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ABSTRACT A mediation analysis approach is proposed for multiple exposures, multiple mediators, and a continuous scalar outcome under the linear structural equation modeling framework. It assumes that there exist orthogonal components that demonstrate parallel mediation mechanisms on the outcome, and thus is named principal component mediation analysis (PCMA). Likelihood‐based estimators are introduced for simultaneous estimation of the component projections and effect parameters. The asymptotic distribution of the estimators is derived for low‐dimensional data. A bootstrap procedure is introduced for inference. Simulation studies illustrate the superior performance of the proposed approach. Applied to a proteomics‐imaging dataset from the Alzheimer's disease neuroimaging initiative (ADNI), the proposed framework identifies protein deposition – brain atrophy – memory deficit mechanisms consistent with existing knowledge and suggests potential AD pathology by integrating data collected from different modalities. [ABSTRACT FROM AUTHOR]

The objectives of this study were to investigate the variable factors associated with cognitive function and cortical atrophy and estimated variable importance of those factors in affecting cognitive function and cortical atrophy in patients with EOAD and LOAD. Patients with EOAD (n = 40), LOAD (n = 34), and healthy volunteers with normal cognition were included (n = 65). All of them performed 3T MRI, [18F]THK5351 PET (THK), [18F]flutemetamol PET (FLUTE), and detailed neuropsychological tests. To investigate factors associated with neuropsychological test results and cortical thickness in each group, we conducted multivariable linear regression models, including amyloid, tau, cerebral small vessel disease markers on MRI, and vascular risk factors. Then, we estimated variable importance in associating cognitive functions and cortical thickness, using relative importance analysis. In patients with EOAD, global THK retention was the most important contributor to the model variances for most neuropsychological tests, except for memory. However, in patients with LOAD, multiple contributors beyond tau were important in explaining variance of neuropsychological tests. In analyses with mean cortical thickness, global THK retention was the main contributor in patients with EOAD, while in LOAD patients, multiple factors contributed equally to mean cortical thickness. Therefore, EOAD and LOAD may have different pathomechanistic courses. [ABSTRACT FROM AUTHOR]

In frontotemporal lobar degeneration (FTLD), pathological protein aggregation in specific brain regions is associated with declines in human-specialized social-emotional and language functions. In most patients, disease protein aggregates contain either TDP-43 (FTLD-TDP) or tau (FTLD-tau). Here, we explored whether FTLD-associated regional degeneration patterns relate to regional gene expression of human accelerated regions (HARs), conserved sequences that have undergone positive selection during recent human evolution. To this end, we used structural neuroimaging from patients with FTLD and human brain regional transcriptomic data from controls to identify genes expressed in FTLD-targeted brain regions. We then integrated primate comparative genomic data to test our hypothesis that FTLD targets brain regions linked to expression levels of recently evolved genes. In addition, we asked whether genes whose expression correlates with FTLD atrophy are enriched for genes that undergo cryptic splicing when TDP-43 function is impaired. We found that FTLD-TDP and FTLD-tau subtypes target brain regions with overlapping and distinct gene expression correlates, highlighting many genes linked to neuromodulatory functions. FTLD atrophy-correlated genes were strongly enriched for HARs. Atrophy-correlated genes in FTLD-TDP showed greater overlap with TDP-43 cryptic splicing genes and genes with more numerous TDP-43 binding sites compared with atrophy-correlated genes in FTLD-tau. Cryptic splicing genes were enriched for HAR genes, and vice versa, but this effect was due to the confounding influence of gene length. Analyses performed at the individual-patient level revealed that the expression of HAR genes and cryptically spliced genes within putative regions of disease onset differed across FTLD-TDP subtypes. Overall, our findings suggest that FTLD targets brain regions that have undergone recent evolutionary specialization and provide intriguing potential leads regarding the transcriptomic basis for selective vulnerability in distinct FTLD molecular-anatomical subtypes. [ABSTRACT FROM AUTHOR]

Neurodegenerative dementia syndromes, such as primary progressive aphasias (PPA), have traditionally been diagnosed based, in part, on verbal and non-verbal cognitive profiles. Debate continues about whether PPA is best divided into three variants and regarding the most distinctive linguistic features for classifying PPA variants. In this cross-sectional study, we initially harnessed the capabilities of artificial intelligence and natural language processing to perform unsupervised classification of short, connected speech samples from 78 pateints with PPA. We then used natural language processing to identify linguistic features that best dissociate the three PPA variants. Large language models discerned three distinct PPA clusters, with 88.5% agreement with independent clinical diagnoses. Patterns of cortical atrophy of three data-driven clusters corresponded to the localization in the clinical diagnostic criteria. In the subsequent supervised classification, 17 distinctive features emerged, including the observation that separating verbs into high- and low-frequency types significantly improved classification accuracy. Using these linguistic features derived from the analysis of short, connected speech samples, we developed a classifier that achieved 97.9% accuracy in classifying the four groups (three PPA variants and healthy controls). The data-driven section of this study showcases the ability of large language models to find natural partitioning in the speech of patients with PPA consistent with conventional variants. In addition, the work identifies a robust set of language features indicative of each PPA variant, emphasizing the significance of dividing verbs into high- and low-frequency categories. Beyond improving diagnostic accuracy, these findings enhance our understanding of the neurobiology of language processing. [ABSTRACT FROM AUTHOR]

Background and objectives: In multiple sclerosis (MS), MRI markers can measure the potential neuroprotective effects of fingolimod beyond its anti-inflammatory activity. In this study we aimed to comprehensively explore, in the real-word setting, whether fingolimod not only reduces clinical/MRI inflammatory activity, but also influences the progression of irreversible focal and whole brain damage in relapsing–remitting [RR] MS patients. Methods: The "EVOLUTION" study, a 24-month observational, prospective, single-arm, multicenter study, enrolled 261 RRMS patients who started fingolimod at 32 Italian MS centers and underwent biannual neurological assessments and annual MRI evaluations. Study outcomes included the proportions of evaluable RRMS patients achieving at 24 months: (1) no new/enlarging T2-hyperintense white matter (WM) lesions and/or clinical relapses; (2) a modified classification of "No Evidence of Disease Activity 4" ("modified NEDA-4") defined as no new/enlarging T2-hyperintense WM lesions, clinical relapses, and 6-month confirmed disability progression, and a yearly percentage lateral ventricular volume change on T2-FLAIR images < 2%; (3) less than 40% of active lesions at baseline and month 12 evolving to permanent black holes (PBHs). Results: At month 24, 76/160 (47.5%; 95% confidence interval [CI] = 39.8%;55.2%) RRMS patients had no clinical/MRI activity. Thirty-nine of 170 RRMS patients (22.9%; 95% CI = 16.6%;29.3%) achieved "modified NEDA-4" status. Forty-four of 72 RRMS patients (61.1%; 95% CI = 49.8%;72.4%) had less than 40% of active WM lesions evolving to PBHs. The study confirmed the established safety and tolerability profile of fingolimod. Discussion: By comparing our results with those from the literature, the EVOLUTION study seems to indicate a neuroprotective effect of fingolimod, limiting inflammatory activity, brain atrophy and PBH development. [ABSTRACT FROM AUTHOR]

Background and objectives: Cerebral small vessel disease (CSVD) is associated to cognitive decline and dementia. Neuroimaging changes of CSVD are highly prevalent above 80 years. Only few studies report on incidence of CSVD in high age. We have investigated the incidence and prevalence of magnetic resonance imaging (MRI) markers of CSVD and risk factors in the general older population. Methods: As part of the general population Good Aging in Skåne cohort study (GÅS), 241 persons (mean age 76.3 years) underwent two brain MRI, 3-T scanner with a mean interval of 5.9 years. The incidence of white matter hyperintensities (WMH), lacunar infarction, cerebral atrophies and cerebral microbleeds (CMB) were calculated and the relationship to risk factors analysed by a multivariate regression analysis. Medial temporal lobe atrophy (MTA) was graded according to Scheltens'18 scale and CMB were defined as having > 1 small (0.2–0.5 cm) hypointense lesion. Results: The 6-year incidence of CMB, WMH and MTA were, 19%, 17% and 13% respectively, corresponding to 170/1,000 py., 172/1,000 py., and respectively 167/1,000 py. The incidence of CSVD according to the modified STRIVE score was 33%, 169/1,000 py and the prevalence at baseline was 73%. Moderate to high intake of alcohol was related to increased incidence of MTA and higher STRIVE score. Exposure to smoking was related to higher incidence of CMB and higher STRIVE score, adjusted for other known risk factors. Conclusion: CSVD is highly prevalent in the general older population and the 6-year incidence of WMH, CMB and MTA ranges from 13 to 19 percent. The modifiable lifestyle factors: smoking, and moderate alcohol intake are related to incident CSVD. [ABSTRACT FROM AUTHOR]

