Annals of Neurology最新文献

Objective: Progressive Supranuclear Palsy (PSP) is a severe neurodegenerative disease characterized by tangles of hyperphosphorylated tau protein and tufted astrocytes. Developing treatments for PSP is challenging due to the lack of disease models reproducing its key pathological features. This study aimed to model sporadic PSP-Richardson's syndrome (PSP-RS) using multi-donor midbrain organoids (MOs).

Methods: The MOs were generated by pooling induced pluripotent stem cells (iPSCs) from 4 patients with sporadic probable PSP-RS and compared them with MOs from 3 healthy control (HC) subjects. We performed comprehensive analyses of MOs over 120 days to assess neuronal death, reactive gliosis, and the accumulation of 4R-tau and hyperphosphorylated tau forms (pThr231, pSer396, pThr181, and pSer202/pThr205 [AT8]) using immunofluorescence microscopy and Western blot. On day 90, immunohistochemical analysis using pSer396 and AT8 antibodies was conducted to assess disease pathology.

Results: PSP-derived MOs showed progressive size reduction compared with HC-derived MOs, linked to upregulated apoptosis-related mRNA markers. Dopaminergic neuron degeneration was marked by decreased tyrosine hydroxylase (TH) and increased neurofilament light chain (NfL). Immunofluorescence and Western blot revealed accumulation of all investigated tau forms with a peak at 90 days, along with a significant rise in GFAP-positive cells in PSP-derived MOs. Immunochemistry confirmed typical PSP histological alterations, such as neurofibrillary tangles and tufted-shaped astrocytes, absent in HC-derived organoids.

Interpretation: We developed a robust in vitro PSP model reproducing the key molecular and histologic features of the disease. This result holds promise for advancing basic and clinical research in PSP, paving the way for in vitro molecular diagnosis and identification of novel therapeutic targets. ANN NEUROL 2025.

Objective: We aimed to evaluate the diagnostic accuracy of heparin-binding protein (HBP) in cerebrospinal fluid for the diagnosis of bacterial meningitis in patients with a suspected central nervous system infection.

Methods: This prospective multicenter cohort study determined the diagnostic accuracy of HBP in cerebrospinal fluid (CSF) for bacterial meningitis among a cohort of consecutive patients with a suspected central nervous infection. The final clinical diagnosis was considered the reference standard. The results were validated in a separate cohort.

Results: A total of 631 Dutch patients were evaluated for the current study, of which 73 (12%) had a final diagnosis of bacterial meningitis. For the differentiation of bacterial meningitis from all other disorders, diagnostic accuracy was high with an area under the curve (AUC) of 0.98 (95% confidence interval [CI] 0.96-1.00). With the proposed cutoff of 5.2 ng/ml, sensitivity was 97% with a specificity of 96%. In the population of patients with a CSF leukocyte count of 5-1,000/mm³, the AUC was 0.96 (95% CI 0.87-1.00), outperforming CSF leukocytes (AUC 0.88 [95% CI 0.79-0.97]). Combining HBP with CSF C-reactive protein (CRP) significantly increased accuracy in this population and reached a 100% sensitivity (AUC 1.00 [95% CI 0.99-1.00], cutoff 0.07, sensitivity 100%, specificity 96%). These results remained robust in an external validation cohort of 120 Danish patients (AUC 0.97 [95% CI 0.93-1.00]).

Interpretation: HBP can correctly distinguish bacterial meningitis from other disorders. It can be of additional value to current diagnostics in cases where CSF leukocyte count is relatively low, particularly when combined with CSF CRP. ANN NEUROL 2025.

The association between prolonged febrile seizure and long-term neurological sequelae in otherwise healthy children remains unclear. We conducted a retrospective cohort study using a Japanese nationwide medical database. In the cohort of 38,465 children with febrile seizures, 610 and 31,157 were classified into the prolonged and non-prolonged groups, respectively. Within a median of 2.70 years of follow-up, the risk of subsequent epilepsy was significantly higher in the prolonged febrile seizure group (hazard ratio, 3.99; 95% confidence interval, 2.40-6.64). The risk of neurodevelopmental disorders was similar between the two groups (hazard ratio, 1.39; 95% confidence interval, 1.00-1.79). ANN NEUROL 2025.

Objective: Despite diagnostic criteria refinements, Parkinson's disease (PD) clinical diagnosis still suffers from a not satisfying accuracy, with the post-mortem examination as the gold standard for diagnosis. Seminal clinicopathological series highlighted that a relevant number of patients alive-diagnosed with idiopathic PD have an alternative post-mortem diagnosis. We evaluated the diagnostic accuracy of PD comparing the in-vivo clinical diagnosis with the post-mortem diagnosis performed through the pathological examination in 2 groups.

