Pattern Of Neurodegeneration Research Articles

Dynamics of Cortical Degeneration Over a Decade in Huntington’s Disease

BackgroundCharacterizing changing brain structure in neurodegeneration is fundamental to understanding long-term effects of pathology and ultimately providing therapeutic targets. It is well established that Huntington’s disease (HD) gene carriers undergo progressive brain changes during the course of disease, yet the long-term trajectory of cortical atrophy is not well defined. Given that genetic therapies currently tested in HD are primarily expected to target the cortex, understanding atrophy across this region is essential. MethodsCapitalizing on a unique longitudinal dataset with a minimum of 3 and maximum of 7 brain scans from 49 HD gene carriers and 49 age-matched control subjects, we implemented a novel dynamical systems approach to infer patterns of regional neurodegeneration over 10 years. We use Bayesian hierarchical modeling to map participant- and group-level trajectories of atrophy spatially and temporally, additionally relating atrophy to the genetic marker of HD (CAG-repeat length) and motor and cognitive symptoms. ResultsWe show, for the first time, that neurodegenerative changes exhibit complex temporal dynamics with substantial regional variation around the point of clinical diagnosis. Although widespread group differences were seen across the cortex, the occipital and parietal regions undergo the greatest rate of cortical atrophy. We have established links between atrophy and genetic markers of HD while demonstrating that specific cortical changes predict decline in motor and cognitive performance. ConclusionsHD gene carriers display regional variability in the spatial pattern of cortical atrophy, which relates to genetic factors and motor and cognitive symptoms. Our findings indicate a complex pattern of neuronal loss, which enables greater characterization of HD progression.

Use of CMAP, MScan fit-MUNE, and MUNIX in understanding neurodegeneration pattern of ALS and detection of early motor neuron loss in daily practice

BackgroundThe pattern of lower motor neuron (LMN) degeneration in amyotrophic lateral sclerosis (ALS), i.e., dying-back (from the nerve ending to cell body) or dying-forward (from the cell body to nerve ending), has been widely discussed. In this study, we aimed to evaluate LMN loss using compound muscle action potential (CMAP), motor unit number index (MUNIX), and MScan-fit-based motor unit number estimation (MUNE) to understand the pattern of neurodegeneration in ALS. MethodsTwenty-five patients were compared with 25 controls using CMAP amplitude and area, MUNIX, and MScan-fit MUNE in three proximal and distal muscles innervated by the ulnar nerve. ResultsUnlike the controls, the CMAP area, MScan-fit MUNE, and MUNIX recorded in ALS patients showed more neurodegeneration in distal muscles than proximal muscles. In ALS patients with unaffected CMAP amplitudes (n = 13), the CMAP area, MScan-fit MUNE, and MUNIX showed subtle motor unit loss of 30.7 %, 53.8 %, and 38.4 %, respectively. ConclusionThe CMAP area, MScan-fit MUNE, and MUNIX showed neurodegeneration earlier than the reduction in CMAP amplitude. These tests confirmed dying-back neurodegeneration, while only MUSIX showed re-innervation in ALS.

Accumulation of neurofibrillary tangles and activated microglia is associated with lower neuron densities in the aphasic variant of Alzheimer's disease.

The neurofibrillary tangles (NFT) and amyloid‐ß plaques (AP) that comprise Alzheimer’s disease (AD) neuropathology are associated with neurodegeneration and microglial activation. Activated microglia exist on a dynamic spectrum of morphologic subtypes that include resting, surveillant microglia capable of converting to activated, hypertrophic microglia closely linked to neuroinflammatory processes and AD neuropathology in amnestic AD. However, quantitative analyses of microglial subtypes and neurons are lacking in non‐amnestic clinical AD variants, including primary progressive aphasia (PPA‐AD). PPA‐AD is a language disorder characterized by cortical atrophy and NFT densities concentrated to the language‐dominant hemisphere. Here, a stereologic investigation of five PPA‐AD participants determined the densities and distributions of neurons and microglial subtypes to examine how cellular changes relate to AD neuropathology and may contribute to cortical atrophy. Adjacent series of sections were immunostained for neurons (NeuN) and microglia (HLA‐DR) from bilateral language and non‐language regions where in vivo cortical atrophy and Thioflavin‐S‐positive APs and NFTs were previously quantified. NeuN‐positive neurons and morphologic subtypes of HLA‐DR‐positive microglia (i.e., resting [ramified] microglia and activated [hypertrophic] microglia) were quantified using unbiased stereology. Relationships between neurons, microglia, AD neuropathology, and cortical atrophy were determined using linear mixed models. NFT densities were positively associated with hypertrophic microglia densities (P < 0.01) and inversely related to neuron densities (P = 0.01). Hypertrophic microglia densities were inversely related to densities of neurons (P < 0.01) and ramified microglia (P < 0.01). Ramified microglia densities were positively associated with neuron densities (P = 0.02) and inversely related to cortical atrophy (P = 0.03). Our findings provide converging evidence of divergent roles for microglial subtypes in patterns of neurodegeneration, which includes hypertrophic microglia likely driving a neuroinflammatory response more sensitive to NFTs than APs in PPA‐AD. Moreover, the accumulation of both NFTs and activated hypertrophic microglia in association with low neuron densities suggest they may collectively contribute to focal neurodegeneration characteristic of PPA‐AD.

