Analysis of muscle magnetic resonance imaging of a large cohort of patient with VCP-mediated disease reveals characteristic features useful for diagnosis.

BACKGROUND: The diagnosis of patients with mutations in the VCP gene can be complicated due to their broad phenotypic spectrum including myopathy, motor neuron disease and peripheral neuropathy. Muscle MRI guides the diagnosis in neuromuscular diseases (NMDs); however, comprehensive muscle MRI features for VCP patients have not been reported so far. METHODS: We collected muscle MRIs of 80 of the 255 patients who participated in the "VCP International Study" and reviewed the T1-weighted (T1w) and short tau inversion recovery (STIR) sequences. We identified a series of potential diagnostic MRI based characteristics useful for the diagnosis of VCP disease and validated them in 1089 MRIs from patients with other genetically confirmed NMDs. RESULTS: Fat replacement of at least one muscle was identified in all symptomatic patients. The most common finding was the existence of patchy areas of fat replacement. Although there was a wide variability of muscles affected, we observed a common pattern characterized by the involvement of periscapular, paraspinal, gluteal and quadriceps muscles. STIR signal was enhanced in 67% of the patients, either in the muscle itself or in the surrounding fascia. We identified 10 diagnostic characteristics based on the pattern identified that allowed us to distinguish VCP disease from other neuromuscular diseases with high accuracy. CONCLUSIONS: Patients with mutations in the VCP gene had common features on muscle MRI that are helpful for diagnosis purposes, including the presence of patchy fat replacement and a prominent involvement of the periscapular, paraspinal, abdominal and thigh muscles.

Hippocampal Metabolic Alterations in Amyotrophic Lateral Sclerosis: A Magnetic Resonance Spectroscopy Study.

BACKGROUND: Magnetic resonance spectroscopy (MRS) in amyotrophic lateral sclerosis (ALS) has been overwhelmingly applied to motor regions to date and our understanding of frontotemporal metabolic signatures is relatively limited. The association between metabolic alterations and cognitive performance in also poorly characterised. MATERIAL AND METHODS: In a multimodal, prospective pilot study, the structural, metabolic, and diffusivity profile of the hippocampus was systematically evaluated in patients with ALS. Patients underwent careful clinical and neurocognitive assessments. All patients were non-demented and exhibited normal memory performance. 1H-MRS spectra of the right and left hippocampi were acquired at 3.0T to determine the concentration of a panel of metabolites. The imaging protocol also included high-resolution T1-weighted structural imaging for subsequent hippocampal grey matter (GM) analyses and diffusion tensor imaging (DTI) for the tractographic evaluation of the integrity of the hippocampal perforant pathway zone (PPZ). RESULTS: ALS patients exhibited higher hippocampal tNAA, tNAA/tCr and tCho bilaterally, despite the absence of volumetric and PPZ diffusivity differences between the two groups. Furthermore, superior memory performance was associated with higher hippocampal tNAA/tCr bilaterally. Both longer symptom duration and greater functional disability correlated with higher tCho levels. CONCLUSION: Hippocampal 1H-MRS may not only contribute to a better academic understanding of extra-motor disease burden in ALS, but given its sensitive correlations with validated clinical metrics, it may serve as practical biomarker for future clinical and clinical trial applications. Neuroimaging protocols in ALS should incorporate MRS in addition to standard structural, functional, and diffusion sequences.

Executive Dysfunction, Social Cognition Impairment, and Gray Matter Pathology in Myotonic Dystrophy Type 2: A Pilot Study.

