Brain Atrophy Research Articles

Pregnancy and delivery after functional hemispherectomy for Rasmussen’s encephalitis: a case report

BackgroundRasmussen’s encephalitis (RE) is a rare neurologic disorder characterized by progressive seizures and unilateral cerebral atrophy with onset during childhood and unknown etiology. When medical therapy appears refractory, surgical disconnection of the affected hemisphere is indicated. Quality of life after functional hemispherectomy is largely good, affected females may therefore pursue pregnancy. However, data on pregnancy and delivery in RE post hemispherectomy is extremely rare.Case presentationWe present the case of a patient with left functional hemispherectomy for RE at the age of seven, who experienced two successful pregnancies. In both pregnancies, her post-surgical symptoms including right-sided spasticity, cephalgia, dizziness, and impairment of vision and speech deteriorated but improved to pre-pregnancy level after delivery. Neurologic sequelae post-hemispherectomy overlapped with clinical signs of preeclampsia and required close diagnostic surveillance during both pregnancies.ConclusionThere are no data on the interaction between RE, hemispherectomy and pregnancy, making maternal and fetal risk assessment difficult. Due to the complexity of the condition and symptoms, management of RE in pregnancy remains highly challenging and requires an interdisciplinary approach. This is the first case description of two successful pregnancies in a woman with RE and status post-hemispherectomy. Further evidence is urgently required to improve counseling and management of affected women.

Frequency and Longitudinal Course of Behavioral and Neuropsychiatric Symptoms in Participants With Genetic Frontotemporal Dementia.

Behavioral and neuropsychiatric symptoms are frequent in patients with genetic frontotemporal dementia (FTD). We aimed to describe behavioral and neuropsychiatric phenotypes in genetic FTD, quantify their temporal association, and investigate their regional association with brain atrophy. We analyzed data of pathogenic variant carriers in the chromosome 9 open reading frame 72 (c9orf72), progranulin (GRN), or microtubule-associated protein tau (MAPT) gene from the Genetic Frontotemporal dementia Initiative cohort study that enrolls both symptomatic pathogenic variant carriers and first-degree relatives of known carriers. Principal component analysis was performed to identify behavioral and neuropsychiatric clusters that were compared with respect to frequency and severity between groups. Associations between neuropsychiatric clusters and MRI-assessed atrophy were determined using voxel-based morphometry. We applied linear mixed effects and generalized linear mixed effects models to assess the longitudinal course of symptoms. A total of 522 participants were included: 221 c9orf72 (138 presymptomatic), 213 GRN (157 presymptomatic), and 88 MAPT (62 presymptomatic) pathogenic variant carriers. Principal component analysis revealed 5 phenotypic clusters (67.6% of variance), labeled diverse behavioral, affective, psychotic, euphoric/hypersexual, and tactile hallucinations phenotype. In participants presenting behavioral or neuropsychiatric symptoms, affective symptoms were most frequent across groups (83.6%-88.1%), followed by diverse behavioral symptoms (68.4%-77.9%). In c9orf72 and GRN pathogenic variant carriers, psychotic symptoms (32.0% and 19.4%, respectively) were more frequent than euphoric/hypersexual symptoms (28.7% and 14.2%, respectively), which was the other way around in MAPT pathogenic variant carriers (28.6% and 23.8%). Although diverse behavioral symptoms were associated with gray and white matter frontotemporal atrophy, only a small atrophy cluster in the right thalamus was associated with psychotic symptoms. Euphoric/hypersexual symptoms were associated with atrophy in mesial temporal lobes, basal forebrain structures, and the striatum (p < 0.05). Estimated time to symptom onset, genetic group, education, and sex influenced behavioral and neuropsychiatric symptoms (p < 0.05). Particularly, in c9orf72 pathogenic variant carriers, psychotic symptoms may be starting decades before recognition of onset of illness. We identified multiple clusters of behavioral and neuropsychiatric symptoms in participants with genetic FTD that relate to distinct cerebral atrophy patterns. Their severity depends on time, affected gene, sex, and education. These clinical-genetic associations can guide diagnostic evaluations and the design of clinical trials for new disease-modifying and preventive treatments.

