Progressive Brain Atrophy Research Articles

Adult-onset neuronal ceroid lipofuscinosis misdiagnosed as autoimmune encephalitis and normal-pressure hydrocephalus: A 10-year case report and case-based review.

Neuronal ceroid lipofuscinoses (NCLs) are rare, fatal, inherited neurodegenerative disorders characterized by myoclonic epilepsy, cognitive decline, brain atrophy, and retinopathy. The pathogenesis and clinical manifestations of NCL are not well understood and frequently result in misdiagnosis and overtreatment. The aim of this case report and review is to improve our understanding of the clinical features and management of NCL. A 36-year-old woman initially presented with refractory epilepsy. Initially diagnosed with autoimmune encephalitis, the patient was later diagnosed with normal-pressure hydrocephalus. A definitive diagnosis of adult-onset neuronal ceroid lipofuscinosis (ANCL) was established after 10 years of observation, utilizing biopsy and genetic testing. High-dose intravenous immunoglobulin and methylprednisolone were administered, along with the insertion of a ventriculoperitoneal shunt. Despite various treatments, the patient's condition did not improve. ANCL typically presents with the clinical triad of refractory seizures, progressive cognitive decline, and movement disorders. Neuroimaging often reveals progressive brain atrophy on magnetic resonance imaging, while electroencephalograms frequently show epileptiform discharges. The prognosis is generally poor. Improved understanding of ANCL from both clinical and radiological perspectives, coupled with early consideration of differential diagnoses, could minimize unnecessary interventions and optimize patient care.

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.

Gray matter matters: Cognitive stability and flexibility in schizophrenia spectrum disorder.

Cognitive dysfunction constitutes a core characteristic of schizophrenia spectrum disorders (SZ). Specifically, deficits in updating generative models (i.e., cognitive flexibility) and shielding against distractions (i.e., cognitive stability) are considered critical contributors to cognitive impairment in these patients. Here, we examined the structural integrity of frontostriatal networks and their associations with reduced cognitive stability and flexibility in SZ patients. In a sample of 21 patients diagnosed with SZ and 22 healthy controls, we measured gray matter volume (GMV) using structural MRI. Further, cognitive stability and flexibility were assessed using a switch-drift paradigm, quantifying the successful ignoring of distracters and detection of rule switches. Compared to controls, patients showed significantly smaller GMV in the whole brain and three predefined regions of interest: the medial prefrontal cortex (mPFC), inferior frontal gyrus (IFG), and caudate nucleus (CN). Notably, GMV in these areas positively correlated with correct rule-switch detection but not with ignoring rule-compatible drifts. Further, the volumetric differences between SZ patients and controls were statistically explainable by considering the behavioral performance in the switch-drift task. Our results indicate that morphological abnormalities in frontostriatal networks are associated with deficient flexibility in SZ patients and highlight the necessity of minimizing neurodevelopmental and progressive brain atrophy in this population.

INTS11-related neurodevelopmental disorder: a case report and literature review.

INTS11 is a critical catalytic component of the Integrator complex that regulates RNA polymerase II termination and modulates gene expression. Until recently, INTS11 mutations were associated with human neurodevelopmental disorders, characterized by global developmental and language delays, generalized hypotonia, and progressive brain atrophy. We report the case of a 2-year-old Chinese girl who presented with global developmental delay, generalized hypotonia, refractory epilepsy, craniofacial dysmorphism, and progressive brain atrophy. Novel variants were identified in exon 2 of INTS11 gene c.588_589del (p. Trp197AspfsTer2) and c.457_459del (p. Glu153del). We identified a compound heterozygous mutation in INTS11, a clinical feature consistent with two previous reports of the variants in human INTS11, but her recurrent seizures were more pronounced and refractory to most antiepileptic drugs and ketogenic diets.

Atypical intrinsic neural timescale in the left angular gyrus in Alzheimer's disease.

