner ear and migraine diagnoses were treated to resolution pre-testing. Vestibular perceptual thresholds were assessed via whole-body rotations in the dark on a computerized rotating chair. Using k-means clustering, vestibular perceptual thresholds of healthy controls and patients were compared resulting in 1.99 {degrees}/s/s or above being classified as vestibular agnosia. Balance was assessed via force platform. ResultsThe change in vestibular perceptual thresholds and sway from acute to follow-up was linked (P < 0.05) and a logistic model indicated (P < 0.05) that those who had acute vestibular agnosia made worse recovery of vestibular mediated function (balance and vestibular perception) as compared to non-vestibular agnosia patients. Moreover, subjective symptoms of imbalance and dizziness (via Dizziness Handicap Inventory) were not linked to objective vestibular recovery of balance and perception (P > 0.05). Neuroimaging findings indicated that the linked vestibular recovery (from vestibular agnosia and imbalance) was mediated by bihemispheric fronto-posterior circuits particularly frontal poles and splenium of corpus callosum. ConclusionAcute vestibular agnosia predicts worse recovery of imbalance and linked recovery of vestibular agnosia and is mediated by partially overlapping, bi-hemispheric circuits. Since vestibular dysfunction may occur without vertigo complaint (from vestibular agnosia), clinical and research assessment of vestibular recovery should assess objective vestibular measures in addition to dizziness symptoms, which poorly track central vestibular recovery. Finally, our cohort were young and without medical co-morbidities, hence understanding the additional impacts of ageing and multimorbidity is required in vestibular recovery in traumatic brain injury cohorts.
Score: 5.2, Published: 2024-02-10
DOI: 10.1101/2024.02.10.24302526
In recent years, the functional importance of the anterior temporal lobes (ATLs) has come to prominence in two active, albeit unconnected branches of the literature. In one branch, neuropsychology and functional neuroimaging evidence emphasises the role of the ATLs in face recognition and linking faces to biographical knowledge. In the other, cognitive and clinical neuroscience investigations have shown that the ATLs are critical to all forms of semantic memory. To draw these literatures together and generate a unified account of ATL function, we test the predictions arising from each literature and examine the effects of bilateral versus unilateral ATL damage on face recognition, person knowledge and semantic memory. Sixteen people with bilateral ATL atrophy from semantic dementia (SD), 17 people with unilateral ATL resection for temporal lobe epilepsy (TLE; left=10, right=7), and 14 controls completed a test battery encompassing general semantic processing, person knowledge and perceptual face matching. SD patients were severely impaired across all semantic tasks, including person knowledge. Despite commensurate total ATL damage, unilateral resection generated mild impairments, with minimal differences between left- and right-ATL resection. Face matching performance was largely preserved but slightly reduced in SD and right TLE. All groups displayed the classic familiarity effect in face matching; however, this benefit was reduced in SD and right TLE groups and was aligned with the level of item-specific semantic knowledge in all participants. We propose a unified neurocognitive framework whereby the ATLs underpin a resilient bilateral representation system that supports semantic memory, person knowledge and face recognition.
Score: 5.3, Published: 2024-01-26
DOI: 10.1101/2024.01.25.24301779
Defining the progression of blood biomarkers of Alzheimers disease (AD) is essential for targeting treatments in patients most likely to benefit from early intervention. We delineated the temporal ordering of blood biomarkers a decade prior to the onset of AD symptoms in participants in the Baltimore Longitudinal Study of Aging. We show that increased astrocyte reactivity, assessed by elevated glial fibrillary acidic protein (GFAP) levels is an early event in the progression of blood biomarker changes in preclinical AD. In AD-converters who are initially cognitively unimpaired (N=158, 377 serial plasma samples), higher plasma GFAP levels are observed as early as 10-years prior to the onset of cognitive impairment due to incident AD compared to individuals who remain cognitively unimpaired (CU, N=160, 379 serial plasma samples). Plasma GFAP levels in AD-converters remain elevated 5-years prior to and coincident with the onset of cognitive impairment due to AD. In participants with neuropathologically confirmed AD, plasma GFAP levels are elevated relative to cognitively normal individuals and intermediate in those who remain cognitively unimpaired despite significant AD pathology (asymptomatic AD). Higher plasma GFAP levels at death are associated with greater severity of both neuritic plaques and neurofibrillary tangles. In the 5XFAD transgenic model of AD, we observed greater GFAP levels in the cortex and hippocampus of transgenic mice relative to wild-type prior to the development of cognitive impairment. Reactive astrocytosis, an established biological response to neuronal injury, may be an early initiator of AD pathogenesis and a promising therapeutic target.