Intragenic duplication disrupting the reading frame of MFSD8 in Small Swiss Hounds with neuronal ceroid lipofuscinosis.

Neuronal ceroid lipofuscinosis (NCL) represents a heterogenous group of lysosomal storage diseases resulting in progressive neurodegeneration. We investigated two Small Swiss Hound littermates that showed progressive ataxia and loss of cognitive functions and vision starting around the age of 12 months. Both dogs had to be euthanized a few months after the onset of disease owing to the severity of their clinical signs. Pathological investigation of one affected dog revealed cerebral and cerebellar atrophy with cytoplasmic accumulation of autofluorescent material in degenerating neurons. The clinical signs in combination with the characteristic histopathology led to a tentative diagnosis of NCL. In the subsequent genetic investigation, the genome of one affected dog was sequenced. This revealed a duplication of 18 819 bp within the MFSD8 gene. The duplication breakpoints were located in intron 3 and exon 12 of the gene and were predicted to disrupt the reading frame. Both affected dogs carried the duplication in a homozygous state and there was perfect cosegregation of the genotypes with the phenotype in a large pedigree, consistent with autosomal recessive inheritance. MFSD8 loss-of-function variants are a known cause of NCL7 in human patients, dogs and other mammalian species. The existing knowledge on MFSD8 together with the experimental data strongly suggests that the identified intragenic MFSD8 duplication caused the disease in the Small Swiss Hounds. These results allow their diagnosis to be refined to NCL7 and enable genetic testing in the breed to avoid further unintentional carrier × carrier matings.

Associations between accelerated forgetting, amyloid deposition and brain atrophy in older adults.

Accelerated long-term forgetting (ALF) is the phenomenon whereby material is retained normally over short intervals (e.g. minutes) but forgotten abnormally rapidly over longer periods (days or weeks). ALF may be an early marker of cognitive decline, but little is known about its relationships with preclinical Alzheimer's disease pathology, and how memory selectivity may influence which material is forgotten. We assessed ALF in 'Insight 46', a sub-study of the MRC National Survey of Health and Development (a population-based cohort born during one week in 1946) (n=429; 47% female; assessed aged ∼73 years). ALF assessment comprised visual and verbal memory tests: Complex Figure Drawing and the Face-Name Associative Memory Exam (FNAME). ALF scores were calculated as the percentage of material retained after 7 days, relative to 30 minutes. In 306 cognitively-normal participants, we investigated effects on ALF of β-amyloid pathology (quantified using 18F-Florbetapir-PET, classified as positive/negative) and whole-brain and hippocampal atrophy rate (quantified from serial T1-MRI over ∼2.4 years preceding the ALF assessment), as well as interactions between these pathologies. We categorized Complex Figure Drawing items as 'outline' or 'detail', to test our hypothesis that forgetting the outline of the structure would be more sensitive to the effect of brain pathologies. We also investigated associations between ALF and Subjective Cognitive Decline, measured with the MyCog questionnaire. Complex Figure 'outline' items were better retained than 'detail' items (mean retention over 7 days = 94% vs 72%). Amyloid-positive participants showed greater forgetting of the Complex Figure outline, compared to amyloid-negatives (90% vs 95%; P<0.01). There were interactions between amyloid pathology and cerebral atrophy, such that whole-brain and hippocampal atrophy predicted greater ALF on Complex Figure Drawing among amyloid-positives only (e.g. 1.9 percentage-points lower retention per ml/year of whole-brain atrophy [95% confidence intervals 0.5, 3.7]; P<0.05). Greater ALF on FNAME was associated with increased rate of hippocampal atrophy. ALF on Complex Figure Drawing also correlated with subjective cognitive decline (-0.45 percentage-points per MyCog point [-0.85, -0.05], P<0.05). These results provide evidence of associations between some measures of ALF and biomarkers of brain pathologies and subjective cognitive decline in cognitively-normal older adults. On Complex Figure Drawing, 'outline' items were better remembered than 'detail' items - illustrating the strategic role of memory selectivity - but 'outline' items were also relatively more vulnerable to ALF in individuals with amyloid pathology. Overall, our findings suggest that ALF may be a sensitive marker of cognitive changes in preclinical Alzheimer's disease.

