Annals of Clinical and Translational Neurology最新文献

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.

Objective

To investigate cortical microstructural measures from diffusion MRI as “neurodegeneration” markers that could improve prognostic accuracy in mild cognitive impairment (MCI).

Methods

The prognostic power of Amyloid/Tau/Neurodegeneration (ATN) biomarkers to predict progression from MCI to AD or non-AD dementia was investigated. Ninety patients underwent clinical evaluation (follow-up interval 32 ± 18 months), lumbar puncture, and MRI. Participants were grouped by clinical stage and cerebrospinal fluid Amyloid and Tau status.

T1-structural and diffusion MRI scans were analyzed to calculate diffusion metrics related to cortical columnar structure (AngleR, ParlPD, PerpPD⁺), cortical mean diffusivity, and fractional anisotropy. Statistical tests were corrected for multiple comparisons. Prognostic power was assessed using receiver operating characteristic (ROC) analysis and related indices.

Results

A progressive increase of whole-brain cortical diffusion values was observed along the AD continuum, with all A+ groups showing significantly higher AngleR than A−T−.

Investigating clinical progression to dementia, the AT biomarkers together showed good positive predictive value (with 90.91% of MCI A+T+ converting to dementia) but poor negative predictive value (with 40% of MCI A−T− progressing to a mix of AD and non-AD dementias). Adding whole-brain AngleR as an N marker, produced good differentiation between stable and converting MCI A−T− patients (0.8 area under ROC curve) and substantially improved negative predictive value (+21.25%).

Interpretation

Results support the clinical utility of cortical microstructure to aid prognosis, especially in A−T− patients. Further work will investigate other complexities of the real-world clinical setting, including A−T+ groups. Diffusion MRI measures of neurodegeneration may complement fluid AT markers to support clinical decision-making.

Objective

To report initial results from the Amyotrophic Lateral Sclerosis (ALS) Identified genetic testing (GT) program on characteristics of individuals tested and frequency of reported disease-causing variants.

Methods

ALS Identified used the Invitae Amyotrophic Lateral Sclerosis panel (Invitae, San Francisco, CA, USA) to assay 22 ALS-associated genes. Sponsored by Biogen (Cambridge, MA, USA), the program was launched in June 2021 and was available at no charge to individuals ≥18 years in the United States and Puerto Rico with an ALS diagnosis or a known family history of ALS. Deidentified data were available to Biogen.

Results

As of 26 October 2023, 998 healthcare professionals ordered the panel at 681 unique care sites. Of 8054 individuals examined, 7483 (92.9%) were reported to have a clinical diagnosis of ALS, while 571 (7.1%) were asymptomatic relatives. Of the individuals with a clinical ALS diagnosis, 57.7% were male (n = 4319) and 42.3% female (n = 3164). Mean (SD) age at diagnosis is 62 (13) years. Out of the 7483 clinically diagnosed individuals, 1810 (24.2%) showed genetic variations in ALS-associated genes. Among these, 865 individuals (47.8%) carried pathogenic variants, and 44 (2.4%) had likely pathogenic variants, totaling 12.1% of the clinically diagnosed population.

Interpretation

Since 2021 there has been robust uptake and sustained use of the ALS Identified program, one of the largest samples of people with ALS to date across the United States, demonstrating the interest and need for genetic ALS testing.

Objectives

Hypoperfusion and tissue hypoxia have been implicated as contributory mechanisms in the neuropathology of multiple sclerosis (MS). Our objective has been to study cortical oxygenation in vivo in patients with MS and age-matched controls.

Methods

A custom, multiwavelength time-domain near-infrared spectroscopy system was developed for assessing tissue hypoxia from the prefrontal cortex. A cross-sectional case–control study was undertaken assessing patients with secondary progressive MS (SPMS) and age-matched controls. Co-registered magnetic resonance imaging was used to verify the location from which near-infrared spectroscopy data were obtained through Monte Carlo simulations of photon propagation. Additional clinical assessments of MS disease severity were carried out by trained neurologists. Linear mixed effect models were used to compare cortical oxygenation between cases and controls, and against measures of MS severity.

Results

Thirty-three patients with secondary progressive MS (median expanded disability status scale 6 [IQR: 5–6.5]; median age 53.0 [IQR: 49–58]) and 20 age-matched controls were recruited. Modeling of photon propagation confirmed spectroscopy data were obtained from the prefrontal cortex. Patients with SPMS had significantly lower cortical hemoglobin oxygenation compared with controls (−6.0% [95% CI: −10.0 to −1.9], P = 0.004). There were no significant associations between cortical oxygenation and MS severity.