Background: Digital monitoring of people with multiple sclerosis (PwMS) using smartphone-based monitoring tools is a promising method to assess disease activity and progression. Objective: To study cross-sectional and longitudinal associations between active and passive digital monitoring parameters and MRI volume measures in PwMS. Methods: In this prospective study, 92 PwMS were included. Clinical tests [Expanded Disability Status Scale (EDSS), Timed 25 Foot Walk test (T25FW), 9-Hole Peg Test (NHPT), and Symbol Digit Modalities Test (SDMT)] and structural MRI scans were performed at baseline (M0) and 12-month follow-up (M12). Active monitoring included the smartphone-based Symbol Digit Modalities Test (sSDMT) and 2 Minute Walk Test (s2MWT), while passive monitoring was based on smartphone keystroke dynamics (KD). Linear regression analyses were used to determine cross-sectional and longitudinal relations between digital and clinical outcomes and brain volumes, with age, disease duration and sex as covariates. Results: In PwMS, both sSDMT and SDMT were associated with thalamic volumes and lesion volumes. KD were related to brain, ventricular, thalamic and lesion volumes. No relations were found between s2MWT and MRI volumes. NHPT scores were associated with lesion volumes only, while EDSS and T25FW were not related to MRI. No longitudinal associations were found for any of the outcome measures between M0 and M12. Conclusion: Our results show clear cross-sectional correlations between digital biomarkers and brain volumes in PwMS, which were not all present for conventional clinical outcomes, supporting the potential added value of digital monitoring tools. [ABSTRACT FROM AUTHOR]

Background: Age represents the largest risk factor for Alzheimer's disease (AD) but is typically treated as a covariate. Still, there are similarities between brain regions affected in AD and those showing accelerated decline in normal aging, suggesting that the distinction between the two might fall on a spectrum. Objective: Our goal was to identify regions showing accelerated atrophy across the brain and investigate whether these overlapped with regions involved in AD or where related to amyloid. Methods: We used a longitudinal sample of 137 healthy older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI), who underwent magnetic resonance imaging (MRI). In addition, a total of 79 participants also had longitudinal positron emission tomography (PET) data. We computed linear-mixed effects models for brain regions declining faster than the average to investigate variability in the rate of change. Results: 23 regions displayed a 0.5 standard deviation (SD) above average decline over 2 years. Of these, 52% overlapped with regions showing similar decline in a matched AD sample. Beyond this, the left precuneus, right superior frontal, transverse temporal, and superior temporal sulcus showed accelerated decline. Lastly, atrophy in the precuneus was associated with increased amyloid load. Conclusions: Accelerated decline in normal aging might contribute to the detection of early signs of AD among healthy individuals. [ABSTRACT FROM AUTHOR]

Cross-cultural differences in the association between neuropsychiatric symptoms and Alzheimer's disease (AD) biomarkers are not well understood. This study aimed to (1) compare depressive symptoms and frequency of reported apathy across diagnostic groups of participants with normal cognition (CN), mild cognitive impairment (MCI), and dementia, as well as ethnic groups of Hispanic Americans (HA) and European Americans (EA); (2) evaluate the relationship between depression and apathy with Aβ deposition and brain atrophy. Statistical analyses included ANCOVAs, chi-squared, nonparametric tests, correlations, and logistic regressions. Higher scores on the Geriatric Depression Scale (GDS-15) were reported in the MCI and dementia cohorts, while older age corresponded with lower GDS-15 scores. The frequency of apathy differed across diagnoses within each ethnicity, but not when comparing ethnic groups. Reduced volume in the rostral anterior cingulate cortex (ACC) significantly correlated with and predicted apathy for the total sample after applying false discovery rate corrections (FDR), controlling for covariates. The EA group separately demonstrated a significant negative relationship between apathy and superior frontal volume, while for HA, there was a relationship between rostral ACC volume and apathy. Apathy corresponded with higher Aβ levels for the total sample and for the CN and HA groups. [ABSTRACT FROM AUTHOR]

The translocator protein (TSPO) has been widely investigated as a PET-imaging biomarker of neuroinflammation and, more recently, as a therapeutic target for the treatment of neurodegenerative disease. TSPO ligands have been shown to exert neuroprotective effects in vivo and in vitro models of Alzheimer's disease (AD), by reducing toxic beta amyloid peptides, and attenuating brain atrophy. Recent transcriptomic and proteomic analyses, and the generation of TSPO-KO mice, have enabled new insights into the mechanistic function of TSPO in AD. Using a multi-omics approach in both TSPO-KO- and TSPO ligand-treated mice, we have demonstrated a key role for TSPO in microglial respiratory metabolism and phagocytosis in AD. In this review, we discuss emerging evidence for therapeutic and immunomodulatory functions of TSPO in AD, and new tools for studying TSPO in the brain. • TSPO is a candidate biomarker of neuroinflammation and potential therapeutic target for Alzheimer's disease. • TSPO is functionally implicated in cellular bioenergetics, lipid and reactive oxygen species homeostasis, and apoptosis. • These functions are thought to underlie TSPO effects on Aβ clearance, cytokine levels, oxidative stress, and neuronal loss. • Despite the promising benefits of TSPO-targeted drugs, their potential use in Alheimer's has not yet been tested. [ABSTRACT FROM AUTHOR]

Pontocerebellar hypoplasia type 10 (PCH10) due to CLP1 gene mutations is characterized by structural brain anomalies, progressive microcephaly, severe intellectual and physical disabilities, and spasticity. In this follow-up study, evolution of phenotypic and neurological characteristics of patients with PCH10 is discussed. Phenotype, growth parameters, motor functions, developmental tests, spasticity assessments, functional independence assessments, electroencephalography (EEG), and brain magnetic resonance imaging (MRI) of 10 patients with PCH10 were monitored on separate examinations. Alterations were recorded. Patients were followed-up for an average of 2.83 years. The tone of the upper extremities was significantly higher than that of the lower extremities, according to Modified Ashworth Scale (MAS) values. Sixty percent of patients could sit unsupported; 20% achieved supported sitting initially but lost the ability during follow-up. Absence of grabbing or sitting was observed in 20% of patients. During follow-up, one person achieved supported sitting and one person achieved head holding. Only one patient was able to speak a few words. Cerebellar atrophy (two of 10), pons hypoplasia (four of 10), cortical atrophy (seven of 10), enlarged ventricles (10 of 10), thinning of the corpus callosum (10 of 10), hypomyelination (six of 10), and increased white matter signal intensity (six of 10) were the observed MRI findings. Progressive cerebral and cerebellar atrophy was demonstrated radiologically for the first time in a PCH10 cohort. It is of crucial importance to identify these patients promptly with the help of dysmorphic findings and spasticity being pronounced in the upper extremities. Furthermore, we note that phenotypic and neurological examination findings tend to change slightly over time. [ABSTRACT FROM AUTHOR]

Objective Autoimmune encephalitis includes a heterogeneous group of rare and complex diseases, usually presenting with severe and disabling symptoms, such as behavioral changes, cognitive deficits, and seizures. Method This report presents the case of a 26-year-old man who was diagnosed with autoimmune encephalitis following SARS-CoV-2 vaccination (<40 days). Symptoms first appeared in February 2022 with a temporal seizure, associated with confusion and memory loss. Psychiatric manifestations such as disorientation and altered thought contents emerged soon after. Results Neuroimaging testing showed signs of hypometabolism in occipital, prefrontal, and temporal regions, whereas an extensive neuropsychological assessment revealed the presence of multiple alterations in memory, executive, and visuoconstructive processes. Conclusions In this case, a combination of neuroimaging testing, psychiatric evaluation, and neuropsychological assessment provided evidence for a diagnosis of autoimmune encephalitis post-vaccination. Early recognition is essential in order to prevent clinical progression; avoid intractable epilepsy, brain atrophy, and cognitive impairment; and improve prognosis. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to explore the pathogenesis of CLCN6‐related disease and to assess whether its Cl−/H+‐exchange activity is crucial for the biological role of ClC‐6. Methods: We performed whole‐exome sequencing on a girl with development delay, intractable epilepsy, behavioral abnormities, retinal dysfunction, progressive brain atrophy, suggestive of neuronal ceroid lipofuscinoses (NCLs). We generated and analyzed the first knock‐in mouse model of a patient variant (p.E200A) and compared it with a Clcn6−/− mouse model. Additional functional tests were performed with heterologous expression of mutant ClC‐6. Results: We identified a de novo heterozygous p.E200A variant in the proband. Expression of disease‐causing ClC‐6E200A or ClC‐6Y553C mutants blocked autophagic flux and activated transcription factors EB (TFEB) and E3 (TFE3), leading to autophagic vesicle and cholesterol accumulation. Such alterations were absent with a transport‐deficient ClC‐6E267A mutant. Clcn6E200A/+ mice developed severe neurodegeneration with typical features of NCLs. Mutant ClC‐6E200A, but not loss of ClC‐6 in Clcn6−/− mice, increased lysosomal biogenesis by suppressing mTORC1‐TFEB signaling, blocked autophagic flux through impairing lysosomal function, and increased apoptosis. Carbohydrate and lipid deposits accumulated in Clcn6E200A/+ brain, while only lipid storage was found in Clcn6−/− brain. Lysosome dysfunction, autophagy defects, and gliosis were early pathogenic events preceding neuron loss. Interpretation: CLCN6 is a novel genetic cause of NCLs, highlighting the importance of considering CLCN6 mutations in the diagnostic workup for molecularly undefined forms of NCLs. Uncoupling of Cl− transport from H+ countertransport in the E200A mutant has a dominant effect on the autophagic/lysosomal pathway. ANN NEUROL 2024;96:608–624 [ABSTRACT FROM AUTHOR]