Treating Alzheimer's Disease: Focusing on Neurodegenerative Consequences.

Neurodegenerative disorders involve progressive dysfunction and loss of synapses and neurons and brain atrophy, slowly declining memories and cognitive skills, throughout a long process. Alzheimer's disease (AD), the leading neurodegenerative disorder, suffers from a lack of effective therapeutic drugs. Decades of efforts targeting its pathologic hallmarks, amyloid plaques and neurofibrillary tangles, in clinical trials have produced therapeutics with marginal benefits that lack meaningful clinical improvements in cognition. Delivering meaningful clinical therapeutics to treat or prevent neurodegenerative disorders thus remains a great challenge to scientists and clinicians. Emerging evidence, however, suggests that dysfunction of various synaptogenic signaling pathways participates in the neurodegenerative progression, resulting in deterioration of operation/structure of the synaptic networks involved in cognition. These derailed endogenous signaling pathways and disease processes are potential pharmacological targets for the therapies. Therapeutics with meaningful clinical benefit in cognition may depend on the effectiveness of arresting and reversing the neurodegenerative process through these targets. In essence, promoting neuro-regeneration may represent the only option to recover degenerated synapses and neurons. These potential directions in clinical trials for AD therapeutics with meaningful clinical benefit in cognitive function are summarized and discussed.

RNA Binding Protein Dysfunction Links Smoldering/Slowly Expanding Lesions to Neurodegeneration in Multiple Sclerosis.

Despite the advances in treatments for multiple sclerosis (MS), unremitting neurodegeneration continues to drive disability and disease progression. Smoldering/slowly expanding lesions (SELs) and dysfunction of the RNA binding protein (RBP) heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) are pathologic hallmarks of MS cortex and intricately tied to disability and neurodegeneration, respectively. We hypothesized that neuronal hnRNP A1 dysfunction contributes to neurodegeneration and is exacerbated by smoldering/SELs in progressive MS. Neuronal hnRNP A1 pathology (nucleocytoplasmic mislocalization of hnRNP A1) was examined in healthy control and MS brains using immunohistochemistry. MS cases were stratified by severity of hnRNP A1 pathology to examine the link between RBP dysfunction, demyelination, and neurodegeneration. We found that smoldering/SELs were only present within a subset of MS tissues characterized by elevated neuronal hnRNP A1 pathology (MS-A1high) in adjacent cortical gray matter. In contrast to healthy controls and MS with low hnRNP A1 pathology (MS-A1low), MS-A1high showed elevated markers of neurodegeneration, including neuronal loss and injury, brain atrophy, axonal loss, and axon degeneration. Additionally, we discovered a subpopulation of morphologically intact neurons lacking expression of NeuN, a neuron-specific RBP, in cortical projection neurons in MS-A1high cases. hnRNP A1 dysfunction contributes to neurodegeneration and may be exacerbated by smoldering/SELs in progressive MS. The discovery of NeuN-negative neurons suggests that some cortical neurons may only be injured and not lost. By characterizing RBP pathology in MS cortex, this study has important implications for understanding the pathogenic mechanisms driving neurodegeneration, the substrate of disability and disease progression. ANN NEUROL 2024.