Alzheimer's disease is characterized by cognitive impairment and progressive brain atrophy. Recent human neuroimaging studies reported atypical anatomical and functional changes in some regions in the default mode network in patients with Alzheimer's disease, but which brain area of the default mode network is the key region whose atrophy disturbs the entire network activity and consequently contributes to the symptoms of the disease remains unidentified. Here, in this case-control study, we aimed to identify crucial neural regions that mediated the phenotype of Alzheimer's disease, and as such, we examined the intrinsic neural timescales-a functional metric to evaluate the capacity to integrate diverse neural information-and grey matter volume of the regions in the default mode network using resting-state functional MRI images and structural MRI data obtained from individuals with Alzheimer's disease and cognitively typical people. After confirming the atypically short neural timescale of the entire default mode network in Alzheimer's disease and its link with the symptoms of the disease, we found that the shortened neural timescale of the default mode network was associated with the aberrantly short neural timescale of the left angular gyrus. Moreover, we revealed that the shortened neural timescale of the angular gyrus was correlated with the atypically reduced grey matter volume of this parietal region. Furthermore, we identified an association between the neural structure, brain function and symptoms and proposed a model in which the reduced grey matter volume of the left angular gyrus shortened the intrinsic neural time of the region, which then destabilized the entire neural timescale of the default mode network and resultantly contributed to cognitive decline in Alzheimer's disease. These findings highlight the key role of the left angular gyrus in the anatomical and functional aetiology of Alzheimer's disease.

Serum NfL and GFAP as biomarkers of progressive neurodegeneration in TBI.

We examined spatial patterns of brain atrophy after mild, moderate, and severe traumatic brain injury (TBI), the relationship between progression of brain atrophy with initial traumatic axonal injury (TAI), cognitive outcome, and with serum biomarkers of brain injury. A total of 143 patients with TBI and 43 controls were studied cross-sectionally and longitudinally up to 5 years with multiple assessments, which included brain magnetic resonance imaging, cognitive testing, and serum biomarkers. TBI patients showed progressive volume loss regardless of injury severity over several years, andTAI was independently associated with accelerated brain atrophy. Cognitive performance improved over time. Higher baseline serum neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) were associated with greater rate of brain atrophy over 5 years. Spatial patterns of atrophy differ by injury severity and TAI is associated with the progression of brain atrophy. Serum NfL and GFAP show promise as non-invasive prognostic biomarkers of progressive neurodegeneration in TBI. In this longitudinal study of patient with mild, moderate, and severe traumatic brain injury (TBI) who were assessed with paired magnetic resonance imaging (MRI), blood biomarkers, and cognitive assessments, we found that brain atrophy after TBI is progressive and continues for many years even after a mild head trauma without signs of brain injury on conventional MRI. We found that spatial pattern of brain atrophy differs between mild, moderate, and severe TBI, where in patients with mild TBI , atrophy is mainly seen in the gray matter, while in those with moderate to severe brain injury atrophy is predominantly seen in the subcortical gray matter and whiter matter. Cognitive performance improves over time after a TBI. Serum measures of neurofilament light or glial fibrillary acidic protein are associated with progression of brain atrophy after TBI.

What Is Brain Damage and Does Electroconvulsive Therapy Cause It?

Surveys show public misperceptions and confusion about brain damage and electroconvulsive therapy (ECT). Fictional movies have misrepresented ECT to suggest brain damage and to ridicule mental illness and psychiatric patients. "Brain damage" has become a colloquial expression without consistent meaning. In contrast, brain injury is the medical term for destruction of brain cells, such as from kinetic impact (concussion), hypoxia, or infection. Studies of both high-resolution magnetic resonance imaging (MRI) and enzyme assays find that causes of brain injury are accompanied by observable structural changes on MRI and elevated blood and cerebrospinal fluid levels of brain enzymes that leak from injured brain cells. Concussion is also followed by intracerebral bleeding, progressive brain atrophy, diffuse axonal injury, cranial nerve injury, and 2-4 fold increased risk for dementia. In contrast, there is no evidence that ECT produces any of these. Studies of ECT patients find no brain edema, structural change persisting 6 months, or elevated levels of leaked brain enzymes. Statistical comparisons between brain injury and ECT effects indicate no similarity ( P < 0.00000001). Moreover, the kinetic, thermal, and electrical effects of ECT are far below levels that could possibly cause harm. This robust evidence shows that there is no basis to claim that ECT causes brain injury.

