Annals of Neurology

OBJECTIVE: SCN8A encephalopathy is a Developmental and Epileptic Encephalopathy (DEE) caused by de novo, gain-of-function mutations of sodium channel Nav 1.6 that result in neuronal hyperactivity. Affected individuals exhibit early-onset drug-resistant seizures, developmental delay and cognitive impairment. This study was carried out to determine whether reducing the abundance of the Scn8a transcript with an anti-sense oligonucleotide (ASO) would delay seizure onset and prolong survival in a mouse model of SCN8A encephalopathy...

OBJECTIVE: Long-term cognitive decline is an adverse outcome after major surgery associated with increased risk for mortality and morbidity. We studied the cerebrospinal fluid (CSF) and serum biochemical inflammatory response to a standardized orthopedic surgical procedure and the possible association with long-term changes in cognitive function. We hypothesized that the CSF inflammatory response pattern after surgery would differ in patients having long-term cognitive decline defined as a composite cognitive z-score ≥1...

No abstract text is available yet for this article.

OBJECTIVE: There are currently no definitive disease modifying therapies for traumatic brain injury (TBI). In this study, we present a strong therapeutic candidate for TBI, immunomodulatory nanoparticles (IMPs), which ablate a specific subset of hematogenous monocytes (hMos). We hypothesized that prevention of infiltration of these cells into brain acutely after TBI would attenuate secondary damage and preserve anatomic and neurologic function. METHODS: IMPs, composed of FDA-approved 500nm carboxylated-poly(lactic-co-glycolic) acid, were infused intravenously into wild-type C57BL/6 mice following two different models of experimental TBI, controlled-cortical impact (CCI) and closed head injury (CHI)...

OBJECTIVE: Spontaneous recovery is an important determinant of upper extremity recovery after stroke, and has been described by the 70% proportional recovery rule for the Fugl-Meyer motor upper extremity (FM-UE) scale. However, this rule is criticized for overestimating the predictability of FM-UE recovery. Our objectives were to (1) develop a longitudinal mixture model of FM-UE recovery, (2) identify FM-UE recovery subgroups, and (3) internally validate the model predictions. METHODS: We developed an exponential recovery function with the following parameters: subgroup assignment probability, proportional recovery coefficient rk , time constant in weeks τk , and distribution of the initial FM-UE scores...

Marked elevation in the brain concentration of N-acetyl-L-aspartate (NAA) is a characteristic feature of Canavan disease, a vacuolar leukodystrophy resulting from deficiency of the oligodendroglial NAA cleaving enzyme aspartoacylase. We now demonstrate that inhibiting NAA synthesis by intracisternal administration of a locked nucleic acid antisense oligonucleotide to young adult aspartoacylase-deficient mice reverses their pre-existing ataxia and diminishes cerebellar and thalamic vacuolation and Purkinje cell dendritic atrophy...

OBJECTIVE: Transcranial Magnetic Stimulation (TMS) has been suggested as a reliable, non-invasive, and inexpensive tool for the diagnosis of neurodegenerative dementias. In this study we assessed the classification performance of TMS parameters in the differential diagnosis of common neurodegenerative disorders, including Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). METHODS: We performed a multicenter study enrolling patients referred to four dementia centers in Italy, in accordance with the Standards for Reporting of Diagnostic Accuracy...

OBJECTIVES: Observational studies have indicated that life course adiposity is associated with amyotrophic lateral sclerosis (ALS). However, whether such an association reflects causality remains unclear. We aimed to determine whether life course adiposity, such as birth weight (BW), childhood body mass index (BMI), adult BMI, body fat percentage (BF%), and waist-to-hip ratio (WHR), have causal effects on ALS. METHODS: Single nucleotide polymorphisms (SNPs) significantly associated with life course adiposity were used as instrumental variables to estimate the causal effects on ALS...

OBJECTIVE: Aging is a major risk factor for numerous neurological disorders and the mechanisms underlying brain aging remain elusive. Recent animal studies demonstrated tight relationship between impairment of glymphatic pathway, meningeal lymphatic vessels and aging. However, the relationship in human brain remains uncertain. METHODS: In this observational cohort study, patients underwent MRI before and at multiple time points after intrathecal administration of contrast agent...