Purpose: The traditional imaging findings reported in Sturge–Weber syndrome (SWS) include endpoints of cortical injury—cortical atrophy and cortical calcifications—but also what has been termed a "leptomeningeal angiomatosis," the latter recognized and reported as a leptomeningeal enhancement on magnetic resonance imaging (MRI). The objective of this study is to demonstrate through neuropathological correlation that the "leptomeningeal angiomatosis" in patients with Sturge–Weber syndrome (SWS), represents a re-opened primitive venous network in the subarachnoid space that likely acts as an alternative venous drainage pathway, seen separately to abnormal pial enhancement. Materials and methods: Retrospective review of MR imaging and surgical pathology of patients that underwent surgery for epilepsy at a tertiary, children's hospital. A pediatric radiologist with more than 20 years of experience reviewed the MR imaging. Surgically resected brain specimens that had been sectioned and fixed in 10% paraformaldehyde for histologic processing, following processing and paraffin embedding, were cut into 5-µm unstained slides which were subsequently stained with hematoxylin and eosin (H&E). Slides were re-examined by a board-certified pediatric neuropathologist, and histologic features specifically relating to cerebral surface and vascularity were documented for correlation with MR imaging of the resected region performed prior to resection. Results: Five patients were reviewed (3 boys and 2 girls; the median age at the onset of seizures was 12 months (IQR, 7 to 45 months); the median age at surgery was 33 months (IQR, 23.5 to 56.5 months)). Surgical procedures included the following: 4, hemispherotomy (right: 2, left: 2) and 1, hemispherectomy (right). A subarachnoid space varicose network was present on both MRI and histology in 4 patients. Calcifications were seen on both MRI and histology in 3 patients. Abnormal leptomeningeal enhancement was present in 5 patients and seen separately from the subarachnoid vascular network in 4 patients. Conclusion: Histopathology confirmed the MRI findings of a subarachnoid space varicose network seen separately from leptomeningeal enhancement and presumed to represent an alternative venous drainage pathway to compensate for maldevelopment of cortical veins, the primary abnormality in SWS. No pial-based angioma was identified. [ABSTRACT FROM AUTHOR]

Background: Neuronal ceroid lipofuscinoses are a genetically heterogeneous group of inherited lysosomal storage disorders. Kufs disease is the predominant form of neuronal ceroid lipofuscinosis in adults, but it's rare and challenging to diagnose. Case description: The proband initially presented with cognitive deterioration and parkinsonian traits. At 35, he was admitted to hospital following a tonic–clonic seizure. Brain magnetic resonance imaging showed atrophy of the cerebral cortex and cerebellum, enlarged ventricles, and thinned corpus callosum. The proband's younger brother and sister were also affected, and the clinical phenotype within the family was consistent. Whole-exome Sequencing of the proband revealed a novel homozygous mutation in CLN6 (NM_017882: c.425A > G, p. Tyr142Cys). Co-segregation analysis revealed that two other affected individuals carried a homozygous mutation at the same locus, with both parents exhibiting heterozygous mutations of c.425A > G. Conclusion: Our study not only provides insights into the clinical presentation and development of the disease within the affected family but also expanded the mutational and phenotypical spectrum of the CLN6 gene. [ABSTRACT FROM AUTHOR]

Introduction: CACNA1A gene variants are correlated with different disorders, including episodic ataxia type 2, spinocerebellar ataxia type 6, and familial hemiplegic migraine type 1. Despite dystonia not being a typical manifestation of CACNA1A variants, there are reports indicating a link between this gene mutation and dystonic features. Methods: We report the case of a patient with a novel missense variant of the CACNA1A gene presenting headache, head and arm tremor, dystonia, episodic painful focal dystonic attacks, and unexplained falls. Results: A 57-year-old woman presented with a history of neck dystonia, head and arm tremor, and headaches since age 15. In 2017, she progressively developed dystonic tremor of the head and arms with an unremarkable brain MRI. In 2018 she experienced worsening of tremor and developed painful dystonic attacks, resistant to treatments including clonazepam, trihexyphenidyl, baclofen, and levodopa/benserazide. Botulinum toxin injections for neck dystonia provided limited benefit. The next-generation sequencing exam revealed a CACNA1A gene missense variant (NM_023035.2:c.1630C > T; p.Arg544Trp). In 2021 we observed a worsening of dystonia, accompanied by weight loss, mood changes, and unexplained falls. Deep brain stimulation was considered but ruled out due to cortical atrophy and mild cognitive deficits revealed by the neuropsychological examination. Discussion: Only a few studies reported dystonia as part of the clinical features in carriers of CACNA1A mutations. This case points out the relevance of a need to expand the literature on voltage-dependent P/Q-type Ca2 + channels' role in dystonia's pathogenesis and stresses the complex phenotype-genotype presentation of CACNA1A mutation. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To evaluate associations between plasma biomarkers of brain injury and MRI and cognitive measures in participants with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. RESEARCH DESIGN AND METHODS: Plasma amyloid-β-40, amyloid-β-42, neurofilament light chain (NfL), phosphorylated Tau-181 (pTau-181), and glial fibrillary acidic protein (GFAP) were measured in 373 adults who participated in the DCCT/EDIC study. MRI assessments included total brain and white matter hyperintensity volumes, white matter mean fractional anisotropy, and indices of Alzheimer disease (AD)–like atrophy and predicted brain age. Cognitive measures included memory and psychomotor and mental efficiency tests and assessments of cognitive impairment. RESULTS: Participants were 60 (range 44–74) years old with 38 (30–51) years' T1D duration. Higher NfL was associated with an increase in predicted brain age (0.51 years per 20% increase in NfL; P < 0.001) and a 19.5% increase in the odds of impaired cognition (P < 0.01). Higher NfL and pTau-181 were associated with lower psychomotor and mental efficiency (P < 0.001) but not poorer memory. Amyloid-β measures were not associated with study measures. A 1% increase in mean HbA1c was associated with a 14.6% higher NfL and 12.8% higher pTau-181 (P < 0.0001). CONCLUSIONS: In this aging T1D cohort, biomarkers of brain injury did not demonstrate an AD-like profile. NfL emerged as a biomarker of interest in T1D because of its association with higher HbA1c, accelerated brain aging on MRI, and cognitive dysfunction. Our study suggests that early neurodegeneration in adults with T1D is likely due to non-AD/nonamyloid mechanisms. [ABSTRACT FROM AUTHOR]

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. Cognitive dysfunction constitutes a core characteristic of schizophrenia spectrum disorders (SZ). The current study indicates that morphological abnormalities in frontostriatal networks are associated with deficient cognitive flexibility in SZ patients and highlight the necessity of minimizing neurodevelopmental and progressive brain atrophy in this population. [ABSTRACT FROM AUTHOR]

Intracerebral hemorrhage (ICH) induces a complex sequence of apoptotic cascades and inflammatory responses, leading to neurological impairment. Transient receptor potential vanilloid 1 (TRPV1), a nonselective cation channel with high calcium permeability, has been implicated in neuronal apoptosis and inflammatory responses. This study used a mouse ICH model and neuronal cultures to examine whether TRPV1 activation exacerbates brain damage and neurological deficits by promoting neuronal apoptosis and neuroinflammation. ICH was induced by injecting collagenase in both wild‐type (WT) C57BL/6 mice and TRPV1−/− mice. Capsaicin (CAP; a TRPV1 agonist) or capsazepine (a TRPV1 antagonist) was administered by intracerebroventricular injection 30 min before ICH induction in WT mice. The effects of genetic deletion or pharmacological inhibition of TRPV1 using CAP or capsazepine on motor deficits, histological damage, apoptotic responses, blood–brain barrier (BBB) permeability, and neuroinflammatory reactions were explored. The antiapoptotic mechanisms and calcium influx induced by TRPV1 inactivation were investigated in cultured hemin‐stimulated neurons. TRPV1 expression was upregulated in the hemorrhagic brain, and TRPV1 was expressed in neurons, microglia, and astrocytes after ICH. Genetic deletion of TRPV1 significantly attenuated motor deficits and brain atrophy for up to 28 days. Deletion of TRPV1 also reduced brain damage, neurodegeneration, microglial activation, cytokine expression, and cell apoptosis at 1 day post‐ICH. Similarly, the administration of CAP ameliorated brain damage, neurodegeneration, brain edema, BBB permeability, and cytokine expression at 1 day post‐ICH. In primary neuronal cultures, pharmacological inactivation of TRPV1 by CAP attenuated neuronal vulnerability to hemin‐induced injury, suppressed apoptosis, and preserved mitochondrial integrity in vitro. Mechanistically, CAP reduced hemin‐stimulated calcium influx and prevented the phosphorylation of CaMKII in cultured neurons, which was associated with reduced activation of P38 and c‐Jun NH2‐terminal kinase mitogen‐activated protein kinase signaling. Our results suggest that TRPV1 inhibition may be a potential therapy for ICH by suppressing mitochondria‐related neuronal apoptosis. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to assess the neuroimaging abnormalities and their progression in patients with Subacute sclerosing panencephalitis (SSPE) and identify clinical predictors of these imaging findings. Methods: This prospective observational study evaluated clinical and neuroimaging features in patients with SSPE. Patients were categorized using Dyken's criteria, Jabbour's staging system, and the definition of fulminant SSPE. They underwent comprehensive clinical assessments, cerebrospinal fluid examination, Electroencephalogram (EEG), and Magnetic Resonance Imaging (MRI) scans. Treatment involved intrathecal interferon‑α and antiepileptic medications. Functional disability was assessed using the modified Barthel index. Follow-ups were performed at 6 months, including reassessment of Modified Barthel Index (MBI) and Jabbour's staging and EEG and MRI scans. Results: The mean age was 13.9 ± 6.7 years, with males comprising 81.5% (44/54) of the cohort. Fulminant SSPE was noted in 33% (18/54) of cases. Disease duration before presentation varied significantly between fulminant and non-fulminant forms (p = 0.001). Neuroimaging abnormalities were more prevalent in JS III stage patients, with diffuse cerebral atrophy being a significant finding (p = 0.011). Basal ganglia involvement correlated with movement disorders. The 6‑month follow-up showed increased cerebral atrophy (p = 0.004). Increasing disease duration was an independent predictor of cerebral atrophy. An Intercomplex interval (ICI) of more than 10 minutes correlated with normal neuroimaging, 10 patients died within the study period, 8 of whom had fulminant SSPE. Conclusion: Parieto-occipital White matter hyperintensity (WMH) is the most prevalent and sensitive neuroimaging finding for the diagnosis of SSPE. Despite interferon treatment, cerebral atrophy progressed in both aggressive and fulminant SSPE. Increasing disease duration is an independent predictor of cerebral atrophy. [ABSTRACT FROM AUTHOR]

