Brain Atrophy Research Articles

Biallelic variants in GTF3C3 encoding a subunit of the TFIIIC2 complex are associated with neurodevelopmental phenotypes in humans and zebrafish

Abstract POLR3 (RNA polymerase III) transcribes essential non-coding RNAs, a process regulated by transcription factors TFIIIB and TFIIIC. Although germline variants in TFIIIC subunit genes have been described in a few patients with neurodevelopmental disorders, the associated pathogenesis and clinical spectrum are not yet well defined. Herein, we describe the identification of biallelic variants in GTF3C3, which encodes a key component of the TFIIIC subunit, in four patients from three unrelated families of different ethnicities collected through GeneMatcher. The patients exhibited microcephaly, developmental delay, intellectual disability, and distinctive dysmorphic facies that appear recognizable in very young children. Their brain imaging showed brain atrophy with predominant cerebellar involvement, as well as hypoplasia of the frontal lobes and one patient had moderate to severe simplified gyral pattern. Seizures were observed in half of the patients. Exome/genome sequencing revealed four different GTF3C3 variants including three missense (p.Cys172Gly, p.Val427Phe, p.Ala509Thr) and one nonsense variant (p.Arg717Ter). Missense variants were not present in known genetic databases and occurred in highly conserved residues. Knockout (KO) of the GTF3C3 ortholog in zebrafish recapitulated the key clinical symptoms including microcephaly, brain anomalies, and seizure susceptibility. We also observed reduced POLR3 target gene expression in the zebrafish KO model. This study describes a new neurodevelopmental syndrome in humans and zebrafish associated with biallelic GTF3C3 variants and underscores the need for further research into the biological impacts of variants in TFIIIC-linked genes and their contribution to POLR3-related pathologies.

Volume Changes in Brain Subfields of Patients with Alzheimer’s Disease After Transcranial Ultrasound Stimulation

Background/Objectives: Alzheimer’s disease (AD) is characterized by progressive brain atrophy marked by cognitive decline and memory loss, which significantly affect patients’ quality of life. Transcranial ultrasound stimulation (TUS) is a potential physical treatment for AD patients. However, the specific brain regions stimulated by TUS and its therapeutic effects remain unclear. Methods: In this study, magnetic resonance imaging (MRI) and FreeSurfer segmentation were employed to assess alterations in the brain volume of AD patients after TUS. Results: Our findings revealed significant volume increases in the corpus callosum (CC) and lateral orbitofrontal cortex (lOFC) in the TUS group. Moreover, the volumetric changes in the CC were strongly correlated with improvements in the Mini-Mental State Examination score, which is a widely used measure of cognitive function of AD patients. Conclusions: TUS has the potential to alleviate disease progression and offers a non-invasive therapeutic approach to the improvement of cognitive function in AD patients.

Late-life parkinsonism in bipolar disorder.

Parkinsonism is a frequently encountered symptom in individuals with bipolar disorder (BD). It can be drug-induced, co-occurring with Parkinson's disease (PD), or a genuine motor abnormality of BD itself. This study aims to address the primary pathophysiology of parkinsonism in BD. Sixteen patients with BD and parkinsonism were recruited from consecutive patients who were referred to a neurology clinic at a tertiary psychiatric centre. The patients underwent clinical assessments, dopamine transporter single-photon computed tomography (DAT-SPECT), cardiac 123I-metaiodo-benzylguanidine (MIBG) scintigraphy, and morphometric magnetic resonance imaging (MRI). The positivity or negativity of Lewy body disease (LBD) biomarkers was determined based on the visual assessment of DAT-SPECT and heart-to-mediastinum ratio on cardiac MIBG scintigraphy. Four out of the 16 participants received 300-600 mg of levodopa. Thirteen patients were diagnosed with BD type 1, and 12 had experienced >5 previous mood episodes. Parkinsonism developed more than 10 years after the onset of BD and after the age of 50 years in all patients. Four cases were positive for LBD biomarkers. Six patients with negative LBD biomarkers showed reduced striatal uptake with z-scores below -2.0. MRI morphometry revealed varying degrees of brain atrophy in most patients. Three of the four patients did not respond to 600 mg of levodopa. The results of this study indicate that the majority of parkinsonism observed in BD is not a consequence of PD/LBD. Instead, it may represent a genuine motor abnormality of BD in late life.

