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Cerebral cortical encephalitis (CCE) is a recently described myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) phenotype. In this observational retrospective study, we characterized 19 CCE patients (6.7% of our MOGAD cohort). Headache (n = 15, 79%), seizures (n = 13, 68%), and encephalopathy (n = 12, 63%) were frequent. Magnetic resonance imaging revealed unilateral (n = 12, 63%) or bilateral (n = 7, 37%) cortical T2 hyperintensity and leptomeningeal enhancement (n = 17, 89%). N-Methyl-D-aspartate receptor autoantibodies coexisted in 2 of 15 tested (13%). CCE pathology (n = 2) showed extensive subpial cortical demyelination (n = 2), microglial reactivity (n = 2), and inflammatory infiltrates (perivascular, n = 1; meningeal, n = 1). Most received high-dose steroids (n = 17, 89%), and all improved, but 3 had CCE relapses. This study highlights the CCE spectrum and provides insight into its pathogenesis. ANN NEUROL 2022.

Background and ObjectivesStudies on tumefactive brain lesions in myelin oligodendrocyte glycoprotein-immunoglobulin G (IgG)–associated disease (MOGAD) are lacking. We sought to characterize the frequency clinical, laboratory, and MRI features of these lesions in MOGAD and compare them with those in multiple sclerosis (MS) and aquaporin-4-IgG–positive neuromyelitis optica spectrum disorder (AQP4+NMOSD).MethodsWe retrospectively searched 194 patients with MOGAD and 359 patients with AQP4+NMOSD with clinical/MRI details available from the Mayo Clinic databases and included those with ≥1 tumefactive brain lesion (maximum transverse diameter ≥2 cm) on MRI. Patients with tumefactive MS were identified using the Mayo Clinic medical record linkage system. Binary multivariable stepwise logistic regression identified independent predictors of MOGAD diagnosis; Cox proportional regression models were used to assess the risk of relapsing disease and gait aid in patients with tumefactive MOGAD vs those with nontumefactive MOGAD.ResultsWe included 108 patients with tumefactive demyelination (MOGAD = 43; AQP4+NMOSD = 16; and MS = 49). Tumefactive lesions were more frequent among those with MOGAD (43/194 [22%]) than among those with AQP4+NMOSD (16/359 [5%],p< 0.001). Risk of relapse and need for gait aid were similar in tumefactive and nontumefactive MOGAD. Clinical features more frequent in MOGAD than in MS included headache (18/43 [42%] vs 10/49 [20%];p= 0.03) and somnolence (12/43 [28%] vs 2/49 [4%];p= 0.003), the latter also more frequent than in AQP4+NMOSD (0/16 [0%];p= 0.02). The presence of peripheral T2-hypointense rim, T1-hypointensity, diffusion restriction (particularly an arc pattern), ring enhancement, and Baló-like or cystic appearance favored MS over MOGAD (p≤ 0.001). MRI features were broadly similar in MOGAD and AQP4+NMOSD, except for more frequent diffusion restriction in AQP4+NMOSD (10/15 [67%]) than in MOGAD (11/42 [26%],p= 0.005). CSF analysis revealed less frequent positive oligoclonal bands in MOGAD (2/37 [5%]) than in MS (30/43 [70%],p< 0.001) and higher median white cell count in MOGAD than in MS (33 vs 6 cells/μL,p< 0.001). At baseline, independent predictors of MOGAD diagnosis were the presence of somnolence/headache, absence of T2-hypointense rim, lack of T1-hypointensity, and no diffusion restriction (NagelkerkeR2= 0.67). Tumefactive lesion resolution was more common in MOGAD than in MS or AQP4+NMOSD and improved model performance.DiscussionTumefactive lesions are frequent in MOGAD but not associated with a worse prognosis. The clinical, MRI, and CSF attributes of tumefactive MOGAD differ from those of tumefactive MS and are more similar to those of tumefactive AQP4+NMOSD with the exception of lesion resolution, which favors MOGAD.