New Onset Refractory Status Epilepticus with diffuse cerebral restricted diffusion in young children; a novel clinical-radiologic presentation

New-onset refractory status epilepticus (NORSE) is a clinical presentation characterized by explosive-onset refractory status epilepticus (RSE) without evident etiology or active epilepsy, often leading to devastating epilepsy. There is heterogeneity in neuroradiographic findings for NORSE. We encountered a series of young patients with NORSE who had diffuse cerebral restriction in diffusion (DCRD) with similar radiographic appearances as acute encephalopathy with biphasic seizures and late restricted diffusion/acute leukoencephalopathy with restricted diffusion (AESD/ALERD). We explore clinical similarities and proposed pathophysiologic overlaps to highlight a novel clinical-radiologic presentation. Retrospective review was completed for patients younger than five years meeting NORSE criteria and then screened for radiographic evidence of DCRD. Demographic, clinical, and outcome data were collected. Eleven patients met NORSE criteria, of whom seven displayed DCRD. Immunosuppressant management varied. All patients required multiple antiseizure medications and continuous infusions for RSE. Only one had an etiology identified (genetic). All but one patient developed diffuse, global, and progressive cerebral atrophy. Two patients died: one after prolonged seizure three years post-NORSE and another of unknown causes two months post-NORSE. Of five survivors, three have medically refractory epilepsy. Most survivors have severe disability. We present a single-center case series of seven patients with NORSE and DCRD, akin to AESD/ALERD. Our patients differed clinically to AESD/ALERD in terms of seizure severity and poorer outcome. There is a need to develop biomarkers for specific NORSE phenotypes. The young child with NORSE and DCRD may represent a novel phenotype with a specific neuroradiographic signature that deserves further attention.

Neuroimaging-Based Brain Morphometry in Alzheimer’s Disease

Background/Objectives: Alzheimer’s disease (AD) is a leading cause of death worldwide, affecting millions of older Americans and resulting in a substantial economic burden. The Alzheimer’s Disease Neuroimaging Initiative (ADNI) aims to investigate and develop treatments for AD. Methods: This study included 60 participants, divided equally into AD and control cohorts, and utilized magnetic resonance imaging (MRI) scans to detect gray matter volumetric alterations, a key biomarker of AD. The participants’ cortical volume and surface area were quantified using an automated pipeline in MIMICS (Materialise Interactive Medical Imaging Control System). Results: A multivariate regression analysis was conducted to explore the relationship between cortical measurements and potential factors influencing AD susceptibility. The study found that both cortical volume and surface area were statistically significant predictors of AD (p = 0.0004 and p = 0.011, respectively). Age was also a significant factor, with the 65–70 age group showing the strongest association (p &lt; 0.001). The model achieved an accuracy of 0.68 in predicting AD. Conclusions: While voxel-based morphometry (VBM) using MIMICS showed promise, further development of the automated pipeline could enhance accuracy and correlation indices. These findings contribute to our understanding of brain atrophy in AD pathophysiology and highlight the potential of MRI morphometry as a tool for AD biomarker development.

Knockout of a single Pax6 gene (toy but not ey) leads to compound eye deficiency and small head in honeybees

The compound eyes are crucial to honeybees, playing pivotal roles in color recognition, orientation, localization, and navigation processes. The development of compound eyes is primarily mastered by an evolutionarily conserved transcription factor Pax6. In honeybees, there are two Pax6 homologs: ey and toy. To gain a deeper understanding of their functions, we knock out both homologs using CRISPR/Cas9 technology. Intriguingly, we observe that toy knockout mutants have smaller heads without compound eyes and exhibit brain atrophy, while ey knockout mutants develop normal compound eyes, most of which die before/during their metamorphosis from pupa to adult. By comparing the head transcriptomes of four stages (larva, prepupa, pupa, and adult) in toy-knockout mutants versus normal controls, we identify significantly perturbed genes related to DNA binding transcription factors, neuron differentiation, and insect visual primordium development. Additionally, we find the interaction network of toy in honeybees differs obviously from that of D. melanogaster. Our findings suggest the two Pax6 genes serve distinct functions in honeybees and toy takes over the central function of ey in master-regulating the development of honeybee compound eyes. This adds new evidence for breaking the simplified view that some of conservative developmental toolkit genes function as all-or-nothing master regulators.