Intrathecal Inflammation in Progressive Multiple Sclerosis

Progressive forms of multiple sclerosis (MS) are associated with chronic demyelination, axonal loss, neurodegeneration, cortical and deep gray matter damage, and atrophy. These changes are strictly associated with compartmentalized sustained inflammation within the brain parenchyma, the leptomeninges, and the cerebrospinal fluid. In progressive MS, molecular mechanisms underlying active demyelination differ from processes that drive neurodegeneration at cortical and subcortical locations. The widespread pattern of neurodegeneration is consistent with mechanisms associated with the inflammatory molecular load of the cerebrospinal fluid. This is at variance with gray matter demyelination that typically occurs at focal subpial sites, in the proximity of ectopic meningeal lymphoid follicles. Accordingly, it is possible that variations in the extent and location of neurodegeneration may be accounted for by individual differences in CSF flow, and by the composition of soluble inflammatory factors and their clearance. In addition, “double hit” damage may occur at sites allowing a bidirectional exchange between interstitial fluid and CSF, such as the Virchow–Robin spaces and the periventricular ependymal barrier. An important aspect of CSF inflammation and deep gray matter damage in MS involves dysfunction of the blood–cerebrospinal fluid barrier and inflammation in the choroid plexus. Here, we provide a comprehensive review on the role of intrathecal inflammation compartmentalized to CNS and non-neural tissues in progressive MS.

Tau pathology associates with in vivo cortical thinning in Lewy body disorders.

ObjectivesTo investigate the impact of Alzheimer’s disease (AD) co‐pathology on an in vivo structural measure of neurodegeneration in Lewy body disorders (LBD).MethodsWe studied 72 LBD patients (Parkinson disease (PD) = 2, PD‐MCI = 25, PD with dementia = 10, dementia with Lewy bodies = 35) with either CSF analysis or neuropathological examination and structural MRI during life. The cohort was divided into those harboring significant AD co‐pathology, either at autopsy (intermediate/high AD neuropathologic change) or with CSF signature indicating AD co‐pathology (t‐tau/Aβ 1‐42 > 0.3) (LBD+AD, N = 19), and those without AD co‐pathology (LBD−AD, N = 53). We also included a reference group of 25 patients with CSF biomarker‐confirmed amnestic AD. We investigated differences in MRI cortical thickness estimates between groups, and in the 21 autopsied LBD patients (LBD−AD = 14, LBD+AD = 7), directly tested the association between antemortem MRI and post‐mortem burdens of tau, Aβ, and alpha‐synuclein using digital histopathology in five representative neocortical regions.ResultsThe LBD+AD group was characterized by cortical thinning in anterior/medial and lateral temporal regions (P < 0.05 FWE‐corrected) relative to LBD−AD. In LBD+AD, cortical thinning was most pronounced in temporal neocortex, whereas the AD reference group showed atrophy that equally encompassed temporal, parietal and frontal neocortex. In autopsied LBD, we found an inverse correlation with cortical thickness and post‐mortem tau pathology, while cortical thickness was not significantly associated with Aβ or alpha‐synuclein pathology.InterpretationLBD+AD is characterized by temporal neocortical thinning on MRI, and cortical thinning directly correlated with post‐mortem histopathologic burden of tau, suggesting that tau pathology influences the pattern of neurodegeneration in LBD.