Interpretation

Using an advanced, multiwavelength time-domain near-infrared spectroscopy system, we demonstrate that patients with SPMS have lower cortical oxygenation compared with controls.

Objective

This study aimed to evaluate subjective cognitive, physical, and mental health symptoms as well as objective cognitive deficits in COVID-19 patients 1 year after infection.

Methods

This was a cross-sectional study. Seventy-four patients, who contracted a SARS-CoV-2 infection in 2020, underwent an in-person neuropsychological assessment in 2021. This included standardized tests of memory, attention, and executive functions. In addition, participants also responded to scales on subjective attention deficits, mental health symptoms, and fatigue. Patients' scores were compared to published norms.

Results

Patients (N = 74) had a median age of 56 years (42% female). According to the initial disease severity, they were classified as mild (outpatients, 32%), moderate (hospitalized, non-ICU-admitted, 45%), or severe (ICU-admitted, 23%). Hospitalized patients were more often affected than outpatients. In general, deficits were most common in attention (23%), followed by memory (15%) and executive functions (3%). Patients reported increased levels of fatigue (51%), anxiety (30%), distractibility in everyday situations (20%), and depression (15%). An additional analysis suggested an association between lower scores in an attention task and hyperferritinemia. As indicated by a hierarchical regression analysis, subjective distractibility was significantly predicted by current anxiety and fatigue symptoms but not by objective attention performance (final model, adj-R ² = 0.588, P < 0.001).

Interpretation

One year after infection, COVID-19 patients can have frequent attention deficits and can complain about symptoms such as fatigue, anxiety, and distractibility. Anxiety and fatigue, more than objective cognitive deficits, have an impact on the patients' experienced impairments in everyday life.

Objective

Sudden unexpected death in epilepsy (SUDEP) is a serious threat to individuals with intractable epilepsies, contributing to premature mortality. Understanding the elusive pathophysiological mechanisms of SUDEP, especially in cases without observable terminal events, remains a crucial area for investigation. This study aimed to shed light on the burden of epileptiform activity preceding SUDEP by utilizing an automated electronic seizure diary derived from a sensing-enabled thalamic deep brain stimulator (DBS).

Methods

Herein, we present the case of a 57-year-old man afflicted with intractable multifocal epilepsy secondary to cortical dysplasia and encephalomalacia resulting from severe traumatic brain injury. Despite an initial successful resection and subsequent resurgence of seizures necessitating DBS treatment, the patient tragically succumbed to SUDEP.

Results

In-depth analysis of the patient's electronic seizure diary, complemented by data from the sensing-enabled DBS, unveiled a terminal electrographic seizure. Notably, we observed a significant increase in power within specific frequency bands recorded from the thalamus preceding the terminal event. Furthermore, these heightened band power events displayed a discernible temporal clustering pattern, primarily manifesting during specific morning and evening hours. An autopsy conclusively confirmed the diagnosis of definite SUDEP.

Interpretation

This unique case report underscores the feasibility of harnessing thalamic DBS sensing capabilities to monitor seizure burden and, potentially, to tailor interventions aimed at reducing seizure frequency and associated mortality risks.

Objectives

Traumatic brain injury (TBI) is associated with sleep deficits, but it is not clear why some report sleep disturbances and others do not. The objective of this study was to assess the associations between axonal injury, sleep, and memory in chronic and acute TBI.

Methods

Data were acquired from two independent datasets which included 156 older adult veterans (69.8 years) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with prior moderate-to-severe TBIs and 90 (69.2 years) controls and 374 (39.6 years) from Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) with a recent mild TBI (mTBI) and 87 controls (39.6 years), all who completed an MRI, memory assessment, and sleep questionnaire.

Results

Older adults with a prior TBI had a significant association between axonal injury and sleep disturbances [β = 9.52, 95% CI (4.1, 14.9), p = 0.01]. Axonal injury predicted changes in memory over 1-year in TBI [β = −8.72, 95% CI (−18, −2.7), p = 0.03]. We externally validated those findings in TRACK-TBI where axonal injury within 2 weeks after mTBI was significantly associated with higher sleep disturbances in the TBI group at 2 weeks[β = −7.2, 95% CI (−14, −0.50), p = 0.04], 6 months [β = −16, 95% CI (−24, −7.6), p ≤ 0.01], and 12 months post-injury [β = −11, 95% CI (−19, −0.85), p = 0.03]. These associations were not significant in controls.

Interpretations

Axonal injury, specifically to the left anterior internal capsule is robustly associated with sleep disturbances in multiple TBI populations. Early assessment of axonal injury following mTBI could identify those at risk for persistent sleep disturbances following injury.