GM1 gangliosidosis type II: Results of a 10-year prospective study

PurposeGM1 gangliosidosis (GM1) a lysosomal disorder caused by pathogenic variants in GLB1, is characterized by relentless neurodegeneration. There are no approved treatments. MethodsForty-one individuals with type II (late-infantile and juvenile) GM1 participated in a single-site prospective observational study. ResultsClassification of 37 distinct variants using American College of Medical Genetics and Genomics criteria resulted in the upgrade of 6 and the submission of 4 new variants. In contrast to type I infantile disease, children with type II had normal or near normal hearing and did not have cherry-red maculae or hepatosplenomegaly. Some older children with juvenile onset disease developed thickened aortic and/or mitral valves. Serial magnetic resonance images demonstrated progressive brain atrophy, more pronounced in late infantile patients. Magnetic resonance spectroscopy showed worsening elevation of myo-inositol and deficit of N-acetyl aspartate that were strongly correlated with scores on the Vineland Adaptive Behavior Scale, progressing more rapidly in late infantile compared with juvenile onset disease. ConclusionSerial phenotyping of type II GM1 patients expands the understanding of disease progression and clarifies common misconceptions about type II patients; these are pivotal steps toward more timely diagnosis and better supportive care. The data amassed through this 10-year effort will serve as a robust comparator for ongoing and future therapeutic trials.

Impact of amyloid and tau positivity on longitudinal brain atrophy in cognitively normal individuals.

Individuals on the preclinical Alzheimer's continuum, particularly those with both amyloid and tau positivity (A + T +), display a rapid cognitive decline and elevated disease progression risk. However, limited studies exist on brain atrophy trajectories within this continuum over extended periods. This study involved 367 ADNI participants grouped based on combinations of amyloid and tau statuses determined through cerebrospinal fluid tests. Using longitudinal MRI scans, brain atrophy was determined according to the whole brain, lateral ventricle, and hippocampal volumes and cortical thickness in AD-signature regions. Cognitive performance was evaluated with the Preclinical Alzheimer's Cognitive Composite (PACC). A generalized linear mixed-effects model was used to examine group × time interactions for these measures. In addition, progression risks to mild cognitive impairment (MCI) or dementia were compared among the groups using Cox proportional hazards models. A total of 367 participants (48 A + T + , 86 A + T - , 63 A - T + , and 170 A - T - ; mean age 73.8years, mean follow-up 5.1years, and 47.4% men) were included. For the lateral ventricle and PACC score, the A + T - and A + T + groups demonstrated statistically significantly greater volume expansion and cognitive decline over time than the A - T - group (lateral ventricle: β = 0.757 cm3/year [95% confidence interval 0.463 to 1.050], P < .001 for A + T - , and β = 0.889 cm3/year [0.523 to 1.255], P < .001 for A + T + ; PACC: β = - 0.19 /year [- 0.36 to - 0.02], P = .029 for A + T - , and β = - 0.59 /year [- 0.80 to - 0.37], P < .001 for A + T +). Notably, the A + T + group exhibited additional brain atrophy including the whole brain (β = - 2.782 cm3/year [- 4.060 to - 1.504], P < .001), hippocampus (β = - 0.057 cm3/year [- 0.085 to - 0.029], P < .001), and AD-signature regions (β = - 0.02mm/year [- 0.03 to - 0.01], P < .001). Cox proportional hazards models suggested an increased risk of progressing to MCI or dementia in the A + T + group versus the A - T - group (adjusted hazard ratio = 3.35 [1.76 to 6.39]). In cognitively normal individuals, A + T + compounds brain atrophy and cognitive deterioration, amplifying the likelihood of disease progression. Therapeutic interventions targeting A + T + individuals could be pivotal in curbing brain atrophy, cognitive decline, and disease progression.

Alzheimer's disease progression detection based on optical fluence rate measurements using alternative laser wavelengths.