DIAGNOSIS OF CHILDREN WITH SANFILIPPO DISEASE – PSYCHOLOGICAL, SOCIAL AND MOTOR ASSESSMENT

Sanfilippo disease (mucopolysaccharidosis, MPS IIIA) is one of the types of mucopolysaccharidosis associated with extensive neurological effects and somatic symptoms. The consequences of neurodegeneration and cognitive impairment are manifested in challenges with the daily functioning of patients who experience problems with communication and following instructions. The aim of this study was to assess the cognitive functioning of three patients with MPS IIIA and to find patterns of neurodegeneration and to make their environment more friendly. Three boys (from 5.5 to 7 years) with MPS IIIA participated in the study. Each participant attended two meetings, and his functioning was assessed by three independent person (using two-way mirror). We used Bayley’s Scale III with some modifications. Interviews with parents were also included. The communication of patients was limited to some vocalizations. Patients presented instrumental use of items, but not all of them were able to repeat actions after diagnostician or presented object permanence. The results showed that the cognitive functioning of participants was significantly hindered by problems related to motor dysfunction, hyperactivity, and ataxia. The psychological data was collated with medical results. This study allows indicating new sources giving the possibility of child phenotype variability and to create specific interventions in the field of psychological therapy for patients with MPS IIIA and their families.

SeSBAT: Single Subject Brain Analysis Toolbox. Application to Huntington's Disease as a Preliminary Study.

Magnetic resonance imaging (MRI) biomarkers require complex processing routines that are time-consuming and labor-intensive for clinical users. The Single Subject Brain Analysis Toolbox (SeSBAT) is a fully automated MATLAB toolbox with a graphical user interface (GUI) that offers standardized and optimized protocols for the pre-processing and analysis of anatomical MRI data at the single-subject level. In this study, the two-fold strategy provided by SeSBAT is illustrated through its application on a cohort of 42 patients with Huntington’s disease (HD), in pre-manifest and early manifest stages, as a suitable model of neurodegenerative processes. On the one hand, hypothesis-driven analysis can be used to extract biomarkers of neurodegeneration in specific brain regions of interest (ROI-based analysis). On the other hand, an exploratory voxel-based morphometry (VBM) approach can detect volume changes due to neurodegeneration throughout the whole brain (whole-brain analysis). That illustration reveals the potential of SeSBAT in providing potential prognostic biomarkers in neurodegenerative processes in clinics, which could be critical to overcoming the limitations of current qualitative evaluation strategies, and thus improve the diagnosis and monitoring of neurodegenerative disorders. Furthermore, the importance of the availability of tools for characterization at the single-subject level has been emphasized, as there is high interindividual variability in the pattern of neurodegeneration. Thus, tools like SeSBAT could pave the way towards more effective and personalized medicine.

Longitudinal anatomic, functional, and molecular characterization of Pick disease phenotypes.

To characterize longitudinal MRI and PET abnormalities in autopsy-confirmed Pick disease (PiD) and determine how patterns of neurodegeneration differ with respect to clinical syndrome. Seventeen patients with PiD were identified who had antemortem MRI (8 with behavioral variant frontotemporal dementia [bvFTD-PiD], 6 with nonfluent/agrammatic primary progressive aphasia [naPPA-PiD], 1 with semantic primary progressive aphasia, 1 with unclassified primary progressive aphasia, and 1 with corticobasal syndrome). Thirteen patients had serial MRI for a total of 56 MRIs, 7 had [18F]fluorodeoxyglucose PET, 4 had Pittsburgh compound B (PiB) PET, and 1 patient had [18F]flortaucipir PET. Cross-sectional and longitudinal comparisons of gray matter volume and metabolism were performed between bvFTD-PiD, naPPA-PiD, and controls. Cortical PiB summaries were calculated to determine β-amyloid positivity. The bvFTD-PiD and naPPA-PiD groups showed different foci of volume loss and hypometabolism early in the disease, with bvFTD-PiD involving bilateral prefrontal and anterior temporal cortices and naPPA-PiD involving left inferior frontal gyrus, insula, and orbitofrontal cortex. However, patterns merged over time, with progressive spread into prefrontal and anterior temporal lobe in naPPA-PiD, and eventual involvement of posterior temporal lobe, motor cortex, and parietal lobe in both groups. Rates of frontotemporal atrophy were faster in bvFTD-PiD than naPPA-PiD. One patient was β-amyloid-positive on PET with low Alzheimer neuropathologic changes at autopsy. Flortaucipir PET showed elevated uptake in frontotemporal white matter. Patterns of atrophy and hypometabolism differ in PiD according to presenting syndrome, although patterns of neurodegeneration appear to converge over time.