Soluble Aβ pathology predicts neurodegeneration and cognitive decline independently on p-tau in the earliest Alzheimer's continuum: Evidence across two independent cohorts.

Identifying the link between early Alzheimer's disease (AD) pathological changes and neurodegeneration in asymptomatic individuals may lead to the discovery of preventive strategies. We assessed longitudinal brain atrophy and cognitive decline as a function of cerebrospinal fluid (CSF) AD biomarkers in two independent cohorts of cognitively unimpaired (CU) individuals. We used longitudinal voxel-based morphometry (VBM) in combination with hippocampal subfield segmentation. Changes in neuroimaging and cognitive variables were inspected using general linear models (GLMs) adjusting by age, sex, apolipoprotein E (APOE) status, follow-up time, and years of education. In both cohorts, baseline CSF amyloid beta (Aβ) biomarkers significantly predicted medial temporal lobe (MTL) atrophy rates and episodic memory (EM) decline independently of CSF phosphorylated tau (p-tau). Our data suggest that soluble Aβ dyshomeostasis triggers MTL longitudinal atrophy and EM decline independently of CSF p-tau. Our data underscore the need for secondary preventive strategies at the earliest stages of the AD pathological cascade. We assessed brain atrophy and cognitive decline in asymptomatic individuals. Aβ biomarkers predicted MTL atrophy independently of p-tau. Our results underscore the importance of undertaking Alzheimer's preclinical trials.

Hyperintensity of the left piriform cortex and amygdala on T2-weighted FLAIR images in patients with probable Alzheimer’s disease correlates with cerebral cortical atrophy

Background The left piriform cortex and amygdala (PC&A) tend to be slightly hyperintense relative to the right PC&A on T2-weighted fluid-attenuated inversion recovery (T2W-FLAIR) images in patients with probable Alzheimer’s disease (pAD). This likely represents the antecedent and thus advanced degeneration of the left PC&A. Purpose To investigate the relationship between left PC&A hyperintensities and cerebral cortical atrophy on magnetic resonance (MR) voxel-based morphometry in patients with pAD and discuss how this finding could relate to AD progression. Material and Methods Patients with pAD ( n = 47; age range = 68–93 years, mean = 80.8 ± 6.7 years; 14 men and 33 women) who underwent T2W-FLAIR imaging and MR morphometric study using a voxel-based specific regional analysis system for AD (VSRAD) were retrospectively examined. To measure signal intensity ratios of the left to right PC&A (L-PC&A/R-PC&A), regions of interest (ROIs) were set on the transaxial images in which both PC&As were most broadly depicted; the ROIs were defined as large as possible. Correlations between the L-PC&A/R-PC&A and medial temporal lobe cortical atrophy (MTLCA) as well as whole cerebral cortical atrophy (WCCA) on VSRAD were determined. Correlation between the L-PC&A/R-PC&A and age was also determined. Results The L-PC&A/R-PC&A correlated with both MTLCA (r = 0.375, p = .010, 95% confidence interval [CI] = 0.095–0.600) and WCCA (r = 0.576, p < .001, 95% CI = 0.343–0.742). The L-PC&A/R-PC&A did not correlate with age (r = 0.013, p = .932, 95% CI = −0.282–0.305). Conclusion Left-sided dominance of PC&A degeneration appeared to accelerate with the progression of AD stages.

Utilizing Quantitative Analysis of CSF Volume from Clinical T1-Weighted MRI to Predict Thrombectomy Outcomes.