The pathogenic mechanisms contributing to neurological disability in progressive multiple sclerosis (PMS) are poorly understood. Cortical neuronal loss independent of cerebral white matter (WM) demyelination in myelocortical MS (MCMS) and identification of MS patients with widespread cortical atrophy and disability progression independent of relapse activity (PIRA) support pathogenic mechanisms other than cerebral WM demyelination. The three-dimensional distribution and underlying pathology of myelinated T2 lesions were investigated in postmortem MCMS brains. Postmortem brain slices from previously characterized MCMS (10 cases) and typical MS (TMS) cases (12 cases) were co-registered with in situ postmortem T2 hyperintensities and T1 hypointensities. T1 intensity thresholds were used to establish a classifier that differentiates MCMS from TMS. The classifier was validated in 36 uncharacterized postmortem brains and applied to baseline MRIs from 255 living PMS participants enrolled in SPRINT-MS. Myelinated T2 hyperintensities in postmortem MCMS brains have a contiguous periventricular distribution that expands at the occipital poles of the lateral ventricles where a surface-in gradient of myelinated axonal degeneration was observed. The MRI classifier distinguished pathologically confirmed postmortem MCMS and TMS cases with an accuracy of 94%. For SPRINT-MS patients, the MRI classifier identified 78% as TMS, 10% as MCMS, and 12% with a paucity of cerebral T1 and T2 intensities. In SPRINT-MS, expanded disability status scale and brain atrophy measures were similar in MCMS and TMS cohorts. A paucity of cerebral WM demyelination in 22% of living PMS patients raises questions regarding a primary role for cerebral WM demyelination in disability progression in all MS patients and has implications for clinical management of MS patients and clinical trial outcomes in PMS. Periventricular myelinated fiber degeneration provides additional support for surface-in gradients of neurodegeneration in MS. [ABSTRACT FROM AUTHOR]

Background Objective Methods Results Conclusions Emerging research implicates tau protein dysregulation in the pathophysiology of Huntington's disease.This study investigated skin tau quantification as a potential biomarker for Huntington's disease and its correlation with disease burden outcomes.In this cross‐sectional study, we measured skin tau levels using enzyme‐linked immunosorbent assay in 23 Huntington's disease mutations carriers and eight control subjects, examining group discrimination, correlations with genetic markers, clinical assessments, and neuroimaging data. Brain atrophy was quantified by both volumetric measurements from brain segmentation and a voxel‐based morphometry approach.Our findings showed elevated skin tau levels in manifest Huntington's disease compared with premanifest and healthy controls. These levels correlated with CAG repeat length, CAG‐Age‐Product score, composite Unified Huntington's Disease Rating Scale Total Motor Score, cognitive assessments, and disease‐related cortical and subcortical volumes, all independent of age and gender. Using skin tau levels in cluster analysis along with genetic and clinical measures led to improved subject stratification, providing enhanced distinction and validity of clusters.This study not only confirms the feasibility of skin tau quantification in Huntington's disease but also establishes its potential as a biomarker for enhancing group classification and assessing disease severity across the Huntington's disease spectrum, opening new directions in biomarker research. © 2024 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Genome-wide association studies identified variants around the BIN1 (bridging integrator 1) gene locus as prominent risk factors for late-onset Alzheimer disease. In the present study, we decreased the expression of BIN1 in mouse hippocampal neurons to investigate its neuronal function. Bin1 knockdown via RNAi reduced the dendritic arbor size in primary cultured hippocampal neurons as well as in mature Cornu Ammonis 1 excitatory neurons. The AAV-mediated Bin1 RNAi knockdown also generated a significant regional volume loss around the injection sites at the organ level, as revealed by 7-Tesla structural magnetic resonance imaging, and an impaired spatial reference memory performance in the Barnes maze test. Unexpectedly, Bin1 knockdown led to concurrent activation of both macroautophagy/autophagy and MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1). Autophagy inhibition with the lysosome inhibitor chloroquine effectively mitigated the Bin1 knockdown-induced dendritic regression. The subsequent molecular studydemonstrated that increased expression of ULK3 (unc-51 like kinase 3), which is MTOR-insensitive, supported autophagosome formation in BIN1 deficiency. Reducing ULK3 activity with SU6668, a receptor tyrosine kinase inhibitor, or decreasing neuronal ULK3 expression through AAV-mediated RNAi, significantly attenuated Bin1 knockdown-induced hippocampal volume loss and spatial memory decline. In Alzheimer disease patients, the major neuronal isoform of BIN1 is specifically reduced. Our work suggests this reduction is probably an important molecular event that increases the autophagy level, which might subsequently promote brain atrophy and cognitive impairment through reducing dendritic structures, and ULK3 is a potential interventional target for relieving these detrimental effects.Abbreviations: AV: adeno-associated virus; Aβ: amyloid-β; ACTB: actin, beta; AD: Alzheimer disease; Aduk: Another Drosophila Unc-51-like kinase; AKT1: thymoma viral proto-oncogene 1; AMPK: AMP-activated protein kinase; AP: autophagosome; BafA1: bafilomycin A1; BDNF: brain derived neurotrophic factor; BIN1: bridging integrator 1; BIN1-iso1: BIN1, isoform 1; CA1: cornu Ammonis 1; CA3: cornu Ammonis 3; CLAP: clathrin and adapter binding; CQ: chloroquine; DMEM: Dulbecco’s modified Eagle medium; EGFP: enhanced green fluorescent protein; GWAS: genome-wide association study; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MRI: magnetic resonance imaging; MTOR; mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; PET: positron emission tomography; qRT-PCR: real-time quantitative reverse transcription PCR; ROS: reactive oxygen species; RPS6KB1: ribosomal protein S6 kinase B1; TFEB: transcription factor EB; ULK1: unc-51 like kinase 1; ULK3: unc-51 like kinase 3. [ABSTRACT FROM AUTHOR]

Background: Posterior cortical atrophy (PCA) is a rare condition characterized by early-onset and progressive visual impairment. Individuals with PCA have relatively early-onset and progressive dementia, posing certain needs for early detection. Hence, this study aimed to investigate the association of alterations in outer retinal and choroidal structure and microvasculature with PCA neuroimaging and clinical features and the possible effects of apolipoprotein E(APOE) ε4 allele on outer retinal and choroidal alterations in participants with PCA, to detect potential ocular biomarkers for PCA screening. Methods: This cross-sectional study included PCA and age- and sex-matched healthy control participants from June 2022 to December 2023. All participants with PCA completed a comprehensive neurological evaluation. All participants were recorded baseline information and underwent an ophthalmic evaluation. Quantitative analyses were performed using swept-source optical coherence tomography (SS-OCT) and angiography (SS-OCTA). Adaptive optics scanning laser ophthalmoscopy (AO-SLO) was performed in some patients. In participants with PCA, the influence of APOE ε4 on outer retinal and choroidal alterations and the correlation of outer retinal and choroidal alterations with PCA neuroimaging and clinical features in participants with PCA were investigated. Results: A total of 28 participants (53 eyes) with PCA and 56 healthy control participants (112 eyes) were included in the current study. Compared with healthy control participants, participants with PCA had significantly reduced outer retinal thickness (ORT) (p < 0.001), choriocapillaris vessel density (VD) (p = 0.007), choroidal vascular index (CVI) (p = 0.005) and choroidal vascular volume (CVV) (p = 0.003). In participants with PCA, APOE ε4 carriers showed thinner ORT (p = 0.009), and increased choriocapillaris VD (p = 0.004) and CVI (p = 0.004). The PCA neuroimaging features were positively associated with the ORT, CVI and CVV. Furthermore, differential correlations were observed of PCA clinical features with the CRT, CVV and CVI. Conclusions: Our findings highlighted the association of outer retinal and choroidal alterations with PCA neuroimaging and clinical features in participants with PCA. Noninvasive SS-OCT and SS-OCTA can provide potential biomarkers for the diagnosis and management of PCA, improving awareness of PCA syndrome among ophthalmologists, neurologists, and primary care providers. [ABSTRACT FROM AUTHOR]