Sex effects on brain structure in de novo Parkinson's disease: a multimodal neuroimaging study.

Parkinson's disease varies in severity and age of onset. One source of this variability is sex. Males are twice as likely as females to develop Parkinson's disease, and tend to have more severe symptoms and greater speed of progression. However, to date, there is little information in large cohorts on sex differences in the patterns of neurodegeneration. Here we used MRI and clinical information from the Parkinson Progression Markers Initiative to measure structural brain differences between sexes in Parkinson's disease after regressing out the expected effect of age and sex. We derived atrophy maps from deformation-based morphometry of T1-weighted MRI and connectivity from diffusion-weighted MRI in de novo Parkinson's disease patients (149 males: 83 females) with comparable clinical severity, and healthy control participants (78 males: 39 females). Overall, even though the two patient groups were matched for disease duration and severity, males demonstrated generally greater brain atrophy and disrupted connectivity. Males with Parkinson's disease had significantly greater tissue loss than females in 11 cortical regions including bilateral frontal and left insular lobe, right postcentral gyrus, left inferior temporal and cingulate gyrus and left thalamus, while females had greater atrophy in six cortical regions, including regions in the left frontal lobe, right parietal lobe, left insular gyrus and right occipital cortex. Local efficiency of white matter connectivity showed greater disruption in males in multiple regions such as basal ganglia, hippocampus, amygdala and thalamus. These findings support the idea that development of Parkinson's disease may involve different pathological mechanisms and yield distinct prognosis in males and females, which may have implications for research into neuroprotection, and stratification for clinical trials.

Early retinal degeneration in Huntington's disease based on optical coherence tomography: a case-control study

Background: The purpose of this study was to analyze optical coherence tomography (OCT) parameters of the choroid and retina in subjects with pre-manifest and manifest Huntington's disease (HD).&#x0D; Methods: In this case-control study, the retinal parameters of patients with genetically confirmed HD and healthy controls were evaluated using spectral-domain optical coherence tomography (SD-OCT). Genetic and neurological assessments were performed besides a thorough ophthalmological examination. Contrast Sensitivity (CS) logarithm was evaluated using the Freiburg Vision Test. The association between OCT parameters and clinical and genetic characteristics was studied.&#x0D; Results: A total of 91 subjects, including 60 HD subjects (60 eyes) and 31 control subjects (31 eyes) were eligible according to the inclusion and exclusion criteria. The range of the CAG (cytosine-adenine-guanine) repeat expansion size was 38–56 repeats, the mean ± standard deviation (SD) of the Unified HD Rating Scale (UHDRS) motor scores was 36.3±29.7, and disease duration was 13.7±7.2 years in HD subjects. Compared to the control group, significant decreases in the mean ganglion cell complex thickness and mean, temporal, superior, inferior, and nasal retinal nerve fiber layer (RNFL) thickness in HD subjects was revealed in OCT examination (P-values &lt; 0.001, &lt; 0.001, &lt; 0.001, 0.023, 0.007 and 0.014, respectively). An inverse correlation between the disease duration and the mean RNFL thickness (r =- 0.470, P = 0.002) was found.&#x0D; Conclusions: Localization of retinal thickness loss shows a specific pattern of retinal neurodegeneration in HD, similar to Parkinson’s disease and mitochondrial diseases. The association with the disease duration confirms the progressive nature of these changes.

Deep learning-enabled analysis reveals distinct neuronal phenotypes induced by aging and cold-shock

BackgroundAccess to quantitative information is crucial to obtain a deeper understanding of biological systems. In addition to being low-throughput, traditional image-based analysis is mostly limited to error-prone qualitative or semi-quantitative assessment of phenotypes, particularly for complex subcellular morphologies. The PVD neuron in Caenorhabditis elegans, which is responsible for harsh touch and thermosensation, undergoes structural degeneration as nematodes age characterized by the appearance of dendritic protrusions. Analysis of these neurodegenerative patterns is labor-intensive and limited to qualitative assessment.ResultsIn this work, we apply deep learning to perform quantitative image-based analysis of complex neurodegeneration patterns exhibited by the PVD neuron in C. elegans. We apply a convolutional neural network algorithm (Mask R-CNN) to identify neurodegenerative subcellular protrusions that appear after cold-shock or as a result of aging. A multiparametric phenotypic profile captures the unique morphological changes induced by each perturbation. We identify that acute cold-shock-induced neurodegeneration is reversible and depends on rearing temperature and, importantly, that aging and cold-shock induce distinct neuronal beading patterns.ConclusionThe results of this work indicate that implementing deep learning for challenging image segmentation of PVD neurodegeneration enables quantitatively tracking subtle morphological changes in an unbiased manner. This analysis revealed that distinct patterns of morphological alteration are induced by aging and cold-shock, suggesting different mechanisms at play. This approach can be used to identify the molecular components involved in orchestrating neurodegeneration and to characterize the effect of other stressors on PVD degeneration.