Endovascular thrombectomy (EVT) is the standard for acute ischemic stroke from large vessel occlusion, but post-EVT functional independence varies. Brain atrophy, linked to higher cerebrospinal fluid volume (CSFV), may affect outcomes. Baseline CSFV could predict EVT benefit by assessing brain health. We aimed to quantify total CSFV from clinical T1-weighted (w) magnetic resonance imaging (MRI) to assess global brain atrophy and its association with functional outcomes following successful EVT. We performed a retrospective analysis of patients achieving thrombolysis-in-cerebral-infarction ≥2b revascularization via prospectively maintained single-institution stroke thrombectomy registry (n = 432) between 2015 and 2021. We included 214 patients (mean age 67.5±14.6, 49% female) with acceptable quality MRI within 14days of EVT and available modified Rankin-scale (mRS) at 90days post EVT. Clinical T1w images were transformed into high-resolution images using the convolutional neural-network SynthSR. FreeSurfer software was then used to estimate total cranial CSFV. To correct for head size, percentage of CSFV to intracranial volume was used. Baseline CSFV% significantly predicted 90-day mRS in an ordinal regression model adjusted for baseline mRS (p<0.001). Further modeling was performed to account for age, sex, 24-h National-Institutes-Health-Stroke-Scale (NIHSS), smoking history, prior stroke, hypertension, congestive heart failure, hemoglobin-A1c, atrial fibrillation, and Alberta-Stroke-Program-Early-CT-Score (ASPECTS). Total CSFV% remained an independent predictor of 90-day mRS (p = 0.012). CSFV% did not significantly predict the occurrence of any type of hemorrhagic transformation in a logistic regression model. Increased CSFV% correlates with poorer functional outcomes post EVT. Total CSFV% may serve as a useful imaging biomarker for clinicians determining patient prognostication prior to EVT.

Cinnamic Acid Derivatives: Recent Discoveries and Development Strategies for Alzheimer's Disease.

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder that leads to cognitive decline and memory impairment. It is characterized by the accumulation of Amyloid-beta (Aβ) plaques, the abnormal phosphorylation of tau protein forming neurofibrillary tangles, and is often accompanied by neuroinflammation and oxidative stress, which contribute to neuronal loss and brain atrophy. At present, clinical anti-AD drugs are mostly single-target, improving the cognitive ability of AD patients, but failing to effectively slow down the progression of AD. Therefore, research on effective multi-target drugs for AD has become an urgent problem to address. The main derivatives of hydroxycinnamic acid, caffeic acid, and ferulic acid, are widely present in nature and have many pharmacological activities, such as antimicrobial, antioxidant, anti-inflammatory, neuroprotective, anti-Aβ deposition, and so on. The occurrence and development of AD are often accompanied by pathologies, such as oxidative stress, neuroinflammation, and Aβ deposition, suggesting that caffeic acid and ferulic acid can be used in the research on anti-AD drugs. Therefore, in this article, we have summarized the multi-target anti-AD derivatives based on caffeic acid and ferulic acid in recent years, and discussed the new design direction of cinnamic acid derivatives as backbone compounds. It is hoped that this review will provide some useful strategies for anti-AD drugs based on cinnamic acid derivatives.

Atidarsagene autotemcel (autologous hematopoietic stem cell gene therapy) preserves cognition, language, and speech and slows brain demyelination and atrophy in early-onset metachromatic leukodystrophy

Atidarsagene autotemcel (autologous hematopoietic stem cell gene therapy) preserves cognition, language, and speech and slows brain demyelination and atrophy in early-onset metachromatic leukodystrophy

Abstract WP188: Differential Patterns of Cerebral Atrophy and Clinical Impacts in Cerebral Amyloid Angiopathy and Hypertensive Cerebral Small Vessel Disease

Abstract WP188: Differential Patterns of Cerebral Atrophy and Clinical Impacts in Cerebral Amyloid Angiopathy and Hypertensive Cerebral Small Vessel Disease

Abstract TP336: Neuropathological changes in the chronic phase of ischemic stroke are marked by persistent alteration of microglial function and neurodegenerative phenotypes