ObjectivesTo report the expanded neurological presentations and oncological associations of tripartite motif-containing protein 46 (TRIM46)-IgG seropositive patients.MethodsArchived sera/cerebrospinal fluid (CSF) were evaluated by tissue-based immunofluorescence assay to identify patients with identical axon initial segment (AIS)-specific staining pattern. Phage immunoprecipitation sequencing (PhIP-Seq) was used to identify the putative autoantigen.ResultsIgG in serum (17) and/or CSF (16) from 25 patients yielded unique AIS-specific staining on murine central nervous system (CNS) tissue. An autoantibody specific for TRIM46 was identified by PhIP-Seq, and autoantigen specificity was confirmed by transfected COS7 cell-based assay. Clinical information was available for 22 TRIM46-IgG seropositive patients. Fifteen were female (68%). Median age was 67 years (range 25–87). Fifteen (68%) patients presented with subacute cerebellar syndrome (six isolated; nine with CNS accompaniments: encephalopathy (three), brainstem signs (two), myelopathy (two), parkinsonism (one)). Other phenotypes included limbic encephalitis (three), encephalopathy with/without seizures (two), myelopathy (two). Eighteen (82%) had cancer: neuroendocrine carcinomas (9; pancreatic (3), small-cell lung (4), oesophagus (1), endometrium (1)), adenocarcinomas (6; lung (2), ovarian (2), endometrial (1), breast (1)), sarcoma (2) and gastrointestinal tumour (1). Neurological symptoms in three followed immune checkpoint inhibitor (ICI) administration.ConclusionsThis study supports TRIM46-IgG being a biomarker of paraneoplastic CNS disorders and expands the neurological phenotypes, oncological and ICI-related adverse event associations.

Neuromyelitis optica is an autoimmune inflammatory disorder targeting aquaporin-4 water channels in CNS astrocytes. Histopathological descriptions of astrocytic lesions reported in neuromyelitis optica so far have emphasized a characteristic loss of aquaporin-4, with deposition of IgG and complement and lysis of astrocytes, but sublytic reactions have been underappreciated. We performed a multi-modality study of 23 neuromyelitis optica autopsy cases (clinically and/or pathologically confirmed; 337 tissue blocks). By evaluating astrocytic morphology, immunohistochemistry and AQP4 RNA transcripts, and their associations with demyelinating activity, we documented a spectrum of astrocytopathy in addition to complement deposition, microglial reaction, granulocyte infiltration and regenerating activity. Within advanced demyelinating lesions, and in periplaque areas, there was remarkable hypertrophic astrogliosis, more subtle than astrocytic lysis. A degenerative component was suggested by ‘dystrophic’ morphology, cytoplasmic vacuolation, Rosenthal fibres and associated stress protein markers. The abundance of AQP4 mRNA transcripts in sublytic reactive astrocytes devoid of aquaporin-4 protein supported in vivo restoration following IgG-induced aquaporin-4 endocytosis/degradation. Astrocytic alterations extending beyond demyelinating lesions speak to astrocytopathy being an early and primary event in the evolving neuromyelitis optica lesion. Focal astrocytopathy observed without aquaporin-4 loss or lytic complement component deposition verifies that astrocytic reactions in neuromyelitis optica are not solely dependent on IgG-mediated aquaporin-4 loss or lysis by complement or by IgG-dependent leucocyte mediators. We conclude that neuromyelitis optica reflects a global astrocytopathy, initiated by binding of IgG to aquaporin-4 and not simply definable by demyelination and astrocytic lysis. The spectrum of astrocytic morphological changes in neuromyelitis optica attests to the complexity of factors influencing the range of astrocytic physiological responses to a targeted attack by aquaporin-4-specific IgG. Sublytic astrocytic reactions are no doubt an important determinant of the lesion’s evolution and potential for repair. Pharmacological manipulation of the astrocytic stress response may offer new avenues for therapeutic intervention.