Unsupervised clustering of dopamine transporter PET imaging discovers heterogeneity of parkinsonism.

Parkinsonism has heterogeneous nature, showing distinctive patterns of disease progression and prognosis. We aimed to find clusters of parkinsonism based on 18F‐fluoropropyl‐carbomethoxyiodophenylnortropane (FP‐CIT) PET as a data‐driven approach to evaluate heterogenous dopaminergic neurodegeneration patterns. Two different cohorts of patients who received FP‐CIT PET were collected. A labeled cohort (n = 94) included patients with parkinsonism who underwent a clinical follow‐up of at least 3 years (mean 59.0 ± 14.6 months). An unlabeled cohort (n = 813) included all FP‐CIT PET data of a single‐center. All PET data were clustered by a dimension reduction method followed by hierarchical clustering. Four distinct clusters were defined according to the imaging patterns. When the diagnosis of the labeled cohort of 94 patients was compared with the corresponding cluster, parkinsonism patients were mostly included in two clusters, cluster “0” and “2.” Specifically, patients with progressive supranuclear palsy were significantly more included in cluster 0. The two distinct clusters showed significantly different clinical features. Furthermore, even in PD patients, two clusters showed a trend of different clinical features. We found distinctive clusters of parkinsonism based on FP‐CIT PET‐derived heterogeneous neurodegeneration patterns, which were associated with different clinical features. Our results support a biological underpinning for the heterogeneity of neurodegeneration in parkinsonism.

Profound regional spectral, connectivity, and network changes reflect visual deficits in posterior cortical atrophy: an EEG study

Patients with posterior cortical atrophy (PCA-AD) show more severe visuospatial and perceptual deficits than those with typical AD (tAD). The aim of this study was to investigate whether functional alterations measured by electroencephalography can help understand the mechanisms that explain this clinical heterogeneity. 21-channel electroencephalography recordings of 29 patients with PCA-AD were compared with 29 patients with tAD and 29 controls matched for age, gender, and disease severity. Patients with PCA-AD and tAD both showed a global decrease in fast and increase in slow oscillatory activity compared with controls. This pattern was, however, more profound in patients with PCA-AD which was driven by more extensive slowing of the posterior regions. Alpha band functional connectivity showed a similar decrease in PCA-AD and tAD. Compared with controls, a less integrated network topology was observed in PCA-AD, with a decrease of posterior and an increase of frontal hubness. In PCA-AD, decreased right parietal peak frequency correlated with worse performance on visual tasks. Regional vulnerability of the posterior network might explain the atypical pattern of neurodegeneration in PCA-AD.

Neurodegenerative changes in early- and late-onset cognitive impairment with and without brain amyloidosis

BackgroundA substantial number of patients clinically diagnosed with Alzheimer’s disease do not harbor amyloid pathology. We analyzed the presence and extent of tau deposition and neurodegeneration in amyloid-positive (AD) and amyloid-negative (nonAD) ADNI subjects while also taking into account age of onset (< or > 65 years) as we expected that the emerging patterns could vary by age and presence or absence of brain amyloidosis.MethodsOne hundred and ten early-onset AD (EOAD), 121 EOnonAD, 364 late-onset AD (LOAD), and 175 LOnonAD mild cognitive impairment (MCI) and dementia (DEM) subjects were compared to 291 ADNI amyloid-negative control subjects using voxel-wise regression in SPM12 with cluster-level family-wise error correction at pFWE < 0.05). A subset of these subjects also received 18F-flortaucipir scans and allowed for analysis of global tau burden.ResultsAs expected, relative to LOAD, EOAD subjects showed more extensive neurodegeneration and tau deposition in AD-relevant regions. EOnonADMCI showed no significant neurodegeneration, while EOnonADDEM showed bilateral medial and lateral temporal, and temporoparietal hypometabolism. LOnonADMCI and LOnonADDEM showed diffuse brain atrophy and a fronto-temporo-parietal hypometabolic pattern. LOnonAD and EOnonAD subjects failed to show significant tau binding.ConclusionsLOnonAD subjects show a fronto-temporal neurodegenerative pattern in the absence of tau binding, which may represent underlying hippocampal sclerosis with TDP-43, also known as limbic-predominant age-related TDP-43 encephalopathy (LATE). The hypometabolic pattern observed in EOnonADDEM seems similar to the one observed in EOADMCI. Further investigation into the underlying etiology of EOnonAD is warranted.

