Brain最新文献

Mutations in the SNCA gene encoding α-synuclein (α-syn) underlie familial early-onset Parkinson's disease (PD). Pathological α-syn deposition may commence decades prior to the emergence of cardinal motor symptoms. Long-term investigation of brain and behavioral development in an SNCA-A53T transgenic macaque model offers critical insights into PD progression. In this study, we systematically characterized SNCA-A53T transgenic rhesus monkeys through multimodal assessments. Our results showed that these transgenic monkeys exhibited phosphorylated α-syn aggregation patterns and dopaminergic degeneration resembling PD patients. Progressive motor and cognitive deficits were observed in transgenic monkeys with aging. Polysomnographic analysis revealed REM sleep behavior disorder manifestations in transgenic animals. Four-year longitudinal MRI tracking demonstrated abnormal developmental patterns of cortical surface area alongside thickness and volume alterations. Single-cell transcriptome revealed that astrocyte-specific gene dysregulation and cell loss contribute to brain atrophy in transgenic monkeys. Cortical and subcortical gray matter regions showing volume reduction were functionally associated with behavioral deficits and differentiated transgenic animals from wild-type controls. Collectively, this comprehensive study provides evidence that SNCA-A53T transgenic monkeys recapitulate PD pathophysiology while demonstrating the utility of longitudinal monitoring in genetically engineered nonhuman primates for tracking neurodegenerative disease progression.

The dystonin gene (DST) encodes three major isoforms, DST-a, DST-b and DST-e. Biallelic pathogenic variants in DST have previously been associated with two allelic monogenic disorders: hereditary sensory and autonomic neuropathy type VI (caused by a loss of DST-a) and epidermolysis bullosa simplex 3 (caused by a loss of DST-e). We investigated patients diagnosed with congenital myopathy using exome or genome sequencing. In 19 affected individuals from 14 unrelated families, we identified nine different variants in biallelic state located in exons 40-41, specific to DST-b. Affected individuals presented with severe neonatal myopathy characterized by arthrogryposis, hypotonia and dilated cardiomyopathy. Postnatal CPAP ventilation was required in nine patients, and seven died within the first three years of life. Survivors showed an improvement of symptoms, with the oldest three patients, now over 25 years old, exhibiting normal cognition and being ambulatory. RNA analyses demonstrated that transcripts encoding DST-b are predominantly expressed in skeletal muscle, heart tissue and cultured fibroblasts, but not in brain, matching the phenotypic spectrum. Patient-derived fibroblasts exhibited reduced DST mRNA expression. Proteomic analysis confirmed a reduction of DST protein levels due to an absence of the DST-b isoform. Muscle biopsies from four patients aged 1 month to 3 years revealed mild, non-specific myopathic changes. Ultrastructural analysis in three individuals showed mild and focal myofibrillar disruption and non-specific undulating nuclear membranes, with these changes observed in two cases each. Additionally, we identified two homozygous variants affecting both DST-a and DST-b isoforms in four patients from two unrelated families; all presented with severe arthrogryposis and died intrauterine or shortly after birth. Genotype-phenotype correlation in these patients and previously published cases with respective variants resulted in the definition of a DST-associated lethal congenital contracture syndrome. Our findings demonstrate that biallelic variants exclusively affecting DST-b cause an autosomal recessive congenital myopathy. Variants that also impact DST-a besides DST-b result in a more severe, lethal congenital contracture syndrome. The location of the variant within DST allows for phenotype prediction. We propose redefining DST as a disease-associated gene linked to four distinct allelic disease phenotypes.

Parkinson's disease is a progressive neurodegenerative disorder characterized by motor dysfunction, dopaminergic neuronal loss in the substantia nigra and abnormal accumulation of α-synuclein Lewy bodies. Research suggests that the cerebrovascular system plays a role in fluid dynamics, waste clearance and removal of abnormal proteins. Imaging studies show that this waste clearance system, known as the glymphatic system, is disrupted in Parkinson's disease, highlighting its involvement in the disease. This immunohistochemical human brain tissue study quantified changes in the cerebrovascular system (perivascular space, string vessels, pericytes, aquaporin-4 and astrocytes) in Parkinson's disease (n = 18) cases with variable disease durations (median = 14 years, range = 19 years) compared with age- and post-mortem-matched (P > 0.05) control cases (n = 7). Analysis was carried out in brain regions variably affected by cell loss (substantia nigra) and protein deposition (substantia nigra and medial temporal cortex). The occipital cortex was included because this region is not affected by cell loss or protein deposition. Group differences were analysed, and the relationship with protein deposition (Lewy body stage, amyloid score and neurofibrillary tangle score) was assessed. Although total astrocyte density did not change (P > 0.05), Parkinson's disease cases exhibited reduced aquaporin-4 in astrocytic endfeet and enlargement of the arteriolar and venular perivascular space. Significant changes in the capillary network were also observed, with increased presence of string vessels (P < 0.001) and pericyte loss (P < 0.001), changes likely to impact blood flow and its regulation. The increased presence of string vessels was significantly correlated with disease duration (P < 0.05), especially in the occipital cortex. The occipital cortex demonstrated the greatest decreases in pericytes (P < 0.001) and aquaporin-4 mislocalization (P < 0.05), and changes in pericyte density were also significant in the substantia nigra. In contrast, these changes were not significant in the medial temporal cortex despite protein deposition in this region. Although no Lewy pathology was detected in the occipital cortex, there was a positive relationship between Lewy body stage and perivascular space size (ρ = 0.6, P < 0.05). These findings reveal progressive, region-specific alterations in the cellular components of the glymphatic system and vascular integrity in Parkinson's disease. Notably, the correlation between increased presence of string vessels and disease duration, even in a region unaffected by protein deposition, suggests that vascular changes might play an important role in disease progression. These results emphasize the need for further investigation into the interplay between regional vascular changes and Parkinson's disease progression, which might offer new insights for therapeutic strategies.