Alzheimer's disease (AD) levels have increased globally, which is considered the sixth reason for deaths. So, a requirement exists for economic and quantitative methods to follow up the gradual progression of AD. The current study presents a simulation for a non-irradiated, safe, wearable, and noninvasive mobile approach for detecting the progression of Alzheimer's brain atrophy using the optical diffusion technique and for investigating the difference between the normal and the diseased brain. The virtual study was accomplished using COMSOL Multiphysics. The simulated head is implemented as the following: scalp, skull, cerebrospinal fluid, gray matter, and white matter. The optical properties of the heterogeneous tissue are observed using the fluence rate after irradiating the head with different wavelengths (630, 700, 810, 915, and 1000 nm) of lasers. Two assessment techniques were applied to evaluate the brain atrophy measurements; the first technique was an array of photodetectors, which were lined at the head posterior, while a matrix of photodetectors was applied over the head surface in the second technique. The results show that the surface photodetectors approach differentiates the normal from AD brains without measuring the brain atrophy percentages by applying 630 nm. The array of photodetectors distinguishes normal from AD brains without detecting the brain atrophy percentages when the wavelengths 630, 700, and 810 nm were applied. The line detector at 1000 nm evaluates the brain atrophy percentages with AD. The future explores applying those techniques in vivo and analyzing the information by the spectrometer for extensively safer early detection of neural disorders.

A Look at the Etiology of Alzheimer's Disease based on the Brain Ischemia Model.

Alzheimer's disease (AD) is the frequent form of dementia in the world. Despite over 100 years of research into the causes of AD, including amyloid and tau protein, the research has stalled and has not led to any conclusions. Moreover, numerous projects aimed at finding a cure for AD have also failed to achieve a breakthrough. Thus, the failure of anti-amyloid and anti-tau protein therapy to treat AD significantly influenced the way we began to think about the etiology of the disease. This situation prompted a group of researchers to focus on ischemic brain episodes, which, like AD, mostly present alterations in the hippocampus. In this context, it has been proposed that cerebral ischemic incidents may play a major role in promoting amyloid and tau protein in neurodegeneration in AD. In this review, we summarized the experimental and clinical research conducted over several years on the role of ischemic brain episodes in the development of AD. Studies have shown changes typical of AD in the course of brain neurodegeneration post-ischemia, i.e., progressive brain and hippocampal atrophy, increased amyloid production, and modification of tau protein. In the post-ischemic brain, the diffuse and senile amyloid plaques and the development of neurofibrillary tangles characteristic of AD were revealed. The above data evidently showed that after brain ischemia, there are modifications in protein folding, leading to massive neuronal death and damage to the neuronal network, which triggers dementia with the AD phenotype.

VentRa: distinguishing frontotemporal dementia from psychiatric disorders.

The volume of the lateral ventricles is a reliable and sensitive indicator of brain atrophy and disease progression in behavioural variant frontotemporal dementia. In this study, we validate our previously developed automated tool using ventricular features (known as VentRa) for the classification of behavioural variant frontotemporal dementia versus a mixed cohort of neurodegenerative, vascular and psychiatric disorders from a clinically representative independent dataset. Lateral ventricles were segmented for 1110 subjects-14 behavioural variant frontotemporal dementia, 30 other frontotemporal dementia, 70 Lewy body disease, 898 Alzheimer's disease, 62 vascular brain injury and 36 primary psychiatric disorder from the publicly accessible National Alzheimer's Coordinating Center dataset to assess the performance of VentRa. Using ventricular features to discriminate behavioural variant frontotemporal dementia subjects from primary psychiatric disorders, VentRa achieved an accuracy rate of 84%, a sensitivity rate of 71% and a specificity rate of 89%. VentRa was able to identify behavioural variant frontotemporal dementia from a mixed age-matched cohort (i.e. other frontotemporal dementia, Lewy body disease, Alzheimer's disease, vascular brain injury and primary psychiatric disorders) and to correctly classify other disorders as 'not compatible with behavioral variant frontotemporal dementia' with a specificity rate of 83%. The specificity rates against each of the other individual cohorts were 80% for other frontotemporal dementia, 83% for Lewy body disease, 83% for Alzheimer's disease, 84% for vascular brain injury and 89% for primary psychiatric disorders. VentRa is a robust and generalizable tool with potential usefulness for improving the diagnostic certainty of behavioural variant frontotemporal dementia, particularly for the differential diagnosis with primary psychiatric disorders.

Staging of progressive supranuclear palsy-Richardson syndrome using MRI brain charts for the human lifespan.