The Influence of Birth Weight, Socio-Economic Status, and Adult Health on Brain Volumes during Ageing

Introduction: Greater late-life brain volumes are associated with resilience against dementia. We examined relationships between birth weight, lifelong socio-economic status, and health with late-life brain volumes. We hypothesised that early life factors directly affect late-life brain volumes. Methods: Adults aged 59–67 y underwent MRI and brain volumes were measured. Birth weight and lifelong health, and socio-economic status were quantified and the principal components of each extracted. Relationships were examined using regression and structural equation analysis. Results: Birth weight (β = 0.095, p = 0.017) and childhood socio-economic status (β = 0.091, p = 0.033, n = 280) were directly associated with brain volume. Childhood socio-economic status was further associated with grey matter volume (β = 0.04, p = 0.047). Adult health was linked to increased brain volume (β = 0.15, p = 0.003). Conclusion: Birth weight and childhood socio-economic status are associated with whole and regional brain volume through direct mechanisms. Optimal fetal development, reduced childhood poverty, and good adult health could reduce brain atrophy and delay dementia onset in late-life.

Biological mechanisms of resilience to tau pathology in Alzheimer’s disease

BackgroundIn Alzheimer’s disease (AD), the associations between tau pathology and brain atrophy and cognitive decline are well established, but imperfect. We investigate whether cerebrospinal fluid (CSF) biomarkers of biological processes (vascular, synaptic, and axonal integrity, neuroinflammation, neurotrophic factors) explain the disconnection between tau pathology and brain atrophy (brain resilience), and tau pathology and cognitive decline (cognitive resilience).MethodsWe included 428 amyloid positive participants (134 cognitively unimpaired (CU), 128 with mild cognitive impairment (MCI), 166 with AD dementia) from the BioFINDER-2 study. At baseline, participants underwent tau positron emission tomography (tau-PET), magnetic resonance imaging (MRI), cognitive testing, and lumbar puncture. Longitudinal data were available for MRI (mean (standard deviation) follow-up 26.4 (10.7) months) and cognition (25.2 (11.4) months). We analysed 18 pre-selected CSF proteins, reflecting vascular, synaptic, and axonal integrity, neuroinflammation, and neurotrophic factors. Stratifying by cognitive status, we performed linear mixed-effects models with cortical thickness (brain resilience) and global cognition (cognitive resilience) as dependent variables to assess whether the CSF biomarkers interacted with tau-PET levels in its effect on cortical atrophy and cognitive decline.ResultsRegarding brain resilience, interaction effects were observed in AD dementia, with vascular integrity biomarkers (VEGF-A (βinteraction = -0.009, pFDR = 0.047) and VEGF-B (βinteraction = -0.010, pFDR = 0.037)) negatively moderating the association between tau-PET signal and atrophy. In MCI, higher NfL levels were associated with more longitudinal cortical atrophy (β = -0.109, pFDR = 0.033) and lower baseline cortical thickness (β = -0.708, pFDR = 0.033) controlling for tau-PET signal. Cognitive resilience analyses in CU revealed interactions with tau-PET signal for inflammatory (GFAP, IL-15; βinteraction -0.073–-0.069, pFDR 0.001–0.045), vascular (VEGF-A, VEGF-D, PGF; βinteraction -0.099–-0.063, pFDR < 0.001–0.046), synaptic (14–3-3ζ/δ; βinteraction = -0.092, pFDR = 0.041), axonal (NfL; βinteraction = -0.079, pFDR < 0.001), and neurotrophic (NGF; βinteraction = 0.091, pFDR < 0.001) biomarkers. In MCI higher NfL levels (βmain = -0.690, pFDR = 0.025) were associated with faster cognitive decline independent of tau-PET signal.ConclusionsBiomarkers of co-existing pathological processes, in particular vascular pathology and axonal degeneration, interact with levels of tau pathology on its association with the downstream effects of AD pathology (i.e. brain atrophy and cognitive decline). This indicates that vascular pathology and axonal degeneration could impact brain and cognitive resilience.