Deep brain stimulation (DBS) of the subthalamic nucleus improves motor symptoms in patients with Parkinson's disease. Using functional MRI, optimal DBS response networks have been characterized. However, neural activity associated with Parkinsonian symptoms is magnitudes faster than what can be resolved by this method. Although both spatial and temporal domains of these networks appear crucial, no single study has yet investigated both domains simultaneously. Here, we aimed at closing this gap by analysing electrophysiological data from a total of n = 127 hemispheres. Using subthalamic local field potentials that were recorded concurrently alongside whole-brain magnetoencephalography in a multi-centre cohort of patients who underwent subthalamic DBS for the treatment of Parkinson's disease (n = 100 hemispheres), we analysed the DBS response network in both spatial and temporal domains. In every cortical vertex, cortico-subthalamic coupling was correlated with stimulation outcomes. This network spatially resembled functional MRI-based findings (R = 0.40, P = 0.039) and explained significant amounts of variance in clinical outcomes (βstd = 0.30, P = 0.002), whereas theta-alpha and low beta coupling did not show significant associations with DBS response (theta-alpha: βstd = -0.02, P = 0.805; low beta: βstd = -0.08, P = 0.426). The 'optimal' high beta coupling map was robust when subjected to various cross-validation designs (10-fold cross-validation: R = 0.29, P = 0.009; split-half design: R = 0.31, P = 0.026) and was able to predict outcomes across DBS centres [R = 0.74; P(1) = 8.9 × 10-5]. We identified a DBS response network that resembles the previously defined MRI network and operates in the high beta band. Maximal connectivity to this network was associated with optimal DBS outcomes and was able to cross-predict clinical improvements across DBS surgeons and centres.

Childhood-onset movement disorders are clinically and genetically heterogeneous, with over 500 implicated genes. Standard clinical genetic testing, including exome sequencing, has limited sensitivity for certain variants, including repeat expansions, structural variants (SVs), copy number variants (CNVs), and deep intronic changes. We evaluated the diagnostic utility of short-read whole genome sequencing (srWGS) and, in selected cases, long-read genome sequencing (lrWGS) in a real-world cohort of children and young adults with early-onset progressive movement disorders and prior nondiagnostic genetic testing. One hundred individuals (<30 years) with progressive movement disorders with a suspected genetic etiology were recruited from a tertiary pediatric movement disorders program. All had prior nondiagnostic testing. SrWGS (Illumina NovaSeq 6000) assessed single nucleotide variants (SNVs), CNVs, SVs, and repeat expansions; lrWGS (Pacific Biosciences) was applied to select unsolved trios. Variants were reviewed by a multidisciplinary team using standard variant interpretation guidelines and phenotype correlation. A molecular diagnosis was achieved in 27% (27/100) of cases, and candidate variants were identified in an additional 33% (33/100). Among solved cases, 81.5% (22/27) were identified from exome-level data, while 18.5% (5/27) required genome-level analysis to detect variants such as repeat expansions in HTT and FXN, an intragenic duplication in MECP2, an Alu insertion in ATM, and a deletion in FA2H. Genome-level analysis contributed an additional diagnostic yield of 5% (5/100) only. Notably, in 33.3% (9/27) of solved cases, variants had been previously reported but not recognized as diagnostic. LrWGS of 14 unsolved trios did not yield additional diagnoses. SrWGS provided a modest incremental yield over exome sequencing in early-onset movement disorders, with most diagnoses achieved through reanalysis of exome-level data. Findings highlight the importance of iterative variant interpretation and the need for improved analytic pipelines to fully realize the potential of genome sequencing.

Human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic, progressive neuroinflammatory disease with no effective treatment. In this study, we investigated whether dimethyl fumarate (DMF), an immunomodulatory agent approved for treating multiple sclerosis, exerts therapeutic effects relevant to HAM/TSP. Peripheral blood mononuclear cells (PBMCs) from 16 people living with HAM/TSP were used to evaluate the effects of DMF on cell viability, spontaneous proliferation, inflammatory cytokine production and HTLV-1 proviral load (PVL). DMF significantly inhibited lymphocyte proliferation in a concentration-dependent manner, with reductions of 42.1% at 10 µM, 56.3% at 25 µM, 60.6% at 50 µM and 69.9% at 100 µM. This suppressive effect was particularly evident in CD8+ T cells, CD4+ T cells and HTLV-1-infected CD4+ T cells. Furthermore, DMF reduced the production of interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) released from these proliferating cells. A reduction in PVL was also observed in a subset of ex vivo PBMC cultures derived from individuals with HAM/TSP exhibiting high viral proliferative activity. These results suggest that DMF suppresses pathogenic immune activation in HAM/TSP and may therefore represent a promising therapeutic candidate for this disabling neuroinflammatory disorder.