No abstract text is available yet for this article.

OBJECTIVE: The primary imaging modalities used to select patients for endovascular thrombectomy (EVT) are non-contrast CT(CT) and CT-perfusion(CTP). However, their relative utility is uncertain. We prospectively assessed CT and CTP concordance/discordance and correlated the imaging profiles on both with EVT treatment decisions and clinical outcomes. METHODS: A phase-II multicenter, prospective-cohort study of large vessel occlusions who presented up-to-24hours from last-known-well was conducted...

No abstract text is available yet for this article.

OBJECTIVE: Leucine-rich glioma-inactivated 1 (LGI1) encephalitis is the second most common autoimmune encephalopathy, but insight into the intrathecal B cell autoimmune response including clonal relationships, isotype distribution, frequency and pathogenic effects of single LGI1 antibodies has remain limited. METHODS: We cloned, expressed and tested antibodies from 90 antibody-secreting cells (ASCs) and B cells from the CSF of several patients with LGI1 encephalitis...

OBJECTIVE: Bridging the gap between experimental stroke and patients by ischemic blood probing during the hyperacute stage of vascular occlusion is crucial to assess the role of inflammation in human stroke and for the development of adjunct treatments beyond recanalization. METHODS: We prospectively observed 151 consecutive ischemic stroke patients with embolic large vessel occlusion of the anterior circulation who underwent mechanical thrombectomy. In all these patients, we attempted microcatheter aspiration of three different arterial blood samples 1) within the core of the occluded vascular compartment, controlled by 2) carotid and 3) femoral samples obtained under physiological flow conditions...

OBJECTIVE: Sensory dysfunction is a common consequence of many forms of neurological injury, including stroke and nerve damage. Rehabilitative paradigms that incorporate sensory retraining can provide modest benefits, but the majority of patients are left with lasting sensory loss. We have developed a novel strategy that uses closed-loop vagus nerve stimulation (VNS) paired with tactile rehabilitation to enhance synaptic plasticity and facilitate recovery of sensory function. METHODS: A clinical case report provides initial evidence that a similar implementation of closed-loop VNS paired with a tactile rehabilitation regimen could improve recovery of somatosensory function...

No abstract text is available yet for this article.

OBJECTIVE: To describe morphological changes associated with degeneration and regeneration of large fibers in the skin using a model of chronic compression of the median nerve. METHODS: We studied cutaneous innervation in 30 patients with chronic compression of the median nerve at the wrist. Before surgery, we assessed the symptom severity and performed neurography, quantitative sensory testing, and the analysis of nerve morphology and morphometry in skin biopsies from the third digit fingertip...

OBJECTIVE: Weight loss has been identified as a negative prognostic factor in amyotrophic lateral sclerosis, but there is no evidence whether a high-caloric diet increases survival. Therefore, we sought to evaluate the efficacy of a high-caloric fatty diet (HCFD) with regard to survival. METHODS: A 1:1 randomized, placebo-controlled, parallel-group, double-blinded trial (LIPCAL-ALS study) was conducted between 02/2015 and 09/2018. Patients were followed up 3, 6, 9, 12, 15, and 18 months after randomisation...

OBJECTIVE: Recently, the ASC-1 complex has been identified as a mechanistic link between ALS and spinal muscular atrophy (SMA), and three mutations of the ASC-1 gene TRIP4 have been associated with SMA or congenital myopathy. Our goal was to define ASC-1 neuromuscular function and the phenotypical spectrum associated with TRIP4 mutations. METHODS: Clinical, molecular, histological and MRI studies in 5 families with 7 novel TRIP4 mutations. FACS and Western blot in patient-derived fibroblasts and muscles and in Trip4 knocked-down C2C12 cells...

OBJECTIVE: Restless legs syndrome is a frequent neurological disorder with substantial burden on individual wellbeing and public health. Genetic risk loci have been identified but the causatives genes at these loci are largely unknown, so that functional investigation and clinical translation of molecular research data are still inhibited. To identify putatively causative genes we searched for highly significant mutational burden in candidate genes. METHODS: We analyzed 84 candidate genes in 4,649 patients and 4,982 controls by next generation sequencing using molecular inversion probes that targeted mainly coding regions...