NAD+-boosting agent nicotinamide mononucleotide potently improves mitochondria stress response in Alzheimer’s disease via ATF4-dependent mitochondrial UPR

Extensive studies indicate that mitochondria dysfunction is pivotal for Alzheimer’s disease (AD) pathogenesis; while cumulative evidence suggests that increased mitochondrial stress response (MSR) may mitigate neurodegeneration in AD, explorations to develop a MSR-targeted therapeutic strategy against AD are scarce. We combined cell biology, molecular biology, and pharmacological approaches to unravel a novel molecular pathway by which NAD+-boosting agent nicotinamide mononucleotide (NMN) regulates MSR in AD models. Here, we report dyshomeostasis plasma UPRmt-mitophagy-mediated MSR profiles in AD patient samples. NMN restores NAD+ metabolic profiles and improves MSR through the ATF4-dependent UPRmt pathway in AD-related cross-species models. At the organismal level, NAD+ repletion with NMN supplementation ameliorates mitochondrial proteotoxicity, decreases hippocampal synaptic disruption, decreases neuronal loss, and brain atrophy in mice model of AD. Remarkably, omics features of the hippocampus with NMN show that NMN leads to transcriptional changes of genes and proteins involved in MSR characteristics, principally within the astrocyte unit rather than microglia and oligodendrocytes. In brief, our work provides evidence that MSR has an active role in the pathogenesis of AD, as reducing mitochondrial homeostasis via atf4 depletion in AD mice aggravates the hallmarks of the disease; conversely, bolstering mitochondrial proteostasis by NMN decreases protein aggregation, restores memory performance, and delays disease progression, ultimately translating to increased healthspan.

Apraxia and Malformation Severity in Brain Tumor Disease: Case Report and Literature Review

Objective: In apraxia, the lack of skill in doing a previously learned task occurs without obvious weakness in the limbs. Material and Method: In this case report, we present a with brain atrophy, diagnosed with posterior cortical atrophy and meningioma tumor in the frontal region, has referred to the clinic. In this patient, due to the analysis of the parietal and frontal cortex of the patient's brain, despite being able to write and draw shapes in the past, they now forget this skill and suffer from ideomotor apraxia. Also, this patient has slowness and weakness due to severe tumor involvement. Result: Accurate and timely diagnosis of especially in prevalent can prevent the unwarranted complications and reduce the morbidity and mortality associated with in allogeneic/autologous transplant recipients. Conclusion: This particular disorder is seen in patients with degeneration of the parietal and frontal cortex of the brain (in dementia, brain tumors and stroke).

A Systematic Review of Traumatic Brain Injury in Modern Rodent Models: Current Status and Future Prospects.

According to the Centers for Disease Control and Prevention (CDC), the national public health agency of the United States, traumatic brain injury is among the leading causes of mortality and disability worldwide. The consequences of TBI include diffuse brain atrophy, local post-traumatic atrophy, arachnoiditis, pachymeningitis, meningocerebral cicatrices, cranial nerve lesions, and cranial defects. In 2019, the economic cost of injuries in the USA alone was USD 4.2 trillion, which included USD 327 billion for medical care, USD 69 billion for work loss, and USD 3.8 trillion for the value of statistical life and quality of life losses. More than half of this cost (USD 2.4 trillion) was among working-age adults (25-64 years old). Currently, the development of new diagnostic approaches and the improvement of treatment techniques require further experimental studies focused on modeling TBI of varying severity.

Relation of CMV and brain atrophy to trajectories of immunosenescence in diverse populations.

Immunosenescence (ISC), the aging of the immune system, has largely been studied in populations of European descent. Here, circulating immune cell cytometric data from African-American, Hispanic, and non-Hispanic White participants were generated. Known and novel age effects were identified using either a meta-analysis approach or a parallel genetic approach. Most results are consistent across the three populations, but some cell populations display evidence of heterogeneity, such as a PD-L1 + CD56 + NK cell subset. The study estimated "Immunological Age" (IA) during physiologic aging. While we found no relation of IA to Multiple Sclerosis, IA is associated with entorhinal cortex atrophy, a presymptomatic feature of Alzheimer's disease, linking neurodegeneration and peripheral immunity. ISC trajectories were also inferred, highlighting age, CMV status, and genetic ancestry as key influences. Our assessment offers reference ISC trajectories for personalization of assessments of immune function over the life course in diverse populations.