Brain charts for the human lifespan have been recently proposed to build dynamic models of brain anatomy in normal aging and various neurological conditions. They offer new possibilities to quantify neuroanatomical changes from preclinical stages to death, where longitudinal MRI data are not available. In this study, we used brain charts to model the progression of brain atrophy in progressive supranuclear palsy-Richardson syndrome. We combined multiple datasets (n = 8170 quality controlled MRI of healthy subjects from 22 cohorts covering the entire lifespan, and n = 62 MRI of progressive supranuclear palsy-Richardson syndrome patients from the Four Repeat Tauopathy Neuroimaging Initiative (4RTNI)) to extrapolate lifetime volumetric models of healthy and progressive supranuclear palsy-Richardson syndrome brain structures. We then mapped in time and space the sequential divergence between healthy and progressive supranuclear palsy-Richardson syndrome charts. We found six major consecutive stages of atrophy progression: (i) ventral diencephalon (including subthalamic nuclei, substantia nigra, and red nuclei), (ii) pallidum, (iii) brainstem, striatum and amygdala, (iv) thalamus, (v) frontal lobe, and (vi) occipital lobe. The three structures with the most severe atrophy over time were the thalamus, followed by the pallidum and the brainstem. These results match the neuropathological staging of tauopathy progression in progressive supranuclear palsy-Richardson syndrome, where the pathology is supposed to start in the pallido-nigro-luysian system and spreads rostrally via the striatum and the amygdala to the cerebral cortex, and caudally to the brainstem. This study supports the use of brain charts for the human lifespan to study the progression of neurodegenerative diseases, especially in the absence of specific biomarkers as in PSP.

Identification of Parkinson's disease subtypes with distinct brain atrophy progression and its association with clinical progression.

Parkinson's disease (PD) patients suffer from progressive gray matter volume (GMV) loss, but whether distinct patterns of atrophy progression exist within PD are still unclear. This study aims to identify PD subtypes with different rates of GMV loss and assess their association with clinical progression. This study included 107 PD patients (mean age: 60.06 ± 9.98 years, 70.09% male) with baseline and ≥ 3-year follow-up structural MRI scans. A linear mixed-effects model was employed to assess the rates of regional GMV loss. Hierarchical cluster analysis was conducted to explore potential subtypes based on individual rates of GMV loss. Clinical score changes were then compared across these subtypes. Two PD subtypes were identified based on brain atrophy rates. Subtype 1 (n = 63) showed moderate atrophy, notably in the prefrontal and lateral temporal lobes, while Subtype 2 (n = 44) had faster atrophy across the brain, particularly in the lateral temporal region. Furthermore, subtype 2 exhibited faster deterioration in non-motor (MDS-UPDRS-Part Ⅰ, β = 1.26±0.18, P=0.016) and motor (MDS-UPDRS-Part Ⅱ, β = 1.34±0.20, P=0.017) symptoms, autonomic dysfunction (SCOPA-AUT, β = 1.15±0.22, P=0.043), memory (HVLT-Retention, β = -0.02±0.01, P=0.016) and depression (GDS, β = 0.26±0.083, P=0.019) compared to subtype 1. The study has identified two PD subtypes with distinct patterns of atrophy progression and clinical progression, which may have implications for developing personalized treatment strategies.

Brain-Derived Neurotrophic Factor Val66Met is Associated with Variation in Cortical Structure in Healthy Aging Subjects.

Aging is associated with progressive brain atrophy and declines in learning and memory, often attributed to hippocampal or cortical deterioration. The role of brain-derived neurotrophic factor (BDNF) in modulating the structural and functional changes in the brain and visual system, particularly in relation to BDNF Val66Met polymorphism, remains underexplored. In this present cross-sectional observational study, we aimed to assess the effects of BDNF polymorphism on brain structural integrity, cognitive function, and visual pathway alterations. A total of 108 older individuals with no evidence of dementia and a mean (SD) age of 67.3 (9.1) years were recruited from the Optic Nerve Decline and Cognitive Change (ONDCC) study cohort. The BDNF Met allele carriage had a significant association with lower entorhinal cortex volume (6.7% lower compared to the Val/Val genotype, P = 0.02) and posterior cingulate volume (3.2% lower than the Val/Val group, P = 0.03), after adjusting for confounding factors including age, sex and estimated total intracranial volumes (eTIV). No significant associations were identified between the BDNF Val66Met genotype and other brain volumetric or diffusion measures, cognitive performances, or vision parameters except for temporal retinal nerve fibre layer thickness. Small but significant correlations were found between visual structural and functional, cognitive, and brain morphological metrics. Our findings suggest that carriage of BDNF Val66Met polymorphism is associated with lower entorhinal cortex and posterior cingulate volumes and may be involved in modulating the cortical morphology along the aging process.