Western-style diets cause disruptions in myelinating cells and astrocytes within the mouse CNS. Increased CD38 expression is present in the cuprizone and experimental autoimmune encephalomyelitis models of demyelination and CD38 is the main nicotinamide adenine dinucleotide (NAD+)-depleting enzyme in the CNS. Altered NAD+metabolism is linked to both high fat consumption and multiple sclerosis (MS). Here, we identify increased CD38 expression in the male mouse spinal cord following chronic high fat consumption, after focal toxin [lysolecithin (LL)]-mediated demyelinating injury, and in reactive astrocytes within active MS lesions. We demonstrate that CD38 catalytically inactive mice are substantially protected from high fat-induced NAD+depletion, oligodendrocyte loss, oxidative damage, and astrogliosis. A CD38 inhibitor, 78c, increased NAD+and attenuated neuroinflammatory changes induced by saturated fat applied to astrocyte cultures. Conditioned media from saturated fat-exposed astrocytes applied to oligodendrocyte cultures impaired myelin protein production, suggesting astrocyte-driven indirect mechanisms of oligodendrogliopathy. In cerebellar organotypic slice cultures subject to LL-demyelination, saturated fat impaired signs of remyelination effects that were mitigated by concomitant 78c treatment. Significantly, oral 78c increased counts of oligodendrocytes and remyelinated axons after focal LL-induced spinal cord demyelination. Using a RiboTag approach, we identified a uniquein vivobrain astrocyte translatome profile induced by 78c-mediated CD38 inhibition in mice, including decreased expression of proinflammatory astrocyte markers and increased growth factors. Our findings suggest that a high-fat diet impairs oligodendrocyte survival and differentiation through astrocyte-linked mechanisms mediated by the NAD+ase CD38 and highlights CD38 inhibitors as potential therapeutic candidates to improve myelin regeneration.SIGNIFICANCE STATEMENTMyelin disturbances and oligodendrocyte loss can leave axons vulnerable, leading to permanent neurologic deficits. The results of this study suggest that metabolic disturbances, triggered by consumption of a diet high in fat, promote oligodendrogliopathy and impair myelin regeneration through astrocyte-linked indirect nicotinamide adenine dinucleotide (NAD+)-dependent mechanisms. We demonstrate that restoring NAD+levels via genetic inactivation of CD38 can overcome these effects. Moreover, we show that therapeutic inactivation of CD38 can enhance myelin regeneration. Together, these findings point to a new metabolic targeting strategy positioned to improve disease course in multiple sclerosis and other conditions in which the integrity of myelin is a key concern.

Multiple sclerosis (MS) is by far the most common central nervous system inflammatory demyelinating disease (CNS-IDD). It is diagnosed according to detailed criteria based on clinical definitions, magnetic resonance imaging (MRI) and cerebrospinal fluid findings. However, in rare instances, atypical syndromes associated with CNS demyelination, such as unusual MRI findings or poor response to standard treatment, may eventually necessitate a CNS biopsy with neuropathological examination. Pathology remains the gold standard in the differentiation of atypical CNS-IDDs, the recognition of which is essential for establishing the correct prognosis and optimal therapy. However, one must bear in mind that between different CNS-IDDs there are still overlapping features, even in the pathology. In this review, we compare and highlight contrasts within a spectrum of CNS-IDDs from the neuropathological perspective. We characterise pathological hallmarks of active vs chronic multiple sclerosis. Also, we define differences in the pathology of MS, acute disseminated encephalomyelitis (ADEM), aquaporin 4-IgG positive (AQP4-IgG+) neuromyelitis optica spectrum disorder (NMOsd), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Detailed description of the particular CNS-IDD pathology is crucial on an individual patient level (when clinically justified in atypical cases) but also from a broader perspective i.e. to advance our understanding of the complex disease mechanisms. Recent immunobiological and pathological discoveries have led to the description of novel inflammatory CNS disorders that were previously classified as rare MS variants, such as NMOsd and MOGAD. Multiple sclerosis remains an umbrella diagnosis, as there is profound heterogeneity between patients. Advances in neuropathology research are likely to disentangle and define further CNS-IDDs that used to be categorised as multiple sclerosis.