APOE ε4 carrier status moderates the effect of lifestyle factors on cognitive reserve.

This study examines the role of lifestyle factors in cognitive reserve among older adults, focusing on the moderating effect of apolipoprotein E (APOE) ε4 status. Data from 157 participants aged 45 and older from the Healthy Brain Initiative (HBI) were analyzed. Cognitive reserve was estimated using residual scores from Cognivue Clarity tests after accounting for brain atrophy and white matter hyperintensities (WMHs). Lifestyle factors included education, occupational attainment, physical activity, social engagement, diet, and mindfulness. Structural equation models were conducted to assess interactions. Significant interactions were found between APOE ε4 status and mindfulness and social engagement on cognitive reserve, indicating stronger associations for APOE ε4 carriers. APOE ε4 carriers may benefit more from certain lifestyle factors, potentially through stress reduction and anti-inflammatory pathways. These findings support integrating APOE ε4 genetic screening into personalized prevention strategies to enhance interventions aimed at preserving cognitive function and delaying dementia onset in at-risk populations. Mindfulness and social engagement have increased cognitive reserve in APOE ε4 carriers. Study uses residual scores from Cognivue Clarity tests to estimate cognitive reserve. APOE ε4 carriers show stronger associations with certain lifestyle factors on cognitive reserve. Personalized interventions could enhance cognitive resilience in genetically at-risk populations. Comprehensive assessment of multiple lifestyle factors highlights targeted intervention benefits.

Dynamics of choroid plexus volume is associated with the presence and development of fatigue in multiple sclerosis

BackgroundImmune-mediated processes are implicated in the pathogenesis of fatigue, a common symptom in multiple sclerosis (MS). The choroid plexus (CP) regulates central nervous system (CNS) immune homeostasis and undergoes volumetric...

Selective neuronal expression of progranulin is sufficient to provide neuroprotective and anti-inflammatory effects after traumatic brain injury

Progranulin (PGRN), which is produced in neurons and microglia, is a neurotrophic and anti-inflammatory glycoprotein. Human loss-of-function mutations cause frontotemporal dementia, and PGRN knockout (KO) mice are a model for dementia. In addition, PGRN KO mice exhibit severe phenotypes in models of traumatic or ischemic central nervous system (CNS) disorders, including traumatic brain injury (TBI). It is unknown whether restoration of progranulin expression in neurons (and not in microglia) might be sufficient to prevent excessive TBI-evoked brain damage. To address this question, we generated mice with Nestin-Cre-driven murine PGRN expression in a PGRN KO line (PGRN-KONestinGrn) to rescue PGRN in neurons. PGRN expression analysis in primary CNS cell cultures from naïve mice and in (non-) injured brain tissue from PGRN-KONestinGrn revealed expression of PGRN in neurons but not in microglia. After experimental TBI, examination of the structural brain damage at 5 days post-injury (dpi) showed that the TBI-induced loss of brain tissue and hippocampal neurons was exacerbated in PGRN-KOGrnflfl mice (PGRN knockout with the mGrn fl-STOP-fl allele, Cre-negative), as expected, whereas the tissue damage in PGRN-KONestinGrn mice was similar to that in PGRN-WT mice. Analysis of CD68+ immunofluorescent microglia and Cd68 mRNA expression showed that excessive microglial activation was rescued in PGRN-KONestinGrn mice, and the correlation of brain injury with Cd68 expression suggested that Cd68 was a surrogate marker for excessive brain injury caused by PGRN deficiency. The results show that restoring neuronal PGRN expression was sufficient to rescue the exacerbated neuropathology of TBI caused by PGRN deficiency, even in the absence of microglial PGRN. Hence, endogenous microglial PGRN expression was not essential for the neuroprotective or anti-inflammatory effects of PGRN after TBI in this study.Graphical

Longitudinal evaluation of retinal neuroaxonal loss in epilepsy using optical coherence tomography.