BACKGROUND: In contrast to myotonic dystrophy type 1, the cognitive and radiologic profile of myotonic dystrophy type 2 (DM2) is relatively poorly characterized. OBJECTIVE: To conduct a pilot study to systematically evaluate cognitive and radiologic features in a cohort of Greek individuals with DM2. METHOD: Eleven genetically confirmed individuals with DM2 and 26 age- and education-matched healthy controls were administered the Edinburgh Cognitive and Behavioural Amyotrophic Lateral Sclerosis Screen (ECAS) to screen for impairment in multiple cognitive domains. MRI data were evaluated by morphometric analyses to identify disease-specific gray and white matter alterations. The following statistical thresholds were used for cognitive comparisons: PFDR < 0.05 and Bayes factor (BF 10 ) >10. RESULTS: The DM2 group exhibited cognitive impairment (ECAS Total score; PFDR = 0.001; BF 10 = 108.887), which was dominated by executive impairment ( PFDR = 0.003; BF 10 = 25.330). A trend toward verbal fluency impairment was also identified. No significant impairments in memory, language, or visuospatial function were captured. The analysis of subscores revealed severe impairments in social cognition and alternation. Voxel-based morphometry identified widespread frontal, occipital, and subcortical gray matter atrophy, including the left superior medial frontal gyrus, right medial orbitofrontal gyrus, right operculum, right precuneus, bilateral fusiform gyri, and bilateral thalami. CONCLUSION: DM2 may be associated with multifocal cortical and thalamic atrophy, which is likely to underpin the range of cognitive manifestations mostly characterized by executive impairment and specifically by impaired social cognition.

The association of theory of mind with language and visuospatial abilities in amyotrophic lateral sclerosis: a pilot study.

Objective: Dysfunction of social cognition is well-recognized as one of amyotrophic lateral sclerosis (ALS) cognitive impairments. Previous studies have mostly associated social cognition subcomponents, including Theory of Mind (ToM), with executive dysfunction using highly-demanding tasks. In the present study, we investigate dysfunction of affective ToM in a sample of ALS patients without dementia and evaluate any possible associations both with executive and non-executive dysfunction.Methods: We included 42 ALS patients and 30 healthy controls (HC) and administered the Edinburgh Cognitive and Behavioral Amyotrophic Lateral Sclerosis Screen (ECAS). Affective ToM was examined based on the ECAS judgment of preference task; total score and type of errors ("favourite", "unclassified") were recorded for all participants.Results: A significant proportion of ALS patients (31%) were impaired on ToM task, scoring significantly lower compared to HC. Impairments in ToM task were more frequent (45%) in patients with cognitive impairment compared to those with intact cognition (15%). ALS patients showed significantly more errors on ToM task compared to HC. A significant association was found between ToM score and ECAS language and visuospatial abilities but not fluency, executive or memory function.Conclusion: Dysfunction of affective ToM appears prevalent in ALS patients without dementia, and associates with language and visuospatial abilities. These associations align with motor and extra-motor symptoms due to the degeneration across corresponding networks. Impaired ToM should be considered in clinical settings, since it might contribute to patients' social life, as well as the burden of their caregivers and relatives.

Neuropsychological Assessment Should Always be Considered in Myotonic Dystrophy Type 2.

Myotonic dystrophies (DMs) are hereditary, multisystem, slowly progressive myopathies. One of the systems they affect is the CNS. In contrast to the well-established cognitive profile of myotonic dystrophy type 1 (DM1), only a few studies have investigated cognitive dysfunction in individuals with myotonic dystrophy type 2 (DM2), and their findings have been inconsistent. To identify the most commonly affected cognitive domains in individuals with DM2, we performed a formal comprehensive review of published DM2 studies. Using the terms "myotonic dystrophy type 2" AND "cognitive deficits," "cognitive," "cognition," "neuropsychological," "neurocognitive," and "neurobehavioral" in all fields, we conducted an advanced search on PubMed. We read and evaluated all of the available original research articles (13) and one case study, 14 in total, and included them in our review. Most of the research studies of DM2 reported primary cognitive deficits in executive functions (dysexecutive syndrome), memory (short-term nonverbal, verbal episodic memory), visuospatial/constructive-motor functions, and attention and processing speed; language was rarely reported to be affected. Based on the few neuroimaging and/or multimodal DM2 studies we could find, the cognitive profile of DM2 is associated with brain abnormalities in several secondary and high-order cortical and subcortical regions and associative white matter tracts. The limited sample size of individuals with DM2 was the most prominent limitation of these studies. The multifaceted profile of cognitive deficits found in individuals with DM2 highlights the need for routine neuropsychological assessment at both baseline and follow-up, which could unveil these individuals' cognitive strengths and deficits.