ObjectiveTo describe clinical, radiologic, and pathologic features of Baló concentric sclerosis (BCS) and assess overlap between BCS and other CNS inflammatory demyelinating diseases.MethodsRetrospective review of BCS cases from US and Australian tertiary care centers.ResultsWe identified 40 BCS cases with 38 available MRIs. Solitary MRI lesions were present in 26% (10/38). We saw >1 active concurrent BCS lesion in 45% (17/38). A third (13/38) had multiple sclerosis–suggestive lesions on the index MRI, of which 10 fulfilled Barkhof criteria. In patients with serial MRI performed within 1 month of the index MRI, lesions expanded radially with sequentially increased numbers of T2 hyperintense rings 52% (14/27). Initially nonenhancing or centrally enhancing lesions subsequently developed single or multiple enhancing rings (41%; 9/22) and incomplete enhancing rings (14%; 3/22). Discordance between rings as they appear on apparent diffusion coefficient, diffusion-weighted imaging, and gadolinium-enhanced imaging was observed in 67% (22/33). Aquaporin-4 immunoglobulin G (n = 26) and myelin oligodendrocyte glycoprotein immunoglobulin G (n = 21) were negative in all patients with serum available. Clinical response to steroid treatment was seen in 46% (13/28). A monophasic clinical course was present in 56% (18/32) at last follow-up (median 27.5 months; range 3–100 months). The initial attack was fatal in 10% (4/40). Median time from symptom onset to death was 23 days (range 19–49 days). All 17 patients with pathology available demonstrated typical findings of multiple sclerosis. Patients with active demyelinating lesions all demonstrated oligodendrocytopathy (pattern III).ConclusionsBCS may be a distinct subtype of multiple sclerosis characterized by pattern III immunopathology.

ObjectiveTo determine whether MRI gadolinium enhancement patterns in myelopathies with longitudinally extensive T2 lesions can be reliably distinguished and assist in diagnosis.MethodsWe retrospectively identified 74 Mayo Clinic patients (January 1, 1996–December 31, 2019) fulfilling the following criteria: (1) clinical myelopathy; (2) MRI spine available; (3) longitudinally extensive T2 hyperintensity (≥3 vertebral segments); and (4) characteristic gadolinium enhancement pattern associated with a specific myelopathy etiology. Thirty-nine cases with alternative myelopathy etiologies, without previously described enhancement patterns, were included as controls. Two independent readers, educated on enhancement patterns, reviewed T2-weighted and postgadolinium T1-weighted images and selected the diagnosis based on this knowledge. These were compared with the true diagnoses, and agreement was measured with Kappa coefficient.ResultsAmong all cases and controls (n = 113), there was excellent agreement for diagnosis using postgadolinium images (kappa, 0.76) but poor agreement with T2-weighted characteristics alone (kappa, 0.25). A correct diagnosis was more likely when assessing postgadolinium image characteristics than with T2-weighted images alone (rater 1: 100/113 [88%] vs 61/113 [54%] correct, p < 0.0001; rater 2: 95/113 [84%] vs 68/113 [60%] correct, p < 0.0001). Of the 74 with characteristic enhancement patterns, 55 (74%) were assigned an alternative incorrect or nonspecific diagnosis when originally evaluated in clinical practice, 12 (16%) received immunotherapy for noninflammatory myelopathies, and 2 (3%) underwent unnecessary spinal cord biopsy.ConclusionsMisdiagnosis of myelopathies is common. The gadolinium enhancement patterns characteristic of specific diagnoses can be identified with excellent agreement between raters educated on this topic. This study highlights the potential diagnostic utility of enhancement patterns in myelopathies with longitudinally extensive T2 lesions.