Methods: In this retrospective case-control study, patients and healthy subjects who consented to the post-mortem pathological diagnosis at the UK Brain Bank were consecutively enrolled from the UK Brain Bank. Medical records were reviewed to classify participants and performance metrics were further calculated using neuropathological diagnosis as the gold standard.

Results: Four thousand five hundred seventy one subjects were eligible for the study. The clinical diagnosis group was: 1,048 Parkinson's patients and 1,242 healthy subjects. Pathology diagnosis group were: 996 Parkinson's patients and 1,288 subjects with no post-mortem abnormality. For the group of clinical diagnosis, PD diagnosis showed: sensitivity of 99%, specificity of 86%, accuracy of 90.96%, F1-Score 0.89, and a receiver operating characteristics area under the curve (ROC AUC) 0.925 (SE ± 0.006) [95% confidence interval [CI]: 0.913, 0.937], 𝑝<0.001. In this group, the most frequent pathology diagnosis among clinically misdiagnosed PD (false positive) patients was dementia with Lewy bodies (19.4%). Conversely, the most frequent clinical diagnosis among PD missed clinical diagnosis (false negative) patients was Alzheimer's disease (18.5%).

Interpretation: Our findings confirm a still significant diagnostic error and emphasize the need for more fine and homogeneous criteria to classify idiopathic Parkinson's patients correctly. ANN NEUROL 2025.

Congenital titinopathy has recently emerged as one of the most common congenital muscle disorders.

Objective: To better understand the presentation and clinical needs of the under-characterized extreme end of the congenital titinopathy severity spectrum.

Methods: We comprehensively analyzed the clinical, imaging, pathology, autopsy, and genetic findings in 15 severely affected individuals from 11 families.

Results: Prenatal features included hypokinesia or akinesia and growth restriction. Six pregnancies were terminated. Nine infants were born at or near term with severe-to-profound weakness and required resuscitation. Seven died following withdrawal of life support. Two surviving children require ongoing respiratory support. Most cohort members had at least 1 disease-causing variant predicted to result in some near-normal-length titin expression. The exceptions, from 2 unrelated families, had homozygous truncating variants predicted to induce complete nonsense mediated decay. However, subsequent analyses suggested that the causative variant in each family had an additional previously unrecognized impact on splicing likely to result in some near-normal-length titin expression. This impact was confirmed by minigene assay for 1 variant.

Interpretation: This study confirms the clinical variability of congenital titinopathy. Severely affected individuals succumb prenatally/during infancy, whereas others survive into adulthood. It is likely that this variability is because of differences in the amount and/or length of expressed titin. If confirmed, analysis of titin expression could facilitate clinical prediction and increasing expression might be an effective treatment strategy. Our findings also further-support the hypothesis that some near-normal-length titin expression is essential to early prenatal survival. Sometimes expression of normal/near-normal-length titin is due to disease-causing variants having an additional impact on splicing. ANN NEUROL 2025.

RETRACTION: J. Chu, J.-M. Zhuo and D. Praticò, “ Transcriptional Regulation of βsecretase-1 by 12/15-Lipoxygenase Results in Enhanced Amyloidogenesis and Cognitive Impairments,” Annals of Neurology 71, no. 1 (2012): 57–67, https://doi.org/10.1002/ana.22625.

The above article, published online on 12 September 2011 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors, J.-M. Zhuo and D. Praticò; the journal Editor-in-Chief, Kenneth L. Tyler; the American Neurological Association and Wiley Periodicals LLC. The retraction has been agreed upon due to the duplication of the actin blots and one of the APP blots shown in figures 2A and 4A. The authors were unable to provide the original data. The editors and the authors, J.-M. Zhuo and D. Praticò, have lost confidence in the data presented and consider the conclusions to be substantially compromised. The author, J. Chu, could not be contacted to inform them of the retraction.

Objective: Parkinson's and Huntington's diseases are characterized by progressive neuronal loss. Previous studies using human postmortem tissues have shown the impact of neurodegenerative disorders on adult neurogenesis. The extent to which adult neural stem cells are activated in the subventricular zone and whether therapeutic treatments such as deep brain stimulation promote adult neurogenesis remains unclear. The goal of the present study is to assess adult neural stem cells activation and neurogenesis in the subventricular zone of patients with Huntington's and Parkinson's diseases who were treated or not by deep brain stimulation.