AbstractBackgroundMethodsResultsConclusionsCentral nervous system dysfunction is common in longstanding hereditary transthyretin amyloidosis (ATTRv) caused by the V30M (p.V50M) mutation. Neuropathology studies show leptomeningeal amyloid deposition and cerebral amyloid angiopathy (CAA). Brain MRI is widely used in the assessment of Aβ associated CAA but there are no systematic studies with brain MRI in ATTRv amyloidosis.we performed 3 T brain MRIs in 16 patients with longstanding (>14 years) ATTRV30M. We additionally retrospectively reviewed 48 brain MRIs from patients followed at our clinic. CNS symptoms and signs were systematically accessed, and MRIs were blindly reviewed for ischaemic and haemorrhagic lesions.in the prospective cohort, we found white matter hyperintensities in 8/16 patients (50%, Fazekas score> =1). There were no relevant microbleeds, large ischaemic or haemorrhagic lesions or superficial siderosis. In the retrospective cohort, microbleeds were found in 5/48 patients (10,4%), two of which with > =20 microbleeds. White matter hyperintensities were found in 20/48 cases (41.7%). White matter lesions, microbleeds and cortical atrophy were not associated with disease duration.white matter hyperintensities are common in ATTRV30M, irrespective of disease duration. Haemorrhagic lesions are rare, even in patients with longstanding disease, suggesting the existence of other risk factors. [ABSTRACT FROM AUTHOR]

AbstractIntroductionMethodResultsDiscussionMemory deficits are the primary symptom in amnestic Mild Cognitive Impairment (aMCI); however, executive function (EF) deficits are common. The current study examined EF in aMCI based upon amyloid status (A+/A−) and regional atrophy in signature areas of Alzheimer’s disease (AD).Participants included 110 individuals with aMCI (A+ = 66; A− = 44) and 33 cognitively healthy participants (HP). EF was assessed using four neuropsychological assessment measures. The cortical thickness of the AD signature areas was calculated using structural MRI data.A + had greater EF deficits and cortical atrophy relative to A − in the supramarginal gyrus and superior parietal lobule. A − had greater EF deficits relative to HP, but no difference in signature area cortical thickness.The current study found that the degree of EF deficits in aMCI are a function of amyloid status and cortical thinning in the parietal cortex. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum-associated degradation (ERAD) is a principal qualitycontrol mechanism responsible for targeting misfolded ER proteins for cytosolic degradation. Evidence suggests that impairment of ERAD contributes to neuron dysfunction and death in neurodegenerative diseases, many of which are characterized by accumulation and aggregation of misfolded proteins. However, the physiological role of ERAD in neurons remains unclear. The Sel1LHrd1 complex consisting of the E3 ubiquitin ligase Hrd1 and its adaptor protein Sel1L is the best-characterized ERAD machinery. Herein, we showed that Sel1L deficiency specifically in neurons of adult mice impaired the ERAD activity of the Sel1L-Hrd1 complex and led to disruption of ER homeostasis, ER stress and activation of the unfold protein response (UPR). Adult mice with Sel1L deficiency in neurons exhibited weight loss and severe motor dysfunction, and rapidly succumbed to death. Interestingly, Sel1L deficiency in neurons caused global brain atrophy, particularly cerebellar and hippocampal atrophy, in adult mice. Moreover, we found that cerebellar and hippocampal atrophy in these mice resulted from degeneration of Purkinje neurons and hippocampal neurons, respectively. These findings indicate that ERAD is required for maintaining ER homeostasis and the viability and function of neurons in adults under physiological conditions. [ABSTRACT FROM AUTHOR]

Background: Atrophy of white and grey matter volumes occurs early in the brains of people with multiple sclerosis (pwMS) and has great clinical relevance. In clinical trials, brain atrophy can be quantified by magnetic resonance imaging (MRI) with automated software tools. Methods: In this study, we analyze volumes of various brain regions with the software "md brain" based on routine MRI scans of 53 pwMS in a real-world setting. We compare brain volumes of pwMS with an EDSS ≥ 3.5 and a disease duration ≥ 10 years to the brain volumes of pwMS with an EDSS < 3.5 and a disease duration < 10 years as well as with or without immunotherapy. Results: pwMS with an EDSS ≥ 3.5 and a disease duration ≥ 10 years had significantly lower volumes of the total brain, the grey matter and of the frontal, temporal, parietal and occipital lobe regions as compared to pwMS with an EDSS < 3.5 and a disease duration < 10 years. Regional brain volumes were significantly lower in pwMS without immunotherapy. Conclusions: The study showed that higher EDSS, longer disease duration and absence of immunotherapy was associated with lower volumes in a number of brain regions. Further real-world studies may include larger patient cohorts in longitudinal analyses. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) exhibits heterogeneity in terms of symptoms and prognosis, likely due to diverse neuroanatomical alterations. This study employs a contrastive deep learning approach to analyze Magnetic Resonance Imaging (MRI) data from 932 PD patients and 366 controls, aiming to disentangle PD-specific neuroanatomical alterations. The results reveal that these neuroanatomical alterations in PD are correlated with individual differences in dopamine transporter binding deficit, neurodegeneration biomarkers, and clinical severity and progression. The correlation with clinical severity is verified in an external cohort. Notably, certain proteins in the cerebrospinal fluid are strongly associated with PD-specific features, particularly those involved in the immune function. The most notable neuroanatomical alterations are observed in both subcortical and temporal regions. Our findings provide deeper insights into the patterns of brain atrophy in PD and potential underlying molecular mechanisms, paving the way for earlier patient stratification and the development of treatments to slow down neurodegeneration. A contrastive deep learning analysis of MRI data in this study revealed PD-specific brain alterations, primarily in subcortical and temporal regions, which correlate with biomarkers, disease severity, and immunerelated cerebrospinal fluid proteins. [ABSTRACT FROM AUTHOR]

Brain glymphatic dysfunction is critical in neurodegenerative processes. While animal studies have provided substantial insights, understandings in humans remains limited. Recent attention has focused on the non‐invasive evaluation of brain glymphatic function. However, its association with brain parenchymal lesions in large‐scale population remains under‐investigated. In this cross‐sectional analysis of 1030 participants (57.14 ± 9.34 years, 37.18% males) from the Shunyi cohort, we developed an automated pipeline to calculate diffusion‐weighted image analysis along the perivascular space (ALPS), with a lower ALPS value indicating worse glymphatic function. The automated ALPS showed high consistency with the manual calculation of this index (ICC = 0.81, 95% CI: 0.662–0.898). We found that those with older age and male sex had lower automated ALPS values (β = −0.051, SE = 0.004, p <.001, per 10 years, and β = −0.036, SE = 0.008, p <.001, respectively). White matter hyperintensity (β = −2.458, SE = 0.175, p <.001) and presence of lacunes (OR = 0.004, 95% CI < 0.002–0.016, p <.001) were significantly correlated with decreased ALPS. The brain parenchymal and hippocampal fractions were significantly associated with decreased ALPS (β = 0.067, SE = 0.007, p <.001 and β = 0.040, SE = 0.014, p =.006, respectively) independent of white matter hyperintensity. Our research implies that the automated ALPS index is potentially a valuable imaging marker for the glymphatic system, deepening our understanding of glymphatic dysfunction. [ABSTRACT FROM AUTHOR]

• Elevated IL-6 levels correlate with reduced cortical and subcortical brain volumes. • Higher plasma IL-6 levels are linked to poorer cognitive performance. • Elevated IL-6 levels have 23–35% increased risk of all-cause dementia. • Peripheral immune activation significant in managing brain health and dementia risk. Recent studies have associated immune abnormalities with dementia. IL-6 is a crucial cytokine in inflammatory responses, and recent evidence has linked elevated IL-6 levels to changes in brain structure and cognitive decline. However, the connection between IL-6 levels, cognition, brain volumes, and dementia risk requires exploration in large prospective cohorts. This study utilized a longitudinal cohort from the UK Biobank to analyze the correlation between IL-6 expression levels, cognitive performance, and cortical and subcortical brain volumes through linear regression. Additionally, we assessed the association between IL-6 levels and long-term dementia risk using Cox regression analysis. We also used one-sample Mendelian randomization to analyze the impact of genetic predisposition of dementia on elevated IL-6 levels. A total of 50,864 participants were included in this study, with 1,391 new cases of all-cause dementia identified. Higher plasma IL-6 levels are associated with cortical and subcortical atrophy in regions such as the fusiform, thalamus proper, hippocampus, and larger ventricle volumes. IL-6 levels are negatively associated with cognitive performance in pair matching, numeric memory, prospective memory, and reaction time tests. Furthermore, elevated IL-6 levels are linked to a 23–35 % increased risk of all-cause dementia over an average follow-up period of 13.2 years. The one-sample Mendelian randomization analysis did not show associations between the genetic predisposition of dementia and elevated IL-6 levels. Increased IL-6 levels are associated with worse cognition, brain atrophy, and a heightened risk of all-cause dementia. Our study highlights the need to focus on the role of peripheral IL-6 levels in managing brain health and dementia risk. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxias (SCAs) are inherited neurodegenerative diseases characterized by loss of balance, coordination, and slurred speech. Recently, a digenic mode of inheritance of TBP/STUB1 contributing to SCA was demonstrated. The clinical manifestations of SCATBP/STUB1 include not only ataxia but also obvious cognitive and behavioral impairment. Here, we describe a Chinese family with SCATBP/STUB1 and performed a literature search for similar cases. We identified a Chinese family with SCATBP/STUB1 and compare our clinical findings with other cases described in the literature so far. Four individuals in this family have been found to carry SCATBP/STUB1, of which three have clinical manifestations. A heterozygous deletion mutation in the STIP1-homologous and U-box containing protein 1 (STUB1) gene, NM_005861.4:c433_435del(p.K145del), was identified. The proband is a 34-year-old female with progressive dementia and dysarthria. The mother and uncle of the proband first presented with motor abnormalities and gradually developed cognitive impairment. The proband and her uncle showed cerebellar atrophy on MRI. The proband's brother carried digenic variants but was asymptomatic. SCATBP/STUB1 is a novel SCA subtype. The main clinical manifestations are motor, cognitive, and behavioral abnormalities. Brain MRI shows significant cerebellar atrophy and cortical thinning. The independent segregation of TBP and STUB1 alleles should be considered when evaluating patients with cognitive impairment and ataxia. [ABSTRACT FROM AUTHOR]