OBJECTIVE Multiple sclerosis (MS) is a heterogeneous inflammatory demyelinating disease. Iron distribution is altered in MS patients' brains, suggesting iron liberation within active lesions amplifies demyelination and neurodegeneration. Whether the amount and distribution of iron are similar or different among different MS immunopatterns is currently unknown. METHODS We used synchrotron X-ray fluorescence imaging, histology, and immunohistochemistry to compare the iron quantity and distribution between immunopattern II and III early active MS lesions. We analyzed archival autopsy and biopsy tissue from 21 MS patients. RESULTS Immunopattern II early active lesions contain 64% more iron (95% confidence interval [CI] = 17-127%, p = 0.004) than immunopattern III lesions, and 30% more iron than the surrounding periplaque white matter (95% CI = 3-64%, p = 0.03). Iron in immunopattern III lesions is 28% lower than in the periplaque white matter (95% CI = -40 to -14%, p

Background: Haemorrhagic demyelinating lesions are rare, and little is known about the demyelinating diseases with which they are associated, or how lesional haemorrhage affects treatment and outcomes. Objective: To examine the clinical characteristics and outcomes of patients with demyelinating lesions and magnetic resonance imaging (MRI) evidence of haemorrhage seen at the Mayo clinic between 1990 and 2018. Methods: The Mayo Clinic’s medical-record diagnostic-linkage system was used to identify patients with CNS demyelinating disease and parenchymal haemorrhage on brain MRI cross-referenced against a database of patients with pathologically confirmed CNS demyelinating disease. The clinical characteristics, diagnosis, MRI findings, brain histopathology, and outcomes of these patients were reviewed. Results: Ten patients with haemorrhagic demyelination were identified, including three patients who underwent a brain biopsy. The main findings were that haemorrhagic demyelinating lesions most often occur in atypical forms of demyelination, especially acute haemorrhagic leukoencephalitis (AHL, or Weston–Hurst disease) and tumefactive demyelination, and rarely in multiple sclerosis. A spectrum of outcomes was observed for these patients ranging from complete remission through to high level disability. Conclusion: Lesional haemorrhage is uncommon in demyelinating disease where it is most closely associated with AHL. Bleeding within a demyelinating lesion does not always herald a poor prognosis.

Although major progress in multiple sclerosis research has been made during the last decades, key questions related to the cause and the mechanisms of brain and spinal cord pathology remain unresolved. These cover a broad range of topics, including disease aetiology, antigenic triggers of the immune response inside and/or outside the CNS and mechanisms of inflammation, demyelination neurodegeneration and tissue repair. Most of these questions can be addressed with novel molecular technologies in the injured CNS. Access to brain and spinal cord tissue from multiple sclerosis patients is, therefore, of critical importance. High-quality tissue is provided in part by the existing brain banks. However, material from early and highly active disease stages is limited. An initiative, realized under the patronage of the European Charcot Foundation, gathered together experts from different disciplines to analyse the current state of multiple sclerosis tissues collected post-mortem or as biopsies. Here, we present an account of what material is currently available and where it can be accessed. We also provide recommendations on how tissue donation from patients in early disease stages could be potentially increased and for procedures of tissue sampling and preservation. We also suggest to create a registry of the available tissues that, depending on the source (autopsy versus biopsy), could be made accessible to clinicians and researchers.

The antigen specificity of Anti-Neuronal Nuclear Antibody-type 3 (ANNA3)-IgG is unknown. We identified Dachshund-homolog 1 (DACH1) as the ANNA3 autoantigen and confirmed it by antigen-specific assays, immunohistochemical colocalization and immune absorption experiments. Patients' median age was 63.5 years (range, 49-88); 67% were female. Neurological manifestations (information available for 30 patients) included one or more of neuropathy, 12; cognitive difficulties, 11; ataxia, 8; dysautonomia, 7. Evidence of a neoplasm was present in 27 of 30 (90%), most of neuroendocrine lineage. DACH1-IgG is rare and represents a novel proposed biomarker of neurological autoimmunity and cancer. ANN NEUROL 2022;91:670-675.