Score: 3.2, Published: 2024-01-30
DOI: 10.1101/2024.01.29.24301950
BackgroundParkinsons disease (PD) therapeutic strategies have evolved since the introduction of levodopa in the 1960s, but there is limited data on their impact on disease progression markers. ObjectiveDelineate the current landscape of PD progression at tertiary subspecialty care and research centers. MethodUsing Accelerating Medicine Partnership-PD (AMP-PD) data harmonized from seven biomarker discovery studies (2010-2020), we extracted: overall [Schwab and England (S&E), PD Questionnaire (PDQ-39)]; motor [Movement Disorders Society Unified PD Rating Scale (MDS-UPDRS)-II and -III and Hoehn & Yahr (HY)]; and non-motor [MDS-UPDRS-I, University of Pennsylvania Smell Identification Test (UPSIT), Montreal Cognitive Assessment (MoCA), and Epworth Sleepiness Scale (ESS)] scores. Age at diagnosis was set as 0 years, and data were tracked for 15 subsequent years. ResultsSubjects (3,001 PD cases: 2,838 white, 1,843 males) mean age at diagnosis was 60.2{+/-}10.3 years and disease duration was 9.9{+/-}6.0 years at the baseline evaluation. Participants largely reported independence (S&E, 5y: 86.6{+/-}12.3; 10y: 78.9{+/-}19.3; 15y: 78.5{+/-}17.0) and good quality of life (PDQ-39, 5y: 15.5{+/-}12.3; 10y: 22.1{+/-}15.8; 15y: 24.3{+/-}14.4). Motor scores displayed a linear progression, whereas non-motor scores plateaued [~]10-15 years. Younger onset age correlated with slower overall (S&E), motor (MDS-UPDRS-III), and non-motor (UPSIT/MoCA) progression, and females had better overall motor (MDS-UPDRS-II-III) and non-motor (UPSIT) scores than males. ConclusionsTwenty-first century PD patients remain largely independent in the first decade of disease. Female and young age of diagnosis were associated with better clinical outcomes. There are data gaps for non-whites and metrics that gauge non-motor progression for >10 years after diagnosis.