Improvements in acute stroke treatment, including EVT and critical care management, have increased survival rates post-stroke. However, many stroke survivors have significant post-stroke disability and cognitive impairment. Despite this, the chronic progression and long-term sequelae of ischemic stroke pathology remains understudied. Methods: We examined the chronicity of neurobehavioral recovery and progressive neuropathology in young male (3 month) and middle-aged male and female (14 month) C57Bl/6 mice at 3 and 6 months after a 60-minute transient middle cerebral artery occlusion (tMCAO) or sham surgery ( n = 10-20/group ). Behavioral testing included NORT, fear conditioning (FC), and tail suspension. Immunohistochemistry (IHC) was performed on mouse brains, as well as post-mortem human brain samples from patients with a chronic infarct ( n = 6/group ), to assess demyelination (MBP), neuronal apoptosis (TUNEL/NeuN), and amyloid burden (Aβ-42). Flow cytometry was performed on the ipsilateral mouse brain hemisphere. RNA isolated from the ipsilateral hemisphere was sent for gene profiling. Results: In both young and middle-aged mice, depressive-like behavior persisted for 6 months post-stroke (PS) (p= &lt;0.0001), while cognitive function progressively worsened from 3 to 6 months, as seen by a reduction in the NORT (p=.0063) and FC (p=.0084). MRI imaging and IHC revealed cerebral atrophy, significant demyelination (mouse, p=.0361; human, p =.0001), and increased microglial density (p=.0059) in the hippocampus of both human and mice. TUNEL/NeuN staining showed ongoing neuronal degeneration in the human hippocampus, distal to the chronic infarct. Human chronic stroke hippocampus had increased amyloid burden compared to age-matched controls (p=.0677). Cytometric anyalses revealed disease-associated microglial (DAM) phenotypes were marked by increased senescence, cytokine production, and an altered redox state. Transcriptomic data showed significant chronic upregulation of DAM genes. Conclusion: Our findings demonstrate that ischemic stroke accelerates inflamm-aging and premature senescence within the chronic infarct microenvironment. Cellular senescence and chronic disease signatures may contribute to progressive cognitive impairment post-stroke. Identification of secondary injury processes, and late pathological events post-stroke, allude to a neurodegenerative etiology and may offer viable targets for delayed treatment to prevent further neurological decline.

Grey-Matter Structure Markers of Alzheimer's Disease, Alzheimer's Conversion, Functioning and Cognition: A Meta-Analysis Across 11 Cohorts.

Alzheimer's disease (AD) brain markers are needed to select people with early-stage AD for clinical trials and as quantitative endpoint measures in trials. Using 10 clinical cohorts (N = 9140) and the community volunteer UK Biobank (N = 37,664) we performed region of interest (ROI) and vertex-wise analyses of grey-matter structure (thickness, surface area and volume). We identified 94 trait-ROI significant associations, and 307 distinct cluster of vertex-associations, which partly overlap the ROI associations. For AD versus controls, smaller hippocampus, amygdala and of the medial temporal lobe (fusiform and parahippocampal gyri) was confirmed and the vertex-wise results provided unprecedented localisation of some of the associated region. We replicated AD associated differences in several subcortical (putamen, accumbens) and cortical regions (inferior parietal, postcentral, middle temporal, transverse temporal, inferior temporal, paracentral, superior frontal). These grey-matter regions and their relative effect sizes can help refine our understanding of the brain regions that may drive or precede the widespread brain atrophy observed in AD. An AD grey-matter score evaluated in independent cohorts was significantly associated with cognition, MCI status, AD conversion (progression from cognitively normal or MCI to AD), genetic risk, and tau concentration in individuals with none or mild cognitive impairments (AUC in 0.54-0.70, p-value < 5e-4). In addition, some of the grey-matter regions associated with cognitive impairment, progression to AD ('conversion'), and cognition/functional scores were also associated with AD, which sheds light on the grey-matter markers of disease stages, and their relationship with cognitive or functional impairment. Our multi-cohort approach provides robust and fine-grained maps the grey-matter structures associated with AD, symptoms, and progression, and calls for even larger initiatives to unveil the full complexity of grey-matter structure in AD.

Synapse vulnerability and resilience underlying Alzheimer's disease.

Synapse preservation is key for healthy cognitive ageing, and synapse loss represents a critical anatomical basis of cognitive dysfunction in Alzheimer's disease (AD), predicting dementia onset, severity, and progression. Synapse loss is viewed as a primary pathologic event, preceding neuronal loss and brain atrophy in AD. Synapses may, therefore, represent one of the earliest and clinically most meaningful targets of the neuropathologic processes driving AD dementia. The synapse loss in AD is highly selective and targets particularly vulnerable synapses while leaving others, termed resilient, largely unaffected. Yet, the anatomic and molecular hallmarks of the vulnerable and resilient synapse populations and their association with AD neuropathologic changes (e.g. amyloid-β plaques and tau tangles) and memory dysfunction remain poorly understood. Characterising the selectively vulnerable and resilient synapses in AD may be key to understanding the mechanisms of cognitive preservation versus loss and enable the development of robust biomarkers and disease-modifying therapies for dementia.