Multiple sclerosis (MS) is a central nervous system inflammatory demyelinating disease and the most common cause of non-traumatic disability in young adults. Despite progress in the treatment of the active relapsing disease, therapeutic options targeting irreversible progressive decline remain limited. Studies using skin fibroblasts derived from patients with neurodegenerative disorders demonstrate that cell stress pathways and bioenergetics are altered when compared to healthy individuals. However, findings in MS skin fibroblasts are limited. Here, we collected skin fibroblasts from 24 healthy control individuals, 30 patients with MS, and ten with amyotrophic lateral sclerosis (ALS) to investigate altered cell stress profiles. We observed endoplasmic reticulum swelling in MS skin fibroblasts, and increased gene expression of cell stress markers including BIP, ATF4, CHOP, GRP94, P53, and P21. When challenged against hydrogen peroxide, MS skin fibroblasts had reduced resiliency compared to ALS and controls. Mitochondrial and glycolytic functions were perturbed in MS skin fibroblasts while exhibiting a significant increase in lactate production over ALS and controls. Our results suggest that MS skin fibroblasts have an underlying stress phenotype, which may be disease specific. Interrogating MS skin fibroblasts may provide patient specific molecular insights and aid in prognosis, diagnosis, and therapeutic testing enhancing individualized medicine.

We sought to define the pathological features of myelin oligodendrocyte glycoprotein (MOG) antibody associated disorders (MOGAD) in an archival autopsy/biopsy cohort. We histopathologically analyzed 2 autopsies and 22 brain biopsies from patients with CNS inflammatory demyelinating diseases seropositive for MOG-antibody by live-cell-based-assay with full length MOG in its conformational form. MOGAD autopsies (ages 52 and 67) demonstrate the full spectrum of histopathological features observed within the 22 brain biopsies (median age, 10 years; range, 1–66; 56% female). Clinical, radiologic, and laboratory characteristics and course (78% relapsing) are consistent with MOGAD. MOGAD pathology is dominated by coexistence of both perivenous and confluent white matter demyelination, with an over-representation of intracortical demyelinated lesions compared to typical MS. Radially expanding confluent slowly expanding smoldering lesions in the white matter as seen in MS, are not present. A CD4+ T-cell dominated inflammatory reaction with granulocytic infiltration predominates. Complement deposition is present in all active white matter lesions, but a preferential loss of MOG is not observed. AQP4 is preserved, with absence of dystrophic astrocytes, and variable oligodendrocyte and axonal destruction. MOGAD is pathologically distinguished from AQP4-IgG seropositive NMOSD, but shares some overlapping features with both MS and ADEM, suggesting a transitional pathology. Complement deposition in the absence of selective MOG protein loss suggest humoral mechanisms are involved, however argue against endocytic internalization of the MOG antigen. Parallels with MOG-EAE suggest MOG may be an amplification factor that augments CNS demyelination, possibly via complement mediated destruction of myelin or ADCC phagocytosis.

Multiple sclerosis (MS) is the most common cause of nontraumatic disability in young adults. It is a chronic inflammatory demyelinating disease of the central nervous system. Traditionally, MS has been considered an autoimmune disorder consisting of myelin autoreactive T cells that drive an inflammatory process, leading to secondary macrophage recruitment and subsequent myelin destruction. However, accumulating data based on increasing numbers of probes that can be effectively applied to MS tissue have indicated that the events involved in the immunopathogenesis of MS may be more complicated.