Obesity is a chronic disease caused by excessive fat accumulation that impacts the body and brain health. Insufficient leptin or leptin receptor (LepR) is involved in the disease pathogenesis. Leptin is involved with several neurological processes, and it has crucial developmental roles. We have previously demonstrated that leptin deficiency in early life leads to permanent developmental problems in young adult mice, including an imbalance in energy homeostasis, alterations in melanocortin and the reproductive system and a reduction in brain mass. Given that in humans, obesity has been associated with brain atrophy and cognitive impairment, it is important to determine the long-term consequences of early-life leptin deficiency on brain structure and memory function. Here, we demonstrate that leptin-deficient (Lep Ob) mice exhibit altered brain volume, decreased neurogenesis and memory impairment. Similar effects were observed in animals that do not express the LepR (LepRNull). Interestingly, restoring the expression of LepR in 10-week-old mice reverses brain atrophy, in addition to neurogenesis and memory impairments in older animals. Our findings indicate that leptin deficiency impairs brain development and memory, which are reversible by restoring leptin signalling in adulthood. [ABSTRACT FROM AUTHOR]

Inherited glycosylphosphatidylinositol deficiency disorders (IGDs) are a group of rare multisystem disorders arising from pathogenic variants in glycosylphosphatidylinositol anchor pathway (GPI-AP) genes. Despite associating 24 of at least 31 GPI-AP genes with human neurogenetic disease, prior reports are limited to single genes without consideration of the GPI-AP as a whole and with limited natural history data. In this multinational retrospective observational study, we systematically analyse the molecular spectrum, phenotypic characteristics and natural history of 83 individuals from 75 unique families with IGDs, including 70 newly reported individuals; the largest single cohort to date. Core clinical features were developmental delay or intellectual disability (DD/ID, 90%), seizures (83%), hypotonia (72%) and motor symptoms (64%). Prognostic and biologically significant neuroimaging features included cerebral atrophy (75%), cerebellar atrophy (60%), callosal anomalies (57%) and symmetric restricted diffusion of the central tegmental tracts (60%). Sixty-one individuals had multisystem involvement including gastrointestinal (66%), cardiac (19%) and renal (14%) anomalies. Though dysmorphic features were appreciated in 82%, no single dysmorphic feature had a prevalence >30%, indicating substantial phenotypic heterogeneity. Follow-up data were available for all individuals, 15 of whom were deceased at the time of writing. Median age at seizure onset was 6 months. Individuals with variants in synthesis stage genes of the GPI-AP exhibited a significantly shorter time to seizure onset than individuals with variants in transamidase and remodelling stage genes of the GPI-AP (P = 0.046). Forty individuals had intractable epilepsy. The majority of individuals experienced delayed or absent speech (95%), motor delay with non-ambulance (64%), and severe-to-profound DD/ID (59%). Individuals with a developmental epileptic encephalopathy (51%) were at greater risk of intractable epilepsy (P = 0.003), non-ambulance (P = 0.035), ongoing enteral feeds (P < 0.001) and cortical visual impairment (P = 0.007). Serial neuroimaging showed progressive cerebral volume loss in 87.5% and progressive cerebellar atrophy in 70.8%, indicating a neurodegenerative process. Genetic analyses identified 93 unique variants (106 total), including 22 novel variants. Exploratory analyses of genotype-phenotype correlations using unsupervised hierarchical clustering identified novel genotypic predictors of clinical phenotype and long-term outcome with meaningful implications for management. In summary, we expand both the mild and severe phenotypic extremities of the IGDs, provide insights into their neurological basis, and vitally, enable meaningful genetic counselling for affected individuals and their families. [ABSTRACT FROM AUTHOR]

Background: A subgroup of people with multiple sclerosis (pwMS) will develop severe disability. The pathophysiology underlying severe MS is unknown. The comprehensive assessment of severely affected MS (CASA–MS) was a case-controlled study that compared severely disabled in skilled nursing (SD/SN) (EDSS ≥ 7.0) to less-disabled (EDSS 3.0–6.5) community dwelling (CD) progressive pwMS, matched on age-, sex- and disease-duration (DDM). Objectives: To identify neuroimaging and molecular biomarker characteristics that distinguish SD/SN from DDM–CD progressive pwMS. Methods: This study was carried at SN facility and at a tertiary MS center. The study collected clinical, molecular (serum neurofilament light chain, sNfL and glial acidic fibrillary protein, sGFAP) and MRI quantitative lesion-, brain volume-, and tissue integrity-derived measures. Statistical analyses were controlled for multiple comparisons. Results: 42 SD/SN and 42 DDM–CD were enrolled. SD/SN pwMS showed significantly lower cortical volume (CV) (p < 0.001, d = 1.375) and thalamic volume (p < 0.001, d = 0.972) compared to DDM–CD pwMS. In a logistic stepwise regression model, the SD/SN pwMS were best differentiated from the DDM–CD pwMS by lower CV (p < 0.001) as the only significant predictor, with the accuracy of 82.3%. No significant differences between the two groups were observed for medulla oblongata volume, a proxy for spinal cord atrophy and white matter lesion burden, while there was a statistical trend for numerically higher sGFAP in SD/SN pwMS. Conclusions: The CASA–MS study showed significantly more gray matter atrophy in severe compared to less-severe progressive MS. [ABSTRACT FROM AUTHOR]

Objectives: Global brain volume changes in patients with myelin oligodendrocyte glycoprotein antibody‐associated disease compared with healthy controls (HC) could be revealed by magnetic resonance imaging, but specific atrophy patterns of cortical structures and relation to cognitive impairment are not yet comprehensively known. Thus, we aimed to investigate cortical thickness differences in patients with myelin oligodendrocyte glycoprotein antibody‐associated disease compared with HC. Methods: 3‐Tesla brain magnetic resonance imaging was performed in 23 patients with myelin oligodendrocyte glycoprotein antibody‐associated disease and 49 HC for voxel‐wise group comparisons and neuropsychological testing in patients. Surface‐based morphometry with region of interest‐based surface analysis and region of interest‐based extraction of cortical thickness was performed in patients compared with HC and in patient subgroups with and without cognitive impairment. Results: Comparing patients with myelin oligodendrocyte glycoprotein antibody‐associated disease with HC, exploratory surface‐based morphometry demonstrated cortical volume reduction in pericalcarine and lingual cortical regions. Region of interest‐based surface analysis specified reduced cortical thickness in the adjacent pericalcarine and orbitofrontal regions in myelin oligodendrocyte glycoprotein antibody‐associated disease, as well as reduced temporal cortical thickness in patients with cognitive impairment (n = 10). Patients without cognitive impairment (n = 13) showed only circumscribed cortical brain volume loss compared with HC in the pericalcarine region. Interpretation: In conclusion, cortical atrophy in myelin oligodendrocyte glycoprotein antibody‐associated disease was characterized by cortical thickness reduction in the adjacent pericalcarine and orbitofrontal regions, with a tendency of temporal thickness reduction in cognitively impaired patients. [ABSTRACT FROM AUTHOR]

Wolfram syndrome 1 (WS1) is an uncommon autosomal recessive neurological disorder that is characterized by diabetes insipidus, early-onset non-autoimmune diabetes mellitus, optic atrophy, and deafness (DIDMOAD). Other clinical manifestations are neuropsychiatric symptoms, urinary tract alterations, and endocrinological disorders. The rapid clinical course of WS1 results in death by the age of 30. Severe brain atrophy leads to central respiratory failure, which is the main cause of death in WS1 patients. Mutations in the WFS1 gene, located on chromosome 4p16, account for approximately 90% of WS1 cases. The gene produces wolframin, a transmembrane glycoprotein widely distributed and highly expressed in retinal, neural, and muscular tissues. Wolframin plays a crucial role in the regulation of apoptosis, insulin signaling, and ER calcium homeostasis, as well as the ER stress response. WS1 has been designated as a neurodegenerative and neurodevelopmental disorder due to the numerous abnormalities in the ER stress-mediated system. WS1 is a devastating neurodegenerative disease that affects patients and their families. Early diagnosis and recognition of the initial clinical signs may slow the disease's progression and improve symptomatology. Moreover, genetic counseling should be provided to the patient's relatives to extend multidisciplinary care to their first-degree family members. Regrettably, there are currently no specific drugs for the therapy of this fatal disease. A better understanding of the etiology of WS1 will make possible the development of new therapeutic approaches that may enhance the life expectancy of patients. This review will examine the pathogenetic mechanisms, development, and progression of neuropsychiatric symptoms commonly associated with WS1. A thorough understanding of WS1's neurophysiopathology is critical for achieving the goal of improving patients' quality of life and life expectancy. [ABSTRACT FROM AUTHOR]