Objective

Previous studies have suggested a link between peripheral inflammation and cognitive outcomes in the general population and individuals with Parkinson's disease (PD). We sought to test the association between peripheral inflammation, measured by the neutrophil-to-lymphocyte ratio (NLR), cognitive performance, and mild cognitive impairment (MCI) status in individuals with PD.

Methods

A retrospective, longitudinal analysis was carried out using data from the Parkinson's Progression Markers Initiative (PPMI), including 422 participants with PD followed over 5 years. Cognitive performance was assessed using a neuropsychological battery including the Montreal Cognitive Assessment (MoCA) and tests of verbal learning, visuospatial function, processing speed, and executive function. Mixed-effect regression models were used to analyze the association between NLR, cognitive performance, and MCI status, controlling for age, sex, education, APOE genotype, and motor severity.

Results

There was a negative association between NLR and MoCA, even after adjusting for covariates (b = −0.12, p = 0.033). MoCA scores for individuals in the high NLR category exhibited a more rapid decline over time compared to the low NLR group (b = −0.16, p = 0.012). Increased NLR was associated with decreased performance across all cognitive domains. However, NLR was not associated with MCI status over 5 years of follow-up.

Interpretation

This study demonstrates a link between elevated NLR and cognitive performance in PD, but not with MCI status over 5 years. This suggests that NLR is more strongly associated with day-to-day cognitive performance than with incident MCI, but this requires further study in more heterogeneous cohorts.

Objectives

The incidence of autoimmune encephalitis (AIE) has risen in the last decade, yet recent studies are lacking. We compared the epidemiology of autoimmune and infectious encephalitis cases in Tel-Aviv Sourasky Medical Center (TASMC) between 2010 and 2020.

Methods

All encephalitis cases, aged 18 and above, admitted to TASMC between the years 2010 and 2020 were reviewed for demographic, clinical, laboratory, and imaging data and categorized based on etiology.

Results

Two hundred and twenty-five patients with encephalitis were identified. The most common identifiable cause was viral (42%), followed by autoimmune encephalitis (35%), bacterial (18%), and fungal/parasitic (5%). The incidence of AIE cases out of the yearly admitted cases increased substantially, from 3.8/100 K in 2010 to 18.8/100 K in 2020. The incidence of viral cases also increased while those of bacterial and fungal/parasitic infections remained stable. Patients with AIE were younger compared to infectious patients (p-value <0.001) and had lower markers of systemic and cerebrospinal fluid inflammation (p-value for all <0.001). Seizures were more common among AIE patients (p-value <0.001), yet one-year mortality rates were higher among infectious patients (p-value <0.001).

Interpretation

AIE incidence has risen significantly in our institution during the past decade, with current rates comparable to those of all infectious causes combined. Based on this cohort, clinical clues for an autoimmune etiology include a non-inflammatory cerebrospinal fluid profile, the presence of seizures, and temporal lobe imaging abnormalities (also common in herpetic encephalitis). In light of its rising incidence and the importance of early treatment, AIE should be considered in the differential diagnosis of all encephalitis cases.

Objective

Treatment of pediatric brain tumors is associated with potential long-term cognitive sequelae. Patients treated with craniospinal irradiation for posterior fossa tumors are at high risk. New biomarkers that could help to differentiate treatment effects from other causes of cognitive dysfunction would be valuable in tailoring optimal survivorship care. Biomarkers that reflect biological mechanisms behind treatment-associated cognitive decline would also be important in the evaluation of future treatment regimens for pediatric brain or skull base tumors.

Methods

In this biomarker-finding study, 10 adult survivors of pediatric medulloblastoma, skull base tumors, and posterior fossa low-grade glioma underwent study specific lumbar puncture at a minimum of 17 years following treatment. We analyzed cerebrospinal fluid biomarkers reflecting neuron and astrocyte integrity, amyloid metabolism, inflammation, extracellular matrix, synaptic integrity, and blood–brain barrier function. The values were compared with biomarker levels in healthy controls of comparable age.

Results

Biomarkers reflecting neuronal injury (neurofilament light chain protein), astrocyte injury or activation (glial fibrillary acidic protein) as well as inflammation (YKL-40) were significantly elevated in cancer survivors compared to controls. Biomarkers reflecting amyloid metabolism showed a pattern of decrease in patients treated for medulloblastoma.

Interpretation

The results suggest a potential chronic low-grade neurodegeneration and astrocyte activation in patients treated for pediatric brain or skull base tumors. Protein biomarkers of CNS disease could potentially be used to increase our understanding of the contribution from different tumor treatments with regard to long-term symptoms in cancer patients.