Score: 2.9, Published: 2024-02-11
DOI: 10.1101/2024.02.10.24302480
BackgroundWeakness of facial, ocular, and axial muscles is a common clinical presentation in congenital myopathies caused by pathogenic variants in genes encoding triad proteins. Abnormalities in triad structure and function resulting in disturbed excitation-contraction coupling and Ca2+ homeostasis can contribute to disease pathology. MethodsWe analysed exome and genome sequencing data from three unrelated individuals with congenital myopathy characterised by striking facial, ocular, and bulbar involvement. We collected deep phenotypic data from the affected individuals. We analysed the RNA-seq data of one proband and performed gene expression outlier analysis in 129 samples. ResultsThe three probands had remarkably similar clinical presentation with prominent facial, ocular, and bulbar features. Disease onset was in the neonatal period with hypotonia, poor feeding, cleft palate and talipes. Muscle weakness was generalised but most prominent in the lower limbs with facial weakness also present. All patients had myopathic facies, bilateral ptosis, ophthalmoplegia and fatiguability. While muscle biopsy on light microscopy did not show any obvious morphological abnormalities, ultrastructural analysis showed slightly reduced triads, and structurally abnormal sarcoplasmic reticulum. DNA sequencing identified three unique homozygous loss of function variants in JPH1, encoding junctophilin-1 in the three families; a stop-gain (c.354C>A; p.Tyr118*) and two frameshift (c.373del p.Asp125Thrfs*30 and c.1738del; p.Leu580Trpfs*16) variants. Muscle RNA-seq showed strong downregulation of JPH1 in the F3 proband. ConclusionsJunctophilin-1 is critical to the formation of skeletal muscle triad junctions by connecting the sarcoplasmic reticulum and T-tubules. Our findings suggest that loss of JPH1 results in a congenital myopathy with prominent facial, bulbar and ocular involvement. Key messageThis study identified novel homozygous loss-of-function variants in the JPH1 gene, linking them to a unique form of congenital myopathy characterised by severe facial and ocular symptoms. Our research sheds light on the critical impact on junctophilin-1 function in skeletal muscle triad junction formation and the consequences of its disruption resulting in a myopathic phenotype. What is already known on this topicPrevious studies have shown that pathogenic variants in genes encoding triad proteins lead to various myopathic phenotypes, with clinical presentations often involving muscle weakness and myopathic facies. The triad structure is essential for excitation-contraction (EC) coupling and calcium homeostasis and is a key element in muscle physiology. What this study adds and how this study might affect research, practice or policyThis study establishes that homozygous loss-of-function mutations in JPH1 cause a congenital myopathy predominantly affecting facial and ocular muscles. This study also provides clinical insights that may aid the clinicians in diagnosing similar genetically unresolved cases.
Score: 1.6, Published: 2024-02-13
DOI: 10.1101/2024.02.11.24302658
Large language models (LLM) ability in natural language processing holds promise for diverse applications, yet their deployment in fields such as neurology faces domain-specific challenges. Hence, we introduce Neura: a scalable, explainable solution to specialize LLM. Blindly evaluated on a select set of five complex clinical cases compared to a cohort of 13 neurologists, Neura achieved normalized scores of 86.17% overall, 85% for differential diagnoses, and 88.24% for final diagnoses (55.11%, 46.15%, and 70.93% for neurologists) with rapid response times of 28.8 and 19 seconds (9 minutes and 37.2 seconds and 8 minutes and 51 seconds for neurologists) while consistently providing relevant, accurately cited information. These findings support the emerging role of LLM-driven applications to articulate human-acquired and integrated data with a vast corpus of knowledge, augmenting human experiential reasoning for clinical and research purposes.
Score: 1.5, Published: 2024-02-11
DOI: 10.1101/2024.02.09.24302358
Temporal lobe epilepsy (TLE) is a common neurological disease characterized by recurrent focal seizures. These seizures often originate from the mesial temporal limbic networks and the parahippocampal neocortex. People with TLE frequently experience comorbidities related to memory, mood, and sleep (MMS). Deep brain stimulation targeting the anterior nucleus of the thalamus (ANT-DBS) is a proven therapy for reducing TLE seizures, but the optimal stimulation parameters for improving seizures and MMS comorbidities remains unclear. We developed a neurotechnology platform for tracking seizures and MMS during ANT-DBS to address this clinical gap. The platform enables bidirectional data streaming between a brain sensing-stimulation implant, compact mobile devices, and cloud-based data storage, viewing, and computing environment. Machine learning algorithms provided accurate, unbiased catalogs of seizures, interictal epileptiform spikes (IES), and wake-sleep brain states to inform ANT-DBS. Remotely administered memory and mood assessments were used to objectively and densely sample cognitive and behavioral response to ANT-DBS. In participants with mesial TLE, we evaluated the efficacy of low-frequency versus high-frequency ANT-DBS. Low-frequency and high-frequency ANT-DBS both reduced reported seizures. But continuous low-frequency ANT-DBS showed greater reductions in electrographic seizures and IES, as well as better sleep and verbal memory compared to high-frequency ANT-DBS. These results highlight the potential of synchronized brain sensing and behavioral tracking for optimizing neuromodulation therapies.