Objectives: Previous studies have shown possible choroid plexus (CP) dysfunction in Alzheimer's disease (AD) and highlighted CP enlargement on magnetic resonance imaging (MRI) as a predictive factor of AD. However, few studies have assessed the relationship between CP volume (CPV) and mild cognitive impairment (MCI). In this large elderly population study, we investigated the changes in CPV in patients with MCI using MRI above 65 years. Methods: This cross-sectional study included 2144 participants (median age, 69 years; 60.9% females) who underwent 3T MRI; they were grouped as 218 MCI participants and 1904 cognitively healthy controls. The total intracranial volume (ICV), total brain volume (TBV), CPV, hippocampal volume (HV), and lateral ventricle volume (LVV) were calculated. Results: CPV/ICV was a significant independent predictor of MCI (p < 0.01) after adjusting for potential confounders (age, sex, hypertension, hyperlipidemia, diabetes, and education level). The CPV/ICV ratio was also a significant independent predictor of MCI after adjusting for the TBV/ICV ratio (p = 0.022) or HV/ICV ratio (p = 0.017), in addition to potential confounders. The CPV was significantly correlated with the LVV (r = 0.97, p < 0.01). Conclusion: We identified a relationship between CPV and MCI, which could not be explained by the degree of brain atrophy. Our results support CP dysfunction in MCI. Clinical relevance statement: Choroid plexus volume measurement may serve as a valuable imaging biomarker for diagnosing and monitoring mild cognitive impairment. The enlargement of the choroid plexus, independent of brain atrophy, suggests its potential role in mild cognitive impairment pathology. Key Points: • The study examines choroid plexus volume in relation to cognitive decline in elderly. • Enlarged choroid plexus volume independently indicates mild cognitive impairment presence. • Choroid plexus volume could be a specific biomarker for early mild cognitive impairment diagnosis. [ABSTRACT FROM AUTHOR]

Objectives: This study investigates the influence of normal cohort (NC) size and the impact of different NCs on automated MRI-based brain atrophy estimation. Methods: A pooled NC of 3945 subjects (NCpool) was retrospectively created from five publicly available cohorts. Voxel-wise gray matter volume atrophy maps were calculated for 48 Alzheimer's disease (AD) patients (55–82 years) using veganbagel and dynamic normal templates with an increasing number of healthy subjects randomly drawn from NCpool (initially three, and finally 100 subjects). Over 100 repeats of the process, the mean over a voxel-wise standard deviation of gray matter z-scores was established and plotted against the number of subjects in the templates. The knee point of these curves was defined as the minimum number of subjects required for consistent brain atrophy estimation. Atrophy maps were calculated using each NC for AD patients and matched healthy controls (HC). Two readers rated the extent of mesiotemporal atrophy to discriminate AD/HC. Results: The maximum knee point was at 15 subjects. For 21 AD/21 HC, a sufficient number of subjects were available in each NC for validation. Readers agreed on the AD diagnosis in all cases (Kappa for the extent of atrophy, 0.98). No differences in diagnoses between NCs were observed (intraclass correlation coefficient, 0.91; Cochran's Q, p = 0.19). Conclusion: At least 15 subjects should be included in age- and sex-specific normal templates for consistent brain atrophy estimation. In the study's context, qualitative interpretation of regional atrophy allows reliable AD diagnosis with a high inter-reader agreement, irrespective of the NC used. Clinical relevance statement: The influence of normal cohorts (NCs) on automated brain atrophy estimation, typically comparing individual scans to NCs, remains largely unexplored. Our study establishes the minimum number of NC-subjects needed and demonstrates minimal impact of different NCs on regional atrophy estimation. Key Points: • Software-based brain atrophy estimation often relies on normal cohorts for comparisons. • At least 15 subjects must be included in an age- and sex-specific normal cohort. • Using different normal cohorts does not influence regional atrophy estimation. [ABSTRACT FROM AUTHOR]

In older patients, delirium after surgery is associated with long-term cognitive decline (LTCD). The neural substrates of this association are unclear. Neurodegenerative changes associated with dementia are possible contributors. We investigated the relationship between brain atrophy rates in Alzheimer's disease (AD) and cognitive aging signature regions from magnetic resonance imaging before and one year after surgery, LTCD assessed by the general cognitive performance (GCP) score over 6 years post-operatively, and delirium in 117 elective surgery patients without dementia (mean age = 76). The annual change in cortical thickness was 0.2(1.7) % (AD-signature p = 0.09) and 0.4(1.7) % (aging-signature p = 0.01). Greater atrophy was associated with LTCD (AD-signature: beta(CI) = 0.24(0.06–0.42) points of GCP/mm of cortical thickness; p < 0.01, aging-signature: beta(CI) = 0.55(0.07–1.03); p = 0.03). Atrophy rates were not significantly different between participants with and without delirium. We found an interaction with delirium severity in the association between atrophy and LTCD (AD-signature: beta(CI) = 0.04(0.00–0.08), p = 0.04; aging-signature: beta(CI) = 0.08(0.03–0.12), p < 0.01). The rate of cortical atrophy and severity of delirium are independent, synergistic factors determining postoperative cognitive decline in the elderly. • Postoperative delirium is an independent risk factor for dementia. • Cortical brain atrophy may represent a substrate of the link delirium-dementia. • Patients with more severe delirium and greater atrophy had faster cognitive decline. • Delirium and cortical atrophy increase the risk of postoperative cognitive decline. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) and dementia are major global public health issues and share common risk factors, especially after the age of 65 and regardless of the presence of stroke. Despite accounting for potential confounders, AF appears to be an independent risk factor for cognitive decline and dementia. The mechanisms are likely to be multifactorial and may include AF-related ischemic stroke, cerebral hypoperfusion, microbleeds, systemic inflammation, genetic factors, and small vessel disease, leading to brain atrophy and white matter damage. The early aggressive management of AF and comorbidities may reduce the risk of dementia. Indeed, the early detection of AF-related cognitive impairment should allow for the early implementation of measures to prevent the development of dementia, mainly through integrative approaches involving the correction of risk factors and maintenance of rhythm control. Well-designed prospective studies are needed to determine whether early detection and AF treatment can prevent dementia and identify whether optimal integrative measures are effective in preventing cognitive impairment and dementia. [ABSTRACT FROM AUTHOR]

Arguably, the most important parameter in treating cognitive decline associated with Alzheimer's disease is the length of time in which improvement, if achieved at all, is sustained. However, monotherapies such as donepezil and memantine are associated with a more rapid decline than no treatment in patients over multi-year follow-ups. Furthermore, anti-amyloid antibody treatment, which at best simply slows decline, is associated with accelerated cerebral atrophy, resulting in earlier dementia-associated brain volumes for those treated at the MCI stage than untreated patients. In contrast, a precision medicine approach, in which the multiple potential drivers of cognitive decline are identified for each patient and then targeted with a personalized protocol (such as ReCODE), has led to documented improvements in patients with cognitive decline, but long-term follow-up (>5 years) has not been reported previously. Therefore, here, we report sustained cognitive improvement, in some cases for over a decade, in patients treated with a precision medicine protocol—something that has not been reported in patients treated with anti-cholinesterase, glutamate receptor inhibitory, anti-amyloid, or other therapeutic methods. These case studies warrant long-term cohort studies to determine how frequently such sustained cognitive improvements occur in patients treated with precision medicine protocols. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a devastating neurologic condition characterized by brain atrophy and neuronal loss, posing a significant global health challenge. Early detection is paramount to impede its progression. This study aims to construct an optimized deep learning (DL) framework for early AD detection and classification using magnetic resonance images (MRI) scans. The classification task involves distinguishing between four AD stages: mild demented (MD), very mild demented (VmD), moderate demented (MoD), and non-demented (ND). To achieve effective classification, three DL models (VGG16, InceptionV3, and ResNet50) are implemented and fine-tuned. A systematic evaluation is conducted to optimize hyper-parameters, with extensive experimentation. The results demonstrate superior classification performance of the customized DL models compared to state-of-the-art methods. Specifically, visual geometry group 16 (VGG16) achieves the highest accuracy of 95.85%, followed by ResNet50 with 89.38%, while InceptionV3 yields the lowest accuracy of 87.23%. This study highlights the critical role of selecting appropriate DL models and customizing them for accurate AD detection and classification across various stages, offering significant insights for advancing clinical diagnosis and treatment strategies. [ABSTRACT FROM AUTHOR]