Neurodegenerative patterns in Wilson’s disease with hepatic or neurological manifestation assessed by morphometric magnetic resonance imaging

Neurodegenerative patterns in Wilson’s disease with hepatic or neurological manifestation assessed by morphometric magnetic resonance imaging

APP-Induced Patterned Neurodegeneration Is Exacerbated by APOE4 in Caenorhabditis elegans.

Genetic and epidemiological studies have found that variations in the amyloid precursor protein (APP) and the apoliopoprotein E (APOE) genes represent major modifiers of the progressive neurodegeneration in Alzheimer’s disease (AD). An extra copy of or gain-of-function mutations in APP correlate with early onset AD. Compared to the other variants (APOE2 and APOE3), the ε4 allele of APOE (APOE4) hastens and exacerbates early and late onset forms of AD. Convenient in vivo models to study how APP and APOE4 interact at the cellular and molecular level to influence neurodegeneration are lacking. Here, we show that the nematode C. elegans can model important aspects of AD including age-related, patterned neurodegeneration that is exacerbated by APOE4. Specifically, we found that APOE4, but not APOE3, acts with APP to hasten and expand the pattern of cholinergic neurodegeneration caused by APP. Molecular mechanisms underlying how APP and APOE4 synergize to kill some neurons while leaving others unaffected may be uncovered using this convenient worm model of neurodegeneration.

Tau and Alpha Synuclein Synergistic Effect in Neurodegenerative Diseases: When the Periphery Is the Core.

In neuronal cells, tau is a microtubule-associated protein placed in axons and alpha synuclein is enriched at presynaptic terminals. They display a propensity to form pathologic aggregates, which are considered the underlying cause of Alzheimer’s and Parkinson’s diseases. Their functional impairment induces loss of axonal transport, synaptic and mitochondrial disarray, leading to a “dying back” pattern of degeneration, which starts at the periphery of cells. In addition, pathologic spreading of alpha-synuclein from the peripheral nervous system to the brain through anatomical connectivity has been demonstrated for Parkinson’s disease. Thus, examination of the extent and types of tau and alpha-synuclein in peripheral tissues and their relation to brain neurodegenerative diseases is of relevance since it may provide insights into patterns of protein aggregation and neurodegeneration. Moreover, peripheral nervous tissues are easily accessible in-vivo and can play a relevant role in the early diagnosis of these conditions. Up-to-date investigations of tau species in peripheral tissues are scant and have mainly been restricted to rodents, whereas, more evidence is available on alpha synuclein in peripheral tissues. Here we aim to review the literature on the functional role of tau and alpha synuclein in physiological conditions and disease at the axonal level, their distribution in peripheral tissues, and discuss possible commonalities/diversities as well as their interaction in proteinopathies.

Magnetic resonance imaging analysis of long-term neuropathology after exposure to the nerve agent soman: correlation with histopathology and neurological dysfunction.