Score: 1.0, Published: 2024-02-15
DOI: 10.1101/2024.02.14.24302844
BackgroundWhile many patients with neurological disorders and conditions use complementary, alternative, and integrative medicine (CAIM), little is known about the use and perceptions of CAIM among neurology researchers and clinicians. With the increasing popularity of CAIM, our objective was to assess practices, perceptions, and attitudes towards CAIM among neurology researchers and clinicians. MethodsWe conducted an anonymous online survey of authors who had published articles in neurology journals indexed in MEDLINE. We emailed potential participants our cross-sectional electronic survey after extracting their email addresses from one of their publications in our sample of journals. Basic descriptive statistics were drawn from quantitative data, and thematic content analysis was used to analyse qualitative data from any open-ended questions. ResultsThe survey was completed by 783 neurology researchers and/or clinicians (1.5% response rate, 83.9% completion rate). Overall, respondents perceived CAIM to be promising in preventing, treating, and/or managing neurological diseases. Mind-body therapies received the most positive responses, indicated by over half of respondents cumulatively agreeing that they are promising (n=368, 59.0%) and safe (n=280, 50.3%). Whole medical systems and biofield therapy were less favourable. Most neurology clinicians reported a lack of formal (n=211, 70.3%) and supplementary training (n=158, 52.5%) on CAIM. Nearly half of clinicians did not feel comfortable counselling patients about CAIM (n = 121, 44.5%), and over half did not feel comfortable recommending it (n=161, 59.3%). A lack of scientific evidence for CAIMs safety and efficacy was reported as the greatest challenge to CAIM (n=515, 92.5%). The majority of respondents believed there is value to conducting research on this topic (n=461, 82.0%) and supported increasing allocation of research funding towards CAIM (n=241, 58.9%). ConclusionsAlthough many participants found CAIM to be promising to the field of neurology, the vast majority did not feel open to integrating CAIM into mainstream medical practices on account of a perceived lack of scientific evidence for its safety and efficacy. Future studies can use our findings to improve educational resources on CAIM within neurology, as well as examine what effects a tailored CAIM education has on the perceptions of neurology researchers and clinicians.
Score: 1.0, Published: 2024-02-14
DOI: 10.1101/2024.02.12.24300689
Diagnosing Amyotrophic Lateral Sclerosis (ALS) remains a hand challenge due to its inherent heterogeneity. Notably, the occurrence of TDP-43 cytoplasmic aggregation in approximately 95% of ALS cases has emerged as a potential indicative hallmark. In order to develop deep learning models capable of distinguishing TDP-43 proteinopathic samples from their healthy counterparts, a comprehensive understanding of the sample set becomes imperative, particularly when the sample size is limited. The samples in question encompassed images obtained via an immunofluorescence procedure, employing super high-resolution microscopy coupled with meticulous processing. A feature-extracted dataset was created to collect meaningful features from every sample to approach three different classification problems (TDP-43 Pathology, TDP-43 Pathology Grades and ALS) based on the number of red and pink pixels, signifying cytoplasmic and nuclear TDP-43 presence. A series of diverse statistical approaches were undertaken. However, definitive outcomes remained elusive, although it was suggested that a classification based on the presence of TDP-43 proteinopathy was better than the one based on the presence of ALS for training the model. The dataset was reduced by eliminating the problematic samples through curation. Analyses were repeated using t-student tests and ANOVA, and visualisation of patient inter-variability was performed using hierarchical clustering. The TDP-43 pathology classification results showed significant differences in the number of red and pink pixels, the total amount of protein and the cytoplasmic and nuclear proportions between healthy and pathological samples between groups. These findings suggested that images classified according to the presence of TDP-43 proteinopathy are more suitable for training deep learning models.