Early-stage volume losses in the corpus callosum and thalamus predict the progression of brain atrophy in patients with multiple sclerosis

BackgroundA method that can be used in the early stage of multiple sclerosis (MS) to predict the progression of brain volume loss (BVL) has not been fully established. MethodsTo develop a method of predicting progressive BVL in patients with MS (pwMS), eighty-two consecutive Japanese pwMS—with either relapsing-remitting MS (86%) or secondary progressive MS (14%)—and 41 healthy controls were included in this longitudinal retrospective analysis over an observational period of approximately 3.5 years. Using a hierarchical cluster analysis with multivariate imaging data obtained by FreeSurfer analysis, we classified the pwMS into clusters. ResultsAt baseline and follow-up, pwMS were cross-sectionally classified into three major clusters (Clusters 1, 2, and 3) in ascending order by disability and BVL. Among the patients included in Cluster 1 at baseline, approximately one-third of patients (12/52) transitioned into Cluster 2 at follow-up. The volumes of the corpus callosum, the thalamus, and the whole brain excluding the ventricles were significantly decreased in the transition group compared with the nontransition group and were found to be the most important predictors of transition. ConclusionDecreased volumes of the corpus callosum and thalamus in the relatively early stage of MS may predict the development of BVL.

Predicting disease-related MRI patterns of multiple sclerosis through GAN-based image editing

IntroductionMultiple sclerosis (MS) is a complex neurodegenerative disorder that affects the brain and spinal cord. In this study, we applied a deep learning-based approach using the StyleGAN model to explore patterns related to MS and predict disease progression in magnetic resonance images (MRI). MethodsWe trained the StyleGAN model unsupervised using T1-weighted GRE MR images and diffusion-based ADC maps of MS patients and healthy controls. We then used the trained model to resample MR images from real input data and modified them by manipulations in the latent space to simulate MS progression. We analyzed the resulting simulation-related patterns mimicking disease progression by comparing the intensity profiles of the original and manipulated images and determined the brain parenchymal fraction (BPF). ResultsOur results show that MS progression can be simulated by manipulating MR images in the latent space, as evidenced by brain volume loss on both T1-weighted and ADC maps and increasing lesion extent on ADC maps. ConclusionOverall, this study demonstrates the potential of the StyleGAN model in medical imaging to study image markers and to shed more light on the relationship between brain atrophy and MS progression through corresponding manipulations in the latent space.

Bi-allelic genetic variants in the translational GTPases GTPBP1 and GTPBP2 cause a distinct identical neurodevelopmental syndrome

The homologous genes GTPBP1 and GTPBP2 encode GTP-binding proteins 1 and 2, which are involved in ribosomal homeostasis. Pathogenic variants in GTPBP2 were recently shown to be an ultra-rare cause of neurodegenerative or neurodevelopmental disorders (NDDs). Until now, no human phenotype has been linked to GTPBP1. Here, we describe individuals carrying bi-allelic GTPBP1 variants that display an identical phenotype with GTPBP2 and characterize the overall spectrum of GTP-binding protein (1/2)-related disorders. In this study, 20 individuals from 16 families with distinct NDDs and syndromic facial features were investigated by whole-exome (WES) or whole-genome (WGS) sequencing. To assess the functional impact of the identified genetic variants, semi-quantitative PCR, western blot, and ribosome profiling assays were performed in fibroblasts from affected individuals. We also investigated the effect of reducing expression of CG2017, an ortholog of human GTPBP1/2, in the fruit fly Drosophila melanogaster. Individuals with bi-allelic GTPBP1 or GTPBP2 variants presented with microcephaly, profound neurodevelopmental impairment, pathognomonic craniofacial features, and ectodermal defects. Abnormal vision and/or hearing, progressive spasticity, choreoathetoid movements, refractory epilepsy, and brain atrophy were part of the core phenotype of this syndrome. Cell line studies identified a loss-of-function (LoF) impact of the disease-associated variants but no significant abnormalities on ribosome profiling. Reduced expression of CG2017 isoforms was associated with locomotor impairment in Drosophila. In conclusion, bi-allelic GTPBP1 and GTPBP2 LoF variants cause an identical, distinct neurodevelopmental syndrome. Mutant CG2017 knockout flies display motor impairment, highlighting the conserved role for GTP-binding proteins in CNS development across species.

