MOG antibody-associated NMO/NMOSD could account for some cases thought previously to be AQP4-seronegative NMO/NMOSD. Our 4 patients appear to have more favorable clinical outcomes than those with typical AQP4 antibody-mediated disease. However, further studies of NMO/NMOSD and other demyelinating conditions are required to help clarify the diagnostic and prognostic relevance of MOG antibodies.

The behavioural variant of frontotemporal dementia (bvFTD) is a frequent cause of early-onset dementia. The diagnosis of bvFTD remains challenging because of the limited accuracy of neuroimaging in the early disease stages and the absence of molecular biomarkers, and therefore relies predominantly on clinical assessment. BvFTD shows significant symptomatic overlap with non-degenerative primary psychiatric disorders including major depressive disorder, bipolar disorder, schizophrenia, obsessive-compulsive disorder, autism spectrum disorders and even personality disorders. To date, ∼50% of patients with bvFTD receive a prior psychiatric diagnosis, and average diagnostic delay is up to 5–6 years from symptom onset. It is also not uncommon for patients with primary psychiatric disorders to be wrongly diagnosed with bvFTD. The Neuropsychiatric International Consortium for Frontotemporal Dementia was recently established to determine the current best clinical practice and set up an international collaboration to share a common dataset for future research. The goal of the present paper was to review the existing literature on the diagnosis of bvFTD and its differential diagnosis with primary psychiatric disorders to provide consensus recommendations on the clinical assessment. A systematic literature search with a narrative review was performed to determine all bvFTD-related diagnostic evidence for the following topics: bvFTD history taking, psychiatric assessment, clinical scales, physical and neurological examination, bedside cognitive tests, neuropsychological assessment, social cognition, structural neuroimaging, functional neuroimaging, CSF and genetic testing. For each topic, responsible team members proposed a set of minimal requirements, optimal clinical recommendations, and tools requiring further research or those that should be developed. Recommendations were listed if they reached a ≥ 85% expert consensus based on an online survey among all consortium participants. New recommendations include performing at least one formal social cognition test in the standard neuropsychological battery for bvFTD. We emphasize the importance of 3D-T1 brain MRI with a standardized review protocol including validated visual atrophy rating scales, and to consider volumetric analyses if available. We clarify the role of 18F-fluorodeoxyglucose PET for the exclusion of bvFTD when normal, whereas non-specific regional metabolism abnormalities should not be over-interpreted in the case of a psychiatric differential diagnosis. We highlight the potential role of serum or CSF neurofilament light chain to differentiate bvFTD from primary psychiatric disorders. Finally, based on the increasing literature and clinical experience, the consortium determined that screening for C9orf72 mutation should be performed in all possible/probable bvFTD cases or suspected cases with strong psychiatric features.

The typical presentation of semantic dementia is associated with marked, left predominant anterior temporal lobe atrophy and with changes in language. About 30% of individuals, however, present with predominant right anterior temporal lobe atrophy, usually accompanied by behavioural changes and prosopagnosia. Here, we aimed to establish whether these initially distinct clinical presentations evolve into a similar syndrome at the neural and behavioural level. Thirty-one patients who presented with predominant anterior temporal lobe atrophy were included. Based on imaging, patients were categorized as either predominant left (n = 22) or right (n = 9) semantic dementia. Thirty-three Alzheimer's disease patients and 25 healthy controls were included for comparison. Participants completed the Addenbrooke's Cognitive Examination, a Face and Emotion Processing Battery and the Cambridge Behavioural Inventory, and underwent magnetic resonance imaging annually. Longitudinal neuroimaging analyses showed greater right temporal pole atrophy in left semantic dementia than Alzheimer's disease, whereas right semantic dementia showed greater orbitofrontal and left temporal lobe atrophy than Alzheimer's disease. Importantly, direct comparisons between semantic dementia groups revealed that over time, left semantic dementia showed progressive thinning in the right temporal pole, whereas right semantic dementia showed thinning in the orbitofrontal cortex and anterior cingulate. Behaviourally, longitudinal analyses revealed that general cognition declined in all patients. In contrast, patients with left and right semantic dementia showed greater emotion recognition decline than Alzheimer's disease. In addition, left semantic dementia showed greater motivation loss than Alzheimer's disease. Correlational analyses revealed that emotion recognition was associated with right temporal pole, right medial orbitofrontal and right fusiform integrity, while changes in motivation were associated with right temporal pole cortical thinning. While left and right semantic dementia show distinct profiles at presentation, both phenotypes develop deficits in emotion recognition and behaviour. These findings highlight the pervasive socio-emotional deficits in frontotemporal dementia, even in patients with an initial language presentation. These changes reflect right anterior temporal and orbitofrontal cortex degeneration, underscoring the role of these regions in social cognition and behaviour.

Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). There is currently no single definitive test for MS. Circulating exosomes represent promising candidate biomarkers for a host of human diseases. Exosomes contain RNA, DNA, and proteins, can cross the blood-brain barrier, and are secreted from almost all cell types including cells of the CNS. We hypothesized that serum exosomal miRNAs could present a useful blood-based assay for MS disease detection and monitoring. Exosome-associated microRNAs in serum samples from MS patients (n = 25) and matched healthy controls (n = 11) were profiled using small RNA next generation sequencing. We identified differentially expressed exosomal miRNAs in both relapsing-remitting MS (RRMS) (miR-15b-5p, miR-451a, miR-30b-5p, miR-342-3p) and progressive MS patient sera (miR-127-3p, miR-370-3p, miR-409-3p, miR-432-5p) in relation to controls. Critically, we identified a group of nine miRNAs (miR-15b-5p, miR-23a-3p, miR-223-3p, miR-374a-5p, miR-30b-5p, miR-433-3p, miR-485-3p, miR-342-3p, miR-432-5p) that distinguished relapsing-remitting from progressive disease. Eight out of nine miRNAs were validated in an independent group (n = 11) of progressive MS cases. This is the first demonstration that microRNAs associated with circulating exosomes are informative biomarkers not only for the diagnosis of MS, but in predicting disease subtype with a high degree of accuracy.

IMPORTANCE While advances have been made in characterizing the C9ORF72 clinical phenotype, the hallmark features that discriminate between carriers and noncarriers remain unclear. OBJECTIVES To determine the frequency of the C9ORF72 mutation in a frontotemporal dementia (FTD) cohort and to define the clinical, neuropsychological, behavioral, and imaging features of C9ORF72 mutation carriers in comparison with noncarriers in a well-defined behavioral-variant (bv)-FTD cohort. DESIGN, SETTING, AND PARTICIPANTS A prospective cohort study of patients assessed during a 5-year period from January 1, 2008, to December 31, 2012, at an FTD specialist referral center (FRONTIER). A total of 114 consecutive patients with FTD, FTD-amyotrophic lateral sclerosis (ALS), and corticobasal syndrome were assessed at FRONTIER. Patients with bvFTD who carried the C9ORF72 mutation (n = 10) were compared with noncarriers (n = 19) and a healthy control group (n = 35). These were matched for age, sex, and education history. Blood sampling for gene analysis was performed after informed consent was obtained. MAIN OUTCOMES AND MEASURES Clinical, behavioral, cognitive, and neuropsychological deficits, cortical atrophy on a magnetic resonance imaging visual rating scale, and family history as quantified by the Goldman Scale. RESULTS In a cohort of 114 FTD cases, 14 patients expressed the C9ORF72 mutation, representing a frequency rate of 34% in bvFTD and 17% in FTD-ALS. Family histories of ALS (P = .001) and psychiatric disorders (P = .02) were significantly more common in mutation carriers. The C9ORF72 carriers were also more likely to experience psychotic symptoms (P = .03). The degree of brain atrophy was significantly less in the C9ORF72 cohort, and in many the progression was slow. Presenting features of C9ORF72 carriers were compared against International Consensus Diagnostic Criteria for bvFTD, and most cases failed to satisfy criteria for probable bvFTD. CONCLUSIONS AND RELEVANCE The C9ORF72 mutation appears to be a common cause of bvFTD. Many of the C9ORF72 carriers have a family history of ALS or psychiatric illness. Psychotic features emerged as the most discriminating clinical feature between mutation carriers and noncarriers. Progression is often slow and brain atrophy is less pronounced than in nonmutation cases of bvFTD. These findings have clinical relevance for both diagnosis and selection of patients for genetic testing.

Tasks of sarcasm detection represent a clinically useful tool to differentiate between bvFTD and AD at baseline. Furthermore, tasks of socioemotional functioning can track progression within bvFTD and identify bvFTD patients more likely to show a faster rate of decline.

Neurodegeneration refers to a heterogeneous group of brain disorders that progressively evolve. It has been increasingly appreciated that many neurodegenerative conditions overlap at multiple levels and therefore traditional clinicopathological correlation approaches to better classify a disease have met with limited success. Neuronal network disintegration is fundamental to neurodegeneration, and concepts based around such a concept may better explain the overlap between their clinical and pathological phenotypes. In this Review, promoters of overlap in neurodegeneration incorporating behavioural, cognitive, metabolic, motor, and extrapyramidal presentations will be critically appraised. In addition, evidence that may support the existence of large-scale networks that might be contributing to phenotypic differentiation will be considered across a neurodegenerative spectrum. Disintegration of neuronal networks through different pathological processes, such as prion-like spread, may provide a better paradigm of disease and thereby facilitate the identification of novel therapies for neurodegeneration.

Neuropsychiatric symptoms appear before classic motor features in ALS, which corroborates the notion that ALS and frontotemporal dementia lie on a disease continuum. The early detection of neuropsychiatric symptoms will be critical to inform clinical decisions and alleviate carer burden. Importantly, subtle neuropsychiatric symptoms alone do not affect survival in ALS, which in turn confirms their pervasive nature in ALS.