In vivo histopathological staging in C9orf72-associated ALS: A tract of interest DTI study.

Background: Diffusion tensor imaging (DTI) can identify amyotrophic lateral sclerosis (ALS)-associated patterns of brain alterations at the group level according to a neuropathological staging system.

Objective: The study was designed to investigate the in vivo staging in ALS patients with the C9orf72 expansion and potential differences to ALS patients with the SOD1 mutation.

Methods: DTI-based white matter mapping was performed both by an unbiased voxel-wise statistical comparison and by a hypothesis-guided tract-wise analysis of fractional anisotropy (FA) maps according to the ALS-staging pattern for 27 ALS patients with C9orf72 expansion vs 15 ALS patients with SOD1 mutation vs 32 matched healthy controls.

Explorative study of emerging blood biomarkers in progressive multiple sclerosis (EmBioProMS): Design of a prospective observational multicentre pilot study.

Background: Defining clinical and subclinical progression in multiple sclerosis (MS) is challenging. Patient history, expanded disability status scale (EDSS), and magnetic resonance imaging (MRI) all have shortcomings and may underestimate disease dynamics. Emerging serum biomarkers such as glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) proved useful in many cross-sectional studies.

Statins, diabetes mellitus and prognosis of amyotrophic lateral sclerosis: data from 501 patients of a population-based registry in southwest Germany.

Background And Purpose: A wide variety of metabolic changes, including an increased incidence of diabetes mellitus (DM) and dyslipidaemia, has been described in amyotrophic lateral sclerosis (ALS). The aim of this study was to investigate the associations of statin use and history of DM with onset of disease and survival in patients with ALS.

Methods: In all, 501 patients (mean age 65.

Functional and structural impairment of transcallosal motor fibres in ALS: a study using transcranial magnetic stimulation, diffusion tensor imaging, and diffusion weighted spectroscopy.

Imaging studies showed that the structure of the corpus callosum (CC) is affected in amyotrophic lateral sclerosis (ALS). Some clinical studies also suggest that interhemispheric connectivity is altered, since mirror movements seem to occur in ALS. Finally, reduced interhemispheric inhibition (IHI), studied by transcranial magnetic stimulation (TMS), has been reported.

Nusinersen in adults with 5q spinal muscular atrophy: a non-interventional, multicentre, observational cohort study.

Background: Nusinersen is approved for the treatment of 5q spinal muscular atrophy of all types and stages in patients of all ages. Although clinical trials have shown improvements in motor function in infants and children treated with the drug, data for adults are scarce. We aimed to assess the safety and efficacy of nusinersen in adults with 5q spinal muscular atrophy.

Histological correlates of postmortem ultra-high-resolution single-section MRI in cortical cerebral microinfarcts.

The identification of cerebral microinfarctions with magnetic resonance imaging (MRI) and histological methods remains challenging in aging and dementia. Here, we matched pathological changes in the microvasculature of cortical cerebral microinfarcts to MRI signals using single 100 μm-thick histological sections scanned with ultra-high-resolution 11.7 T MRI.

Different CSF protein profiles in amyotrophic lateral sclerosis and frontotemporal dementia with hexanucleotide repeat expansion.

Objectives: The hexanucleotide repeat expansion in the gene is the most common mutation associated with amyotrophic lateral sclerosis (C9-ALS) and frontotemporal dementia (C9-FTD). Until now, it is unknown which factors define whether mutation carriers develop ALS or FTD. Our aim was to identify protein biomarker candidates in the cerebrospinal fluid (CSF) which differentiate between C9-ALS and C9-FTD and might be indicative for the outcome of the mutation.

Focal alterations of the callosal area III in primary lateral sclerosis: An MRI planimetry and texture analysis.

Background: The regional distribution of cerebral morphological alterations in primary lateral sclerosis (PLS) is considered to include the area III of the corpus callosum (CC).

Objective: The study was designed to investigate regional white matter (WM) alterations in the callosal area III by T1 weighted magnetic resonance imaging (T1w-MRI) data in PLS patients compared with healthy controls, in order to identify atrophy and texture changes in vivo.

Methods: T1w-MRI-based white matter mapping was used to perform an operator-independent CC-segmentation for the different areas of the CC in 67 PLS patients vs 82 matched healthy controls and vs 85 ALS patients.