Synthetic MR: Clinical applications in neuroradiology.

Synthetic MR is a quantitative MRI method that measures tissue relaxation times and generates multiple contrast-weighted images using suitable algorithms. The present article principally discusses the multiple dynamic multiple echo (MDME) technique of synthetic MR and briefly describes other quantitative MR sequences. Using illustrative cases, various applications of the MDME sequence in neuroradiology are explained. The MDME sequence allows rapid quantification of tissue relaxation times in a scan duration of 5-7 minutes for full brain coverage. It also has the additional advantages of myelin quantification and automatic segmentation of brain volumes. Applications including reducing scan time, improved detection of demyelinating plaques in Multiple Sclerosis (MS), objective assessment and follow-up for brain atrophy in neurodegenerative MS and dementia cases, and applications in stroke imaging and neuro-oncology are discussed. Uses in the pediatric population, including assessment of brain development and progression of myelination in children, evaluation of white matter disorders, and evaluation of pediatric and adult epilepsy, are elaborated. Quantitative evaluation by synthetic MR is discussed, which allows homogenization and objectification of the radiology data and can serve as a valuable source for artificial intelligence and future multicentre studies. A brief discussion on the technique, other quantitative MR methods, and limitations of the MDME sequence is also presented. The article intends to provide an explicit and comprehensive review of the applications of synthetic MR in neuroradiology, exploring its potential as a routine sequence in daily neuroimaging practice.

Characterizing the Spatial Patterns and Determinants of Cerebrospinal Fluid Pseudorandom Flow in the Human Brain with Low b-value Diffusion MRI

Abstract The circulation of cerebrospinal fluid (CSF) is essential for maintaining brain homeostasis and clearance, and impairments in its flow can lead to various brain disorders. Recent studies have shown that CSF effective motility can be interrogated using low b-value diffusion magnetic resonance imaging (low-b dMRI). Nevertheless, the spatial organization of intracranial CSF flow dynamics remains largely elusive. Here, we developed a whole-brain voxel-based analysis framework, termed CSF pseudo-diffusion spatial statistics (CΨSS), to examine CSF mean pseudo-diffusivity (MΨ), a measure of CSF flow magnitude derived from low-b dMRI. We showed that intracranial CSF MΨ demonstrates characteristic covariance patterns by employing seed-based correlation analysis. Next, we applied non-negative matrix factorization analysis to further elucidate the covariance patterns of CSF MΨ in a hypothesis-free, data-driven way. We identified ten distinct CSF compartments with high reproducibility and reliability, reflected by a high mean adjusted Rand index with a low standard deviation (0.82 [SD: 0.018]) in split-half analyses of the discovery multimodal aging dataset (n = 187). The identified patterns displayed similar MΨ across three replication datasets. In discovery and replication multimodal aging cohorts (unique n = 264), our study revealed that age, sex, brain atrophy, ventricular anatomy, and cerebral perfusion differentially influence MΨ across these CSF spaces. Notably, of the 35 individuals exhibited anomalous CSF flow patterns, five displayed clinically consequential incidental findings on multimodal neuroradiological examinations, which were not observed in other participants (p = 3.04×10-5). Our work sets forth a new paradigm to study CSF flow, with potential applications in clinical settings.

Positive impact of cladribine tablets on reducing brain atrophy in patients with relapsing-remitting multiple sclerosis: A longitudinal study.