Methods: Postmortem brain samples from Huntington's and Parkinson's disease patients who had received or not long-term deep brain stimulation of the subthalamic nucleus were used.

Results: Our results indicate a significant increase in the thickness of the subventricular zone and in the density of proliferating cells and activated stem cells in the brain of Huntington's disease subjects and Parkinson's disease patients treated with deep brain stimulation. We also observed an increase in the density of immature neurons in the brain of these patients.

Interpretation: Overall, our data indicate that long-term deep brain stimulation of the subthalamic nucleus promotes cell proliferation and neurogenesis in the subventricular zone that are reduced in Parkinson's disease. Taken together, our results also provide a detailed characterization of the cellular composition of the adult human subventricular zone and caudate nucleus in normal condition and in Parkinson's and Huntington's diseases and demonstrate the plasticity of these regions in response to neurodegeneration. ANN NEUROL 2025.

Objective: The objective of this study was to delineate synaptic density alterations in multiple system atrophy (MSA) and explore its potential role as a biomarker for MSA diagnosis and disease severity monitoring using [¹⁸F]SynVesT-1 positron emission tomography / computed tomography (PET CT).

Methods: In this prospective study, 60 patients with MSA (30 patients with MSA-parkinsonian [MSA-P] subtype and 30 patients with MSA-cerebellar [MSA-C] subtype), 30 patients with Parkinson's disease (PD), and 30 age-matched healthy controls (HCs) underwent [¹⁸F]SynVesT-1 PET/CT for synaptic density assessment. Visual, voxel, and volumetric region of interest (VOI) analyses were used to elucidate synaptic density patterns in the MSA brain and establish diagnostic criteria. The diagnostic performances of both visual and VOI-based diagnostics were evaluated using receiver operating characteristic (ROC) analysis. Spearman correlation analyses were conducted to investigate the relationship between brain synaptic density and disease severity RESULTS: Patients with MSA displayed extensive reductions in synaptic density throughout the brain, notably affecting both primary VOIs (the cerebellum and putamen) and secondary VOIs including the medulla oblongata, ventral tegmental area, and pons. Notably, patients with MSA-C exhibited a remarkable decrease in cerebellar synaptic density, whereas patients with MSA-P demonstrated significant synaptic loss within the posterior putamen. Compared with patients with PD, the patients with MSA show a more pronounced reduction in synaptic density in infratentorial brain regions. VOI-based diagnosis significantly outperformed visual analysis in diagnosing and differentiating MSA and its subtypes. Synaptic density in primary and multiple secondary VOIs correlated significantly with motor scales in patients with MSA.

Interpretation: Our study identified widespread synaptic density reductions in MSA, particularly in the basal ganglia and infratentorial region, suggesting [¹⁸F]SynVesT-1 PET as a potential biomarker for diagnosing and evaluating the disease, and guiding synaptic restoration trials. ANN NEUROL 2025.

Objective: This study assesses whether longitudinal quantitative pupillometry predicts neurological deterioration after large middle cerebral artery (MCA) stroke and determines how early changes are detectable.

Methods: This prospective, single-center observational cohort study included patients with large MCA stroke admitted to Boston Medical Center's intensive care unit (2019-2024). Associations between time-to-neurologic deterioration and quantitative pupillometry, including Neurological Pupil Index (NPi), were assessed using Cox proportional hazards models with time-dependent covariates adjusted for age, sex, and Alberta Stroke Program Early CT Score. Models using dilation velocity were compared with partial likelihood ratio tests. Pupillometric changes over 2-h intervals in the 12 h preceding deterioration were analyzed with linear mixed-effects modeling and Tukey's test. Matched referents (age, sex, stroke side, follow-up duration) were used for comparison. Optimal thresholds were identified using the Youden Index.

Results: Among 71 patients (mean age 66.5 years; 59.2% women), 32 (45.1%) experienced deterioration. A 1-unit decrease in NPi was associated with a higher hazard of deterioration (hazard ratio 2.46; 95% confidence interval 1.68-3.61). Dilation velocity improved model performance compared to NPi alone. NPi was significantly lower at 0-2 h (3.81 vs. 4.38, p = 0.001) and 2-4 h (3.71 vs. 4.38, p < 0.001) before deterioration compared to 10-12 h prior. Optimal thresholds were 4.01 for NPi, 0.49 mm/s for dilation velocity, and -0.15 change in NPi over 12 h.

Interpretation: Quantitative pupillometry predicts neurological deterioration in MCA stroke, with declines detectable up to 12 h prior. Dilation velocity shows promise as a novel biomarker. ANN NEUROL 2025.