Targeted Mass Spectrometry Suggests Beta-Synuclein as Synaptic Blood Marker in Alzheimer's Disease.

Synaptic degeneration is a major hallmark of Alzheimer's disease (AD) and the best pathological correlate of cognitive dysfunction. Synaptic markers are therefore a highly desired read-out for patient diagnosis and possible follow-up in clinical trials. Several synaptic markers for AD are described in cerebrospinal fluid (CSF), but studies in blood have failed so far.

[Gene-specific treatment approaches in amyotrophic lateral sclerosis in the present and future].

Amyotrophic lateral sclerosis (ALS) is monogenic in up to 10% of cases. Various mutation types result in a loss of function, a gain of toxicity or a combination of both. Due to the continuous development of gene-specific approaches, the treatment of the various ALS forms is no longer a dream.

Fabry Disease With Concomitant Lewy Body Disease.

Although Gaucher disease can be accompanied by Lewy pathology (LP) and extrapyramidal symptoms, it is unknown if LP exists in Fabry disease (FD), another progressive multisystem lysosomal storage disorder. We aimed to elucidate the distribution patterns of FD-related inclusions and LP in the brain of a 58-year-old cognitively unimpaired male FD patient suffering from predominant hypokinesia. Immunohistochemistry (CD77, α-synuclein, collagen IV) and neuropathological staging were performed on 100-µm sections.

Sporadic inclusion body myositis: no specific cardiac involvement in cardiac magnetic resonance tomography.

Objective: To investigate cardiac involvement in patients with sporadic inclusion body myositis (IBM) by cardiac magnetic resonance tomography (CMR).

Methods: A case series of 20 patients with IBM underwent basic cardiac assessment and CMR including functional imaging, native and contrast-enhanced T1-weighted, and late gadolinium enhancement (LGE) imaging.

Results: All IBM patients reported no cardiac symptoms.

Camptocormia as a Novel Phenotype in a Heterozygous Mutation.

Mitochondrial dysfunction is known to play a key role in the pathophysiological pathway of neurodegenerative disorders. Nuclear-encoded proteins are involved in mtDNA replication, including DNA polymerase gamma, which is the only known replicative mtDNA polymerase, encoded by nuclear genes Polymerase gamma 1 (POLG) and Polymerase gamma 2 (POLG2). mutations are well-known as a frequent cause of mitochondrial myopathies of nuclear origin.

Association of Insulin-like Growth Factor 1 Concentrations with Risk for and Prognosis of Amyotrophic Lateral Sclerosis - Results from the ALS Registry Swabia.

We investigated the associations of serum concentration of insulin-like growth factor 1 (IGF1) with risk and prognosis of ALS in the ALS registry (October 2010-June 2014, median follow-up 67.6 months) in a case-control and cohort study, respectively. Serum samples were measured for IGF-1.

CSF SerpinA1 in Creutzfeldt-Jakob disease and frontotemporal lobar degeneration.

Objective: SerpinA1 (alpha-1 antitrypsin) is an acute inflammatory protein, which seems to play a role in neurodegeneration and neuroinflammation. In Alzheimer's disease and synucleinopathies, SerpinA1 is overexpressed in the brain and the cerebrospinal fluid (CSF) showing abnormal patterns of its charge isoforms. To date, no comprehensive studies explored SerpinA1 CSF isoforms in Creutzfeldt-Jakob disease (CJD) and frontotemporal lobar degeneration (FTLD).

Clinical and neuroimaging disparity between Chinese and German patients with cerebral small vessel disease: a comparative study.

Ethnic disparity of cerebral small vessel disease (CSVD) has been reported previously but understanding of its clinical-anatomical is sparse. Two cohorts of CSVD patients from Peking University First Hospital, China and University Hospital of Ulm, Germany were retrospectively collected between 2013 and 2017. Visual rating scales and semiautomatic computer-assisted quantitative analysis were used to describe the neuroimaging features of CSVD, including lacunes, enlarged perivascular spaces, white matter changes and microbleeds.

SQSTM1/p62 variants in 486 patients with familial ALS from Germany and Sweden.