Neuroimaging data indicate divergent mesial temporal lobe profiles in amyotrophic lateral sclerosis, Alzheimer's disease and healthy aging.

A prospective, standardised neuroimaging protocol was implemented to characterise mesial temporal lobe pathology in amyotrophic lateral sclerosis, Alzheimer's disease and healthy controls focusing on the evaluation of interconnected white and grey matter structures. "Hippocampal pathology in Amyotrophic Lateral Sclerosis: selective vulnerability of subfields and their associated projections" [1]. High-resolution diffusion tensor and structural imaging data were acquired on a 3 T MRI platform using standardised sequence parameters. The integrity of the fornix and the perforant pathway was assessed by tractography, to provide fractional anisotropy, axial diffusivity and radial diffusivity measures. Quantitative structural imaging was used to estimate the total intracranial volume, total hippocampal volumes and hippocampal subfield volumes for each participant. Raw white- and grey-matter measures, demographic and clinical data are available online at 'Mendeley Data'. Amyotrophic lateral sclerosis and Alzheimer's disease exhibit divergent hippocampal profiles.

Hippocampal pathology in amyotrophic lateral sclerosis: selective vulnerability of subfields and their associated projections.

Although hippocampal involvement in amyotrophic lateral sclerosis (ALS) has been consistently highlighted by postmortem studies, memory impairment remains under-recognized and the involvement of specific hippocampal subfields and their connectivity patterns are poorly characterized in vivo. A prospective multimodal neuroimaging study has been undertaken with 50 well-characterized ALS patients, 18 patients with Alzheimer's disease, and 40 healthy controls to evaluate their mesial temporal lobe profile. Patients with ALS and Alzheimer's disease have divergent hippocampal signatures. The cornu ammonis 2/3 subfield and the hippocampus-amygdala transition area are the most affected regions in ALS in contrast to Alzheimer's disease, where the presubiculum and subiculum are the most vulnerable regions. Tractography reveals considerable fornix and perforant pathway pathology in both patient groups. Mesial temporal lobe structures in ALS have a selective and disease-specific vulnerability profiles, and their white matter projections exhibit concomitant degeneration. Our combined gray and white matter analyses indicate a connectivity-based, network-defined involvement of interconnected temporal lobe structures as opposed to contiguous involvement of adjacent structures. Our findings underline the importance of screening for memory deficits and personalized management strategies in ALS.

Human Tau isoform-specific presynaptic deficits in a Drosophila Central Nervous System circuit.

Accumulation of normal or mutant human Tau isoforms in Central Nervous System (CNS) neurons of vertebrate and invertebrate models underlies pathologies ranging from behavioral deficits to neurodegeneration that broadly recapitulate human Tauopathies. Although some functional differences have begun to emerge, it is still largely unclear whether normal and mutant Tau isoforms induce differential effects on the synaptic physiology of CNS neurons. We use the oligosynaptic Giant Fiber System in the adult Drosophila CNS to address this question and reveal that 3R and 4R isoforms affect distinct synaptic parameters. Whereas 0N3R increased failure rate upon high frequency stimulation, 0N4R compromised stimulus conduction and response speed at a specific cholinergic synapse in an age-dependent manner. In contrast, accumulation of the R406W mutant of 0N4R induced mild, age-dependent conduction velocity defects. Because 0N4R and its mutant isoform are expressed equivalently, this demonstrates that the defects are not merely consequent of exogenous human Tau accumulation and suggests distinct functional properties of 3R and 4R isoforms in cholinergic presynapses.