Nerve agents (NAs) produce acute and long-term brain injury and dysfunction, as evident from the Japan and Syria incidents. Magnetic resonance imaging (MRI) is a versatile technique to examine such chronic anatomical, functional, and neuronal damage in the brain. The objective of this study was to investigate long-term structural and neuronal lesion abnormalities in rats exposed to acute soman intoxication. T2-weighted MRI images of 10 control and 17 soman-exposed rats were acquired using a Siemens MRI system at 90days after soman exposure. Quantification of brain tissue volumes and T2 signal intensity was conducted using the Inveon Research Workplace software and the extent of damage was correlated with histopathology and cognitive function. Soman-exposed rats showed drastic hippocampal atrophy with neuronal loss and reduced hippocampal volume (HV), indicating severe damage, but had similar T2 relaxation times to the control group, suggesting limited scarring and fluid density changes despite the volume decrease. Conversely, soman-exposed rats displayed significant increases in lateral ventricle volumes and T2 times, signifying strong cerebrospinal fluid expansion in compensation for tissue atrophy. The total brain volume, thalamic volume, and thalamic T2 time were similar in both groups, however, suggesting that some brain regions remained more intact long-term after soman intoxication. The MRI neuronal lesions were positively correlated with the histological markers of neurodegeneration and neuroinflammation 90days after soman exposure. The predominant MRI hippocampal atrophy (25%) was highly consistent with massive reduction (35%) of neuronal nuclear antigen-positive (NeuN+ ) principal neurons and parvalbumin-positive (PV+ ) inhibitory interneurons within this brain region. The HV was significantly correlated with both inflammatory markers of GFAP+ astrogliosis and IBA1+ microgliosis. The reduced HV was also directly correlated with significant memory deficits in the soman-exposed cohort, confirming a possible neurobiological basis for neurological dysfunction. Together, these findings provide powerful insight on long-term region-specific neurodegenerative patterns after soman exposure and demonstrate the feasibility of in vivo neuroimaging to monitor neuropathology, predict the risk of neurological deficits, and evaluate response to medical countermeasures for NAs.

Using machine learning to quantify structural MRI neurodegeneration patterns of Alzheimer's disease into dementia score: Independent validation on 8,834 images from ADNI, AIBL, OASIS, and MIRIAD databases.

Biomarkers for dementia of Alzheimer's type (DAT) are sought to facilitate accurate prediction of the disease onset, ideally predating the onset of cognitive deterioration. T1‐weighted magnetic resonance imaging (MRI) is a commonly used neuroimaging modality for measuring brain structure in vivo, potentially providing information enabling the design of biomarkers for DAT. We propose a novel biomarker using structural MRI volume‐based features to compute a similarity score for the individual's structural patterns relative to those observed in the DAT group. We employed ensemble‐learning framework that combines structural features in most discriminative ROIs to create an aggregate measure of neurodegeneration in the brain. This classifier is trained on 423 stable normal control (NC) and 330 DAT subjects, where clinical diagnosis is likely to have the highest certainty. Independent validation on 8,834 unseen images from ADNI, AIBL, OASIS, and MIRIAD Alzheimer's disease (AD) databases showed promising potential to predict the development of DAT depending on the time‐to‐conversion (TTC). Classification performance on stable versus progressive mild cognitive impairment (MCI) groups achieved an AUC of 0.81 for TTC of 6 months and 0.73 for TTC of up to 7 years, achieving state‐of‐the‐art results. The output score, indicating similarity to patterns seen in DAT, provides an intuitive measure of how closely the individual's brain features resemble the DAT group. This score can be used for assessing the presence of AD structural atrophy patterns in normal aging and MCI stages, as well as monitoring the progression of the individual's brain along with the disease course.

Developmental demands contribute to early neuromuscular degeneration in CMT2D mice

Dominantly inherited, missense mutations in the widely expressed housekeeping gene, GARS1, cause Charcot-Marie-Tooth type 2D (CMT2D), a peripheral neuropathy characterised by muscle weakness and wasting in limb extremities. Mice modelling CMT2D display early and selective neuromuscular junction (NMJ) pathology, epitomised by disturbed maturation and neurotransmission, leading to denervation. Indeed, the NMJ disruption has been reported in several different muscles; however, a systematic comparison of neuromuscular synapses from distinct body locations has yet to be performed. We therefore analysed NMJ development and degeneration across five different wholemount muscles to identify key synaptic features contributing to the distinct pattern of neurodegeneration in CMT2D mice. Denervation was found to occur along a distal-to-proximal gradient, providing a cellular explanation for the greater weakness observed in mutant Gars hindlimbs compared with forelimbs. Nonetheless, muscles from similar locations and innervated by axons of equivalent length showed significant differences in neuropathology, suggestive of additional factors impacting on site-specific neuromuscular degeneration. Defective NMJ development preceded and associated with degeneration, but was not linked to a delay of wild-type NMJ maturation processes. Correlation analyses indicate that muscle fibre type nor synaptic architecture explain the differential denervation of CMT2D NMJs, rather it is the extent of post-natal synaptic growth that predisposes to neurodegeneration. Together, this work improves our understanding of the mechanisms driving synaptic vulnerability in CMT2D and hints at pertinent pathogenic pathways.