Several studies reported amyotrophic lateral sclerosis (ALS)-linked mutations in TBK1, OPTN, VCP, UBQLN2, and SQSTM1 genes encoding proteins involved in autophagy. SQSTM1 was originally identified by a candidate gene approach because it encodes p62, a multifunctional protein involved in protein degradation both through proteasomal regulation and autophagy. Both p62 and optineurin (encoded by OPTN) are direct interaction partners and substrates of TBK1, and these 3 proteins form the core of a genetic and functional network that may connect autophagy with ALS.

Effect of High-Caloric Nutrition on Survival in Amyotrophic Lateral Sclerosis.

Objective: Weight loss has been identified as a negative prognostic factor in amyotrophic lateral sclerosis, but there is no evidence regarding whether a high-caloric diet increases survival. Therefore, we sought to evaluate the efficacy of a high-caloric fatty diet (HCFD) for increasing survival.

Methods: A 1:1 randomized, placebo-controlled, parallel-group, double-blinded trial (LIPCAL-ALS study) was conducted between February 2015 and September 2018.

Safety and efficacy of immunoadsorption versus plasma exchange in steroid-refractory relapse of multiple sclerosis and clinically isolated syndrome: A randomised, parallel-group, controlled trial.

Background: Plasma exchange (PE) constitutes the standard therapy for steroid-refractory relapse in multiple sclerosis and clinically isolated syndrome. Immunoadsorption (IA) is an alternative method of apheresis which selectively removes immunoglobulines (Ig) while preserving other plasma proteins. Although IA is regarded as a well-tolerated, low-risk procedure, high-level evidence for its efficacy is lacking.

Severe white matter damage in SHANK3 deficiency: a human and translational study.

Objective: Heterozygous SHANK3 mutations or partial deletions of the long arm of chromosome 22, also known as Phelan-McDermid syndrome, result in a syndromic form of the autism spectrum as well as in global developmental delay, intellectual disability, and several neuropsychiatric comorbidities. The exact pathophysiological mechanisms underlying the disease are still far from being deciphered but studies of SHANK3 models have contributed to the understanding of how the loss of the synaptic protein SHANK3 affects neuronal function.

Methods And Results: Diffusion tensor imaging-based and automatic volumetric brain mapping were performed in 12 SHANK3-deficient participants (mean age 19 ± 15 years) versus 14 age- and gender-matched controls (mean age 29 ± 5 years).

Routine Cerebrospinal Fluid (CSF) Parameters in Patients With Spinal Muscular Atrophy (SMA) Treated With Nusinersen.

Nusinersen is an antisense-oligonucleotide (ASO) approved for treatment of 5q-spinal muscular atrophy (SMA). Since the drug cannot cross the blood-brain barrier (BBB), it must be administered into the cerebrospinal fluid (CSF) space repeatedly by lumbar puncture. However, little is known whether ASOs have an impact on CSF routine parameters that may yield information on CSF flow and/or intrathecal inflammation.

In Vivo Protein Complementation Demonstrates Presynaptic α-Synuclein Oligomerization and Age-Dependent Accumulation of 8-16-mer Oligomer Species.

Intracellular accumulation of α-synuclein (α-syn) and formation of Lewy bodies are neuropathological characteristics of Parkinson's disease (PD) and related α-synucleinopathies. Oligomerization and spreading of α-syn from neuron to neuron have been suggested as key events contributing to the progression of PD. To directly visualize and characterize α-syn oligomerization and spreading in vivo, we generated two independent conditional transgenic mouse models based on α-syn protein complementation assays using neuron-specifically expressed split Gaussia luciferase or split Venus yellow fluorescent protein (YFP).

Patient-Reported Prevalence of Non-motor Symptoms Is Low in Adult Patients Suffering From 5q Spinal Muscular Atrophy.

5q spinal muscular atrophy (SMA) is an autosomal recessive lower motoneuron disease caused by deletion or mutations in the survival motor neuron 1 gene () which results in reduced expression of full-length SMN protein. The main symptoms are caused by spinal motor neuron demise leading to muscle atrophy, and medical care mostly refers to motor symptoms. However, new insights of recent studies in severe SMA type I revealed disease involvement of several non-motor regions, for example cardiac, vascular, sensory nerve involvement, and thalamic lesions.