People with epilepsy (PwE) suffer from progressive brain atrophy, which is reflected as neuroaxonal loss on the retinal level. This study aims to provide initial insight into the longitudinal dynamics of the retinal neuroaxonal loss and possible driving factors. PwE and healthy controls (HC; 18-55 years of age) underwent spectral domain optical coherence tomography at baseline and 7.0 ± 1.5 and 6.7 ± 1.0 months later, respectively. The change in retinal thickness/volume and annualized percentage change (APC) were calculated for the peripapillary retinal nerve fiber layer (pRNFL), the macular RNFL (mRNFL), the ganglion cell inner plexiform layer (GCIP), the inner nuclear layer, and the total macular volume (TMV). Group comparisons and multiple linear models with stepwise backward selection were performed to evaluate associations with demographic and clinical parameters. PwE (n = 44, 21 females, mean age = 35.6 ± 10.9 years) revealed a significant decrease in the pRNFL, mRNFL, GCIP, and TMV thickness or volume in the study interval. When compared to HC (n = 56, 37 females, mean age = 32.7 ± 8.3 years), the APC of the pRNFL (-.98 ± 3.13%/year) and the GCIP (-1.24 ± 2.56%/year) were significantly more pronounced in PwE (p = .01 and p = .046, respectively). Of note, atrophy of the mRNFL was significantly influenced by the number of antiseizure medications (ASMs; p = .047) and increasing age of PwE (p = .03). Contradictory results, however, were revealed for the impact of seizures. In epilepsy, progression of retinal neuroaxonal loss was already detectable at short-term follow-up. PwE who receive a high number of ASMs seem to be at risk for accelerated neuroaxonal loss, stressing the importance of well-considered and effective antiseizure therapy.

Elevated plasma and CSF neurofilament light chain concentrations are stabilized in response to mutant huntingtin lowering in the brains of Huntington’s disease mice

BackgroundTherapeutic approaches aimed at lowering toxic mutant huntingtin (mHTT) levels in the brain can reverse disease phenotypes in animal models of Huntington's disease (HD) and are currently being evaluated in clinical trials. Sensitive and dynamic response biomarkers are needed to assess the efficacy of such candidate therapies. Neurofilament light chain (NfL) is a biomarker of neurodegeneration that increases in cerebrospinal fluid (CSF) and blood with progression of HD. However, it remains unknown whether NfL in biofluids could serve as a response biomarker for assessing the efficacy of disease-modifying therapies for HD.MethodsLongitudinal plasma and cross-sectional CSF samples were collected from the YAC128 transgenic mouse model of HD and wild-type (WT) littermate control mice throughout the natural history of disease. Additionally, biofluids were collected from YAC128 mice following intracerebroventricular administration of an antisense oligonucleotide (ASO) targeting the mutant HTT transgene (HTT ASO), at ages both before and after the onset of disease phenotypes. NfL concentrations in plasma and CSF were quantified using ultrasensitive single-molecule array technology.ResultsPlasma and CSF NfL concentrations were significantly elevated in YAC128 compared to WT littermate control mice from 9 months of age. Treatment of YAC128 mice with either 15 or 50 µg HTT ASO resulted in a dose-dependent, allele-selective reduction of mHTT throughout the brain at a 3-month interval, which was sustained with high-dose HTT ASO treatment for up to 6 months. Lowering of brain mHTT prior to the onset of regional brain atrophy and HD-like motor deficits in this model had minimal effect on plasma NfL at either dose, but led to a dose-dependent reduction of CSF NfL. In contrast, initiating mHTT lowering in the brain after the onset of neuropathological and behavioural phenotypes in YAC128 mice resulted in a dose-dependent stabilization of NfL increases in both plasma and CSF.ConclusionsOur data provide evidence that the response of NfL in biofluids is influenced by the magnitude of mHTT lowering in the brain and the timing of intervention, suggesting that NfL may serve as a promising exploratory response biomarker for HD.