Annals of Neurology

BackgroundTerazosin, doxazosin, and alfuzosin (Tz/Dz/Az) are -1 adrenergic receptor antagonists that also bind to and activate a key ATP-producing enzyme in glycolysis. Recent work has suggested a potentially neuroprotective effect of use of Tz/Dz/Az in Parkinsons disease in both animal and human studies. We investigated neuroprotective effects of Tz/Dz/Az in a closely related disease, dementia with Lewy bodies (DLB). MethodsWe used a new user active comparator design in the merative Marketscan...

Skin biopsies of patients with parkinsonism, mild cognitive impairment or dementia might offer a simple and relatively non-invasive means to determine whether -synuclein aggregates might be the underlying pathology. Accurate biomarkers are critically needed for Lewy body disease (LBD) clinical trials but currently there are none that have undergone full regulatory scrutiny. We sought to simulate the rigor of a diagnostic study done with regulatory oversight in this study of the accuracy of skin...

There is an unmet need for reliable biomarkers for amyotrophic lateral sclerosis (ALS). Recent studies demonstrated that the levels of the microtubule-associated protein tau are altered in plasma and cerebrospinal fluid (CSF) from people living with ALS. Our previous findings revealed that while the ratio between tau and phosphorylated tau at T181 (pTau-T181) is lower in ALS CSF compared to healthy controls (HC), higher CSF tau levels correlated with faster disease progression. Here, we measured...

BackgroundHereditary transthyretin-mediated (hATTR) amyloidosis is a rare, progressively debilitating, and fatal disease caused by deposition of aggregated transthyretin amyloid in multiple organs and tissues. Highly variable disease penetrance has made it difficult to predict disease onset and progression. Clinically validated, non-invasive plasma biomarkers may facilitate earlier diagnosis and aid monitoring of disease progression. MethodsPlasma levels of >1000 proteins were measured in patie...

A key role for inflammation in amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) has been identified. It is vital to assess which central nervous system structures are most affected and which inflammatory processes are responsible in humans. The inflammatory transcriptome was characterized in the cervical spinal cord and motor cortex in post mortem frozen and formalin-fixed paraffin embedded specimens from human sporadic ALS/MND and control cases using the nCounter(R) Neuroinflammatio...

The relationship between in vivo synaptic density and tau burden in primary tauopathies is key to understanding the impact of tauopathy on functional decline and in informing new early therapeutic strategies. In this cross-sectional observational study, we determine the in vivo relationship between synaptic density and molecular pathology, in the primary tauopathies of Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD), as a function of disease severity. Twenty three patie...

In frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS), subsequent motor or cognitive-behavioral features, respectively, are associated with shorter survival. However, factors influencing subsequent feature development remain largely unexplored. In this study, we examined whether the presence of a C9orf72 expansion or the initial clinical syndrome was associated with increased risk of subsequent feature development in individuals with ALS and FTD. We performed a retrospect...

BackgroundChitotriosidase (Chit-1) and chitinase-3-like protein 1 (CHI3L1) protein levels are increased in the cerebrospinal fluid (CSF) of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimers disease (AD). Few studies have examined the spatial expression of chitinase expressing cells with respect to neuropathologic hallmarks of disease. MethodsRNA-sequencing was used to examine Chit-1 and CHI3L1 gene expression in the spinal c...

ObjectiveIdentify preferred neurofilament assays, and clinically validate serum NfL and pNfH as prognostic and potential pharmacodynamic biomarkers relevant to ALS therapy development. MethodsProspective, multi-center, longitudinal observational study of patients with ALS (n=229), primary lateral sclerosis (PLS, n=20) and progressive muscular atrophy (PMA, n=11). Biological specimens were collected, processed and stored according to strict standard operating procedures (SOPs) 1. Neurofilament a...

Background and ObjectivePeople with multiple sclerosis (pwMS) receiving B cell-depleting therapies have impaired antibody responses to vaccination. In a proportion of individuals, repeat vaccination against COVID-19 leads to seroconversion. We sought to describe the immune phenotype of pwMS on ocrelizumab, and identify clinical and immunological determinants of an effective vaccine response. MethodsThis was a single-centre, prospective cohort study. Peripheral blood samples were collected from ...

BackgroundAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by abnormal protein aggregates in motor neurons. Present and earlier proteomic studies to characterize peptides in cerebrospinal fluid (CSF) associated with motoneuron pathology did not target the low molecular weight proteins and peptides. We generated the hypothesis that specific changes in CSF peptides or low molecular weight proteins are significantly changed in ALS, and that these changes may support ...

The activity of the RNase III enzyme DICER is downregulated in both sporadic and genetic forms of Amyotrophic Lateral Sclerosis (ALS). Accordingly, hundreds of microRNAs (miRNAs) are broadly downregulated, leading to derepression of their mRNA targets. Enoxacin is a fluoroquinolone that enhances DICER activity and miRNA biogenesis. Here, we tested for the first time the molecular effect of Enoxacin on miRNA biogenesis in ALS patients and demonstrated that Enoxacins engagement with DICER can be p...

BackgroundNovel supportive diagnostic and prognostic biomarkers for Parkinsons disease (PD) are needed to enable its early diagnosis and inform clinical trials. Proteomic studies have identified cerebrospinal fluid (CSF) DOPA decarboxylase (DDC) as a promising biomarker candidate, but its role has not been well characterized. The aim of this study was to gain further insight into the potential of DDC as biomarker for PD. MethodsWe developed and validated a single molecule counting immunoassay f...

INTRODUCTIONWe report in vivo patterns of neuroinflammation and abnormal protein aggregation in seven cases of familial frontotemporal dementia with mutations in MAPT, GRN and C9orf72 genes. METHODSUsing positron emission tomography (PET), we explored the association of the distribution of activated microglia, as measured by the radioligand [11C]PK11195, and the regional distribution of tau- or TDP-43 pathology, indexed using the radioligand [18F]AV-1451. The familial FTD PET data were compared...

Background and ObjectivesThe collection of cerebrospinal fluid (CSF) serves an essential role in biomarker research. New Parkinsons disease (PD) classifications include CSF -synuclein status as a key biological anchor to enrich research trial design. Previous reports have established the safety of lumbar punctures (LPs) at baseline, but further investigation of longitudinal LP feasibility is needed. This study aimed to evaluate the safety and feasibility of serial CSF collection in participants ...

Essential tremor is a disabling and highly prevalent movement disorder. Deep brain stimulation of the ventral intermediate nucleus provides substantial symptom relief; however, many patients experience diminishing benefit over time. The underlying causes range from natural disease progression and worsening ataxia to, less commonly, habituation or tolerance. We performed a retrospective longitudinal analysis of 86 individuals with essential tremor who underwent unilateral ventral intermediate nu...

TDP-43 proteinopathy is a neuropathological hallmark of nearly all amyotrophic lateral sclerosis (ALS) and approximately half of frontotemporal dementia (FTD) cases. Nuclear loss of TDP-43 leads to widespread RNA misprocessing, such as the inclusion of cryptic exons that are no longer repressed by TDP-43. Notably, in-frame cryptic exons encode novel cryptic peptides that can be detected in biofluids, including that found in the HDGFL2 transcript. Here, we quantified HDGFL2 cryptic peptide and ne...

BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with a largely unknown duration and pathophysiology of the pre-diagnostic phase, especially for the common non-monogenic form. MethodsWe leveraged the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort with up to 30 years of follow-up to identify incident ALS cases across five European countries. Pre-diagnostic plasma samples from initially healthy participants underwent high-throughput p...

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with limited therapeutic options. Riluzole remains the only widely available treatment in ALS, yet its benefits are modest and highly variable across patients. Genetic variation in cytochrome P450 2D6 (CYP2D6), a major enzyme in drug metabolism, detoxification of environmental toxins, and biotransformation of endogenous transmitters, has been implicated as a risk factor in neurodegenerative diseases. It has been obse...

BackgroundComorbid Alzheimers disease (AD) neuropathology is common in Lewy body disease (LBD); however, AD comorbidity in the prodromal phase of LBD remains unclarified. This study investigated AD comorbidity in the prodromal and symptomatic phases of LBD by analysing plasma biomarkers in patients with Parkinsons disease (PD) and dementia with Lewy bodies (DLB) and at-risk individuals of LBD (NaT-PROBE cohort). MethodsPatients with PD (PD group, n=84) and DLB (DLB group, n=16) and individuals ...