Measuring brain volume changes over time is an objective and dependable surrogate marker for the pathological processes that damage the brain in relapsing-remitting multiple sclerosis (RRMS). These measures are particularly valuable for monitoring the long-term impact of immunomodulatory treatments such as cladribine. To evaluate the long-term impact of oral cladribine treatment on brain volume loss in patients with RRMS. This real-world study processed magnetic resonance imaging (MRI) scans using FreeSurfer's recon-all-clinical pipeline leveraging SynthSeg for brain segmentation. Piecewise linear regression was used to analyze brain atrophy changes over 4.5 years before and after cladribine treatment and estimate the time breakpoint of atrophy rate change. A total of 448 MRI exams from 102 RRMS patients were analyzed. Before the initiation of cladribine treatment, brain atrophy rates were significantly steep with an α1 slope between -1.27 and -0.62 for the Thalamus, DGM, Subcortical GM, Cerebral WM, and BP. Over 2 years after treatment, breakpoints marked a shift in atrophy rates, with post-breakpoint slopes (α2) becoming non-significant, reflecting stabilization of brain atrophy. Cladribine treatment in highly active RRMS patients protects the brain from atrophy, with stabilization occurring over 2 years after initiation. The extended observation period highlights its sustained benefits compared with shorter clinical trials.

Nutrition: A non-negligible factor in the pathogenesis and treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a degenerative disease characterized by progressive cognitive dysfunction. The strong link between nutrition and the occurrence and progression of AD pathology has been well documented. Poor nutritional status accelerates AD progress by potentially aggravating amyloid beta (Aβ) and tau deposition, exacerbating oxidative stress response, modulating the microbiota-gut-brain axis, and disrupting blood-brain barrier function. The advanced stage of AD tends to lead to malnutrition due to cognitive impairments, sensory dysfunctions, brain atrophy, and behavioral and psychological symptoms of dementia (BPSD). This, in turn, produces a vicious cycle between malnutrition and AD. This review discusses how nutritional factors and AD deteriorate each other from the early stage of AD to the terminal stages of AD, focusing on the potential of different levels of nutritional factors, ranging from micronutrients to diet patterns. This review provides novel insights into reducing the risk of AD, delaying its progression, and improving prognosis. HIGHLIGHTS: Two-fifths of Alzheimer's disease (AD) cases worldwide have been attributed to potentially modifiable risk factors. Up to ≈26% of community-dwelling patients with AD are malnourished, compared to 7%∼76% of institutionalized patients. Undernutrition effects the onset, progression, and prognosis of AD through multiple mechanisms. Various levels of nutritional supports were confirmed to be protective factors for AD via specific mechanisms.

Phenotypic variability in progressive encephalopathy with brain atrophy and thin corpus callosum: insights from two families.

The cytoskeleton, composed of microtubules, intermediate filaments and actin filaments is vital for various cellular functions, particularly within the nervous system, where microtubules play a key role in intracellular transport, cell morphology, and synaptic plasticity. Tubulin-specific chaperones, including tubulin folding cofactors (TBCA, TBCB, TBCC, TBCD, TBCE), assist in the proper formation of α/β-tubulin heterodimers, essential for microtubule stability. Pathogenic variants in these chaperone-encoding genes, especially TBCD, have been linked to Progressive Encephalopathy with Brain Atrophy and Thin Corpus Callosum (PEBAT, OMIM #604,649), a severe neurodevelopmental disorder. We report three cases from two consanguineous families with varying clinical presentations of PEBAT syndrome due to homozygous pathogenic variants in the TBCD. In Family 1, two siblings (F1C1 and F1C2) harboring the homozygous c.2314C > T, p.(Arg772Cys) variant exhibited severe neurodevelopmental regression, spastic tetraplegia, seizures, and brain atrophy. In contrast, Family 2, Case 3 (F2C3), with the homozygous c.230A > G, p.(His77Arg) variant, presented a milder phenotype, including absence seizures, slight developmental delay, and less pronounced neuroanatomical abnormalities. These findings contribute to the expanding phenotypic spectrum of PEBAT and suggesting that modifier genes or epigenetic factors may influence disease severity.

Clinical Diagnosis and Differential Diagnosis Between CSF1R- and AARS2-Related Leukoencephalopathy.