Inflammation is an important factor in Alzheimer's disease (AD). An NMR measurement in plasma, glycoprotein acetyls (GlycA), captures the overall level of protein production and glycosylation implicated in systemic inflammation. With its additional advantage of reducing biological variability, GlycA might be useful in monitoring the relationship between peripheral inflammation and brain changes relevant to AD. However, the associations between GlycA and these brain changes have not been fully evaluated. Here, we performed Spearman's correlation analyses to evaluate these associations cross-sectionally and determined whether GlycA can inform AD-relevant longitudinal measurements among participants in the Alzheimer's Disease Neuroimaging Initiative (n = 1506), with additional linear models and stratification analyses to evaluate the influences of sex or diagnosis status and confirm findings from Spearman's correlation analyses. We found that GlycA was elevated in AD patients compared to cognitively normal participants. GlycA correlated negatively with multiple concurrent regional brain volumes in females diagnosed with late mild cognitive impairment (LMCI) or AD. Baseline GlycA level was associated with executive function decline at 3–9 year follow-up in participants diagnosed with LMCI at baseline, with similar but not identical trends observed in the future decline of memory and entorhinal cortex volume. Results here indicated that GlycA is an inflammatory biomarker relevant to AD pathogenesis and that the stage of LMCI might be relevant to inflammation-related intervention. [ABSTRACT FROM AUTHOR]

AbstractBackground: Knowledge is still lacking regarding the preferred method for evaluation of learning in the Rey Auditory Verbal Learning Test (RAVLT). Validity of different methods was examined by the effect size in differentiating diagnostic stages in memory clinic patients versus healthy adults and the strength of association between RAVLT performance and brain atrophy. Method: The study included individuals with dementia (n = 247), Mild Cognitive Impairment (MCI, n = 709), Subjective Cognitive Impairment (SCI, n = 175) and cognitively unimpaired adults serving as healthy controls (HC, n = 102). All patients went through a comprehensive clinical examination and neuropsychological assessment of cognition including episodic memory gauged with RAVLT and brain imaging of medial temporal atrophy, cortical atrophy, and white matter hyperintensity. Results: The standard method for evaluation of learning in RAVLT (summed score over five trials) together with the late learning method (mean of trials 4 and 5) were the two most powerful methods according to group differentiation (discriminant validity). Both methods also showed considerable association with medial temporal atrophy (construct validity). The initial RAVLT performance represented by results on trial 1 and the constant in regression analysis with the power function provided information regarding attention that was important for the separation of SCI and HC. Conclusions: The most favorable clinical utility was indicated by discriminant and construct validity by total learning (standard method) including both attention- and learning-related parts and late learning of RAVLT performance, while theoretical understanding of mental processes involved in RAVLT performance was provided by the distinction between initial versus the subsequent learning performance. [ABSTRACT FROM AUTHOR]

The principles of cerebrospinal fluid (CSF) production, circulation and outflow and regulation of fluid volumes and pressures in the normal brain are summarised. Abnormalities in these aspects in intracranial hypertension, ventriculomegaly and hydrocephalus are discussed. The brain parenchyma has a cellular framework with interstitial fluid (ISF) in the intervening spaces. Framework stress and interstitial fluid pressure (ISFP) combined provide the total stress which, after allowing for gravity, normally equals intracerebral pressure (ICP) with gradients of total stress too small to measure. Fluid pressure may differ from ICP in the parenchyma and collapsed subarachnoid spaces when the parenchyma presses against the meninges. Fluid pressure gradients determine fluid movements. In adults, restricting CSF outflow from subarachnoid spaces produces intracranial hypertension which, when CSF volumes change very little, is called idiopathic intracranial hypertension (iIH). Raised ICP in iIH is accompanied by increased venous sinus pressure, though which is cause and which effect is unclear. In infants with growing skulls, restriction in outflow leads to increased head and CSF volumes. In adults, ventriculomegaly can arise due to cerebral atrophy or, in hydrocephalus, to obstructions to intracranial CSF flow. In non-communicating hydrocephalus, flow through or out of the ventricles is somehow obstructed, whereas in communicating hydrocephalus, the obstruction is somewhere between the cisterna magna and cranial sites of outflow. When normal outflow routes are obstructed, continued CSF production in the ventricles may be partially balanced by outflow through the parenchyma via an oedematous periventricular layer and perivascular spaces. In adults, secondary hydrocephalus with raised ICP results from obvious obstructions to flow. By contrast, with the more subtly obstructed flow seen in normal pressure hydrocephalus (NPH), fluid pressure must be reduced elsewhere, e.g. in some subarachnoid spaces. In idiopathic NPH, where ventriculomegaly is accompanied by gait disturbance, dementia and/or urinary incontinence, the functional deficits can sometimes be reversed by shunting or third ventriculostomy. Parenchymal shrinkage is irreversible in late stage hydrocephalus with cellular framework loss but may not occur in early stages, whether by exclusion of fluid or otherwise. Further studies that are needed to explain the development of hydrocephalus are outlined. [ABSTRACT FROM AUTHOR]

Background Case Presentation Conclusions Rasmussen's encephalitis (RE) is a rare autoimmune encephalopathy typically manifesting in early childhood, causing unilateral autoimmune inflammation of the cerebral cortex, leading to progressive neurological deficits, notably focal epileptic seizures. The late‐onset variant of RE in adults progresses slower and presents atypical features. Despite extensive research, the etiology remains elusive, hindering accurate diagnosis and treatment options.We present a biopsy‐confirmed late‐onset variant of RE case in a 71‐year‐old man with a disease course of 12 years. After the initiation of intravenous immunoglobulin therapy and immunosuppressive treatment, disease stabilization was achieved, as evidenced by clinical assessments and imaging. Initially, the affected hemisphere swelled hyperacutely, followed by years of atrophic encephalopathy stabilizing into a residual state, with emerging focal disease signs in the contralateral hemisphere. Multimodal rehabilitation and immune therapy attenuated brain atrophy and reduced signal enhancement.Late‐onset variant of RE rehabilitation remains underdeveloped, focusing on symptom management and functional recovery post‐surgery. Longitudinal imaging is crucial for monitoring immune therapy response in clinical practice. [ABSTRACT FROM AUTHOR]

Background: Post-stroke psychosis (PSP) is a rare but serious neuropsychiatric condition characterized by delusions and/or hallucinations following a stroke. Despite its impact on prognosis and quality of life, PSP remains underdiagnosed and undertreated, with limited data on its prevalence and risk factors. The purpose of this study is to assess the prevalence and determinants of post-stroke psychosis (PSP), as well as to compare PSP and non-PSP patients in terms of improvement and daily living outcomes. This nested case–control study included 2,624 acute stroke patients from a university hospital between May 2017 and April 2022. Patients who developed PSP within 6 months post-stroke were identified as cases (n = 108), and 119 patients without PSP were randomly selected as controls. Comprehensive assessments included clinical, laboratory, and imaging evaluations at baseline. After 6 months, follow-up evaluations were conducted, including neurological examinations, psychiatric assessments, and stroke severity assessments using the Barthel index (BI). The psychiatric assessments included the Hamilton Depression Rating Scale for depression and the Mini-Mental State Examination for cognitive status. Results: The prevalence of PSP was 5.4%. risk factors significantly associated with PSP included older age, male patients, lower education level (≤ 5 years), hemiplegia, sphincter affection, cortical lesion, brain atrophy, small vessel disease, ischemic stroke, post-stroke dementia, and seizures. Non-specified psychosis and delusional disorder were the most common psychosis subtypes. There was a significantly higher percentage of excellent patients in the non-PSP group compared to those who had PSP regarding the observed improvement in the patient's condition. Also, there is a higher percentage of deteriorated patients in the PSP group (46.6%) compared to another group (18.9%) regarding BI. Conclusion: PSP is a prevalent post-stroke complication associated with distinct risk factors and poor functional outcomes. Early screening and identification of high-risk patients, along with multidisciplinary management strategies, are crucial for optimizing recovery and quality of life in stroke survivors. [ABSTRACT FROM AUTHOR]

Wilson's disease (WD) is a genetic disorder of copper metabolism with pathological copper accumulation in many organs, resulting in clinical symptoms, mostly hepatic and neuropsychiatric. As copper accumulates in the brain during WD, and almost 50% of WD patients at diagnosis present with neurological symptoms, neuroimaging studies (especially brain magnetic resonance imaging (MRI)) are part of WD diagnosis. The classical sequences (T1, T2, and fluid-attenuated inversion recovery) were used to describe brain MRI; however, with the development of neuroradiology, several papers proposed the use of new MRI sequences and techniques like susceptibility-weighted images, T2*, diffusion MRI, tractography, volumetric assessment and post-processing brain MRI analysis of paramagnetic accumulation—quantitative susceptibility mapping. Based on these neuroradiological data in WD, currently, brain MRI semiquantitative scale and the pathognomonic neuroradiological brain MRI signs in WD were proposed. Further, the volumetric studies and brain iron accumulation MRI analysis suggested brain atrophy and iron accumulation as biomarkers of neurological WD disease severity. All these results highlight the significance of brain MRI examinations in WD. Due to the extreme progress of these studies, based on the available literature, the authors present the current state of knowledge about the significance, practical aspects, and future directions of brain MRI in WD. [ABSTRACT FROM AUTHOR]