More rapid progression of brain atrophy in patients on peritoneal dialysis compared with hemodialysis: The VCOHP Study.

We previously reported that brain atrophy was more severe and progressed more rapidly in patients with end-stage kidney disease on peritoneal dialysis (PD) than those with non-dialysis-dependent chronic kidney disease. However, it remains unknown whether there is a difference between patients on PD and hemodialysis (HD). In total, 73 PD and 34 HD patients who underwent brain magnetic resonance imaging (MRI) were recruited for a cross-sectional analysis. Among them, 42 PD and 25 HD patients who underwent a second brain MRI after 2 years were recruited for a longitudinal analysis. T1-weighted MRI images were analyzed. Total gray matter volume (GMV), total white matter volume, and cerebrospinal fluid volume were segmented, and each volume was quantified using statistical parametric mapping software. The ratio of GMV (GMR) was calculated by dividing GMV by intracranial volume, to adjust for variations in head size. We compared GMR between PD and HD patients in the cross-sectional analysis and the annual change in GMR(AC-GMR) in the longitudinal analysis. In the cross-sectional analysis, age- and sex-adjusted GMR was significantly lower in PD than HD patients [least square mean (LSM): 39.2% vs. 40.0%, P = 0.018]. AC-GMRwas significantly greater in PD than HD patients and this difference remained significant even after adjustment for potential confounding factors (LSM: -0.68 vs. -0.28 percentage-points/year, P = 0.011). In conclusion, the present study demonstrated amore rapid progression of brain atrophy in PD patients compared with HD patients. We demonstrated that decline in GMR progressed significantly more rapidly in PD than HD patients independent of potential confounding factors. GMR gray matter volume ratio, HD hemodialysis, PD peritoneal dialysis.

Significant dose‐dependent reduction in neurofilament light chain concentration in plasma with oral tau aggregation inhibitor hydromethylthionine mesylate

AbstractBackgroundHydromethylthionine mesylate (HMTM) is a potent oral tau aggregation inhibitor. Recent results from Study TRx‐237‐039 (LUCIDITY) suggest strong effects on cognitive and functional decline and progression of brain atrophy. We investigated the effect of HMTM on change in the plasma biomarker neurofilament light chain (NfL) in LUCIDITY. NfL is a clinically accessible and established biomarker for neurodegeneration that is known to be correlated with measures of clinical decline and brain atrophy in AD and MCI due to AD (MCI‐AD).MethodLUCIDITY is a double‐blind randomised controlled Phase 3 clinical trial comparing change over 12 months in cognitive, functional and brain atrophy outcomes at HMTM doses of 16 mg/day, 8 mg/day and methylthioninium chloride (MTC) at a dose of 4 mg twice weekly as a control in a 4:1:4 randomisation, with a subsequent 12 month blinded open‐label extension phase in which all participants received 16 mg/day.ResultBaseline and 12‐month NfL plasma levels were available as randomised in 161/185 participants receiving HMTM 16 mg/day, 38/48 receiving HMTM 8 mg/day and 136/185 receiving MTC 8 mg/week. The corresponding prespecified analysis model showed a 93% reduction in the change in NfL levels relative to control for HMTM 16 mg/day overall (p = 0.0278). Reduction in NfL change in the MCI‐AD subgroup was significant also at HMTM 8 mg/day (p = 0.0242). In the AD subgroup, there were directional dose‐dependent trends that did not reach statistical significance. Change in NfL level at 12 months was significantly correlated with change in ADAS‐cog11 (p = 0.0038) and whole brain volume (p = 0.0359) over 24 months.ConclusionThese results demonstrate that the orally administered tau aggregation‐inhibitor, HMTM, is able to produce a significant dose‐dependent reduction in neurodegeneration in AD as measured by change in plasma NfL levels.