CSF1R-related leukoencephalopathy (CSF1R-L) and AARS2-related leukoencephalopathy (AARS2-L) were two disease entities sharing similar phenotype and even pathological changes. Although clinically, radiologically, and pathologically similar, they were caused by mutation of two different genes. As the rarity of the two diseases, the differential diagnosis of them was difficult. 23 CSF1R-L and 6 AARS2-L patients were enrolled from the Leukoencephalopathy Clinic, Peking Union Medical College Hospital in China. Detailed clinical information, neuroimaging manifestations, and genetic data were collected and analyzed. Demographically, female patients were more in AARS2-L than CSF1R-L. Clinically, cognitive impairment and emotion/personality change were common in both groups. Bulbar palsy, extrapyramidal symptoms, and hemiplegia/pyramidal impairment were more common in CSF1R-L, while ataxia was significantly more common in AARS2-L. Abnormal menstruation including infertility was significantly more in AARS2-L. Radiologically, similar features were found, including lateral ventricle-centered white matter lesions, involving corpus callosum, avoiding U fibers. The lesions showed persistent hyperintensity on DWI image and were not contrasted after gadolinium enhancement. In CSF1R-L, the lesions could be widespread confluent or patchy and spotted, extending to centrum semiovale and subcortical white matter occasionally, which was significantly different from AARS2-L. Besides, brain stem lesion caused by pyramidal degeneration, spotted or linear calcification and obviously brain atrophy were common in CSF1R-L. In AARS2-L, periventricular white matter rarefaction was significantly common. No genotype and phenotype association was found in these two diseases. Although similar, there were several clinical and radiological features helping differentiating the two distinct diseases.

Educational attainment, Aβ, tau, and structural brain reserve in Alzheimer's disease.

Alzheimer's disease (AD) patients with higher educational attainment (EA) often exhibit better cognitive function. However, the relationship among EA status, AD pathology, structural brain reserve, and cognitive decline requires further investigation. We compared cognitive performance across different amyloid beta (Aβ) positron emission tomography (A±) statuses and EA levels (High EA/Low EA). We examined the effects of Aβ plaques, tau tangles, and gray matter volume (GMV) on the relationship between EA and domain-specific cognitive decline. A+/High-EA individuals exhibited slower cognitive decline in global cognition and language domains than A+/Low-EA individuals. This cognitive benefit was independently and synergistically explained by reduced AD pathology, including lower Aβ and tau burdens, as well as preserved GMV. Additionally, High-EA individuals experienced a median delay of 1.9 years in the onset of significant brain atrophy among A+ individuals. These findings highlight the independent and synergistic contributions of EA-associated AD pathology and GMV alterations to longitudinal cognitive decline. Alzheimer's disease (AD) individuals with high educational attainment (EA) show slower declines in global cognition and language. EA-related slower cognitive decline is linked to reduced tau and greater gray matter volume in AD. AD individuals with high EA show a median 1.9 year delayed onset of brain atrophy.

Pediatric, adult, and late onset multiple sclerosis: Cognitive phenotypes and gray matter atrophy.

We aim to investigate cognitive phenotype distribution and MRI correlates across pediatric-, elderly-, and adult-onset MS patients as a function of disease duration. In this cross-sectional study, we enrolled 1262 MS patients and 238 healthy controls, with neurological and cognitive assessments. A subset of 222 MS patients and 92 controls underwent 3T-MRI scan for brain atrophy and lesion analysis. Multinomial probabilistic models identified likelihood of belonging to cognitive phenotypes ("preserved-cognition," "mild verbal memory/semantic fluency," "mild multi-domain," "severe attention/executive," and "severe multi-domain") and experiencing MRI abnormalities based on disease duration and age at onset. In all groups, the likelihood of "preserved-cognition" phenotype decreased, whereas "mild multi-domain" increased with longer disease duration. In pediatric- and adult-onset patients, the likelihood of "mild verbal memory/semantic fluency" phenotypes decreased with longer disease duration, and that of "severe multi-domain" increased with longer disease duration. Only in adult-onset patients, the likelihood of "severe executive/attention" phenotype increased with longer disease duration. All groups displayed escalating probabilities of cortical, thalamic, hippocampal, and deep gray matter atrophy over disease course. Compared to adult, pediatric-onset patients showed lower probability of experiencing thalamic atrophy with longer disease duration, while elderly-onset showed higher probability of experiencing cortical and hippocampal atrophy. Age at MS onset significantly influences the distribution of cognitive phenotypes and the patterns of regional gray matter atrophy throughout the disease course.