A 35-year-old man sought care for progressive visual disturbance. Magnetic resonance imaging of the brain showed a large, left-sided, parieto-occipital, contrast-enhancing lesion. He was treated with dexamethasone with brief improvement in vision. Within 5 days he had progressive vision worsening. Two weeks after the onset of his symptoms, brain magnetic resonance imaging showed a decrease in lesion size, and corticosteroids were discontinued. Two months after symptom onset he was found to have alexia without agraphia, and follow-up magnetic resonance imaging showed an increased size of the lesion. Two months after disease onset, the patient underwent a left occipital brain biopsy, which demonstrated a macrophage-enriched active demyelinating lesion with relative axonal sparing. Right arm weakness and aphasia developed, along with a fever. He was treated with dexamethasone. Electroencephalography indicated multiple seizures. Repeated cerebrospinal fluid analysis showed a slightly increased white blood cell count, increased protein level, immunoglobulin G index of 0.84, and the presence of 3 cerebrospinal fluid-unique oligoclonal bands. He was treated with 5 days of intravenous methylprednisolone and levetiracetam, with improvement. Three and a half years later, the patient came to the emergency department with weakness of the left leg associated with reduced sensation. Spinal magnetic resonance imaging showed a new demyelinating contrast-enhancing lesion from T2 to T7. He was treated with 5 days of intravenous methylprednisolone followed by 6 sessions of plasma exchange, with improvement. A diagnosis of relapsing tumefactive demyelination was made. The patient was subsequently treated with ocrelizumab. Tumefactive demyelinating lesions pose a diagnostic challenge, especially if they are the first manifestations of demyelinating disease. Typically, tumefactive demyelinating lesions are large (>2 cm) and are associated with edema, mass effect, and variable patterns of contrast enhancement.

OBJECTIVE Histology reveals that early active multiple sclerosis lesions can be classified into 3 main interindividually heterogeneous but intraindividually stable immunopathological patterns of active demyelination (patterns I-III). In patterns I and II, a T-cell- and macrophage-associated demyelination is suggested, with pattern II only showing signs of a humoral immune response. Pattern III is characterized by inflammatory lesions with an oligodendrocyte degeneration. Patterns suggest pathogenic heterogeneity, and we postulated that they have distinct magnetic resonance imaging (MRI) correlates that may serve as biomarkers. METHODS We evaluated in an international collaborative retrospective cohort study the MRI lesion characteristics of 789 conventional prebiopsy and follow-up MRIs in relation to their histopathologically classified immunopathological patterns (n = 161 subjects) and lesion edge features (n = 112). RESULTS A strong association of a ringlike enhancement and a hypointense T2-weighted (T2w) rim with patterns I and II, but not pattern III, was observed. Only a fraction of pattern III patients showed a ringlike enhancement, and this was always atypical. Ringlike enhancement and T2w rims colocalized, and ringlike enhancement showed a strong association with macrophage rims as shown by histology. A strong concordance of MRI lesion characteristics, meaning that different lesions showed the same features, was found when comparing biopsied and nonbiopsied lesions at a given time point, indicating lesion homogeneity within individual patients. INTERPRETATION We provide robust evidence that MRI characteristics reflect specific morphological features of multiple sclerosis immunopatterns and that ringlike enhancement and T2w hypointense rims might serve as a valuable noninvasive biomarker to differentiate pathological patterns of demyelination. ANN NEUROL 2021;90:440-454.

Background: Limited studies have described long-term outcomes in pathology confirmed multiple sclerosis (MS). Objectives: To describe long-term clinical–radiographic–cognitive outcomes in a prospectively followed cohort of patients with pathologically confirmed CNS demyelinating disease, consistent with MS. Methods: Subjects underwent clinical assessment, standardized 3T-MRI brain, and cognitive battery. Results: Seventy-five patients were included. Biopsied lesion size was ⩾ 2 cm in 62/75. At follow-up, median duration since biopsy was 11 years. Median EDSS was 3 and lesion burden was large (median 10 cm3). At follow-up, 57/75 met MS criteria, 17/75 had clinically isolated syndrome, and 1 radiographic changes only. Disability scores were comparable to a prevalence cohort in Olmsted County ( p < 0.001, n = 218). Cognitive outcomes below age-normed standards included psychomotor, attention, working memory, and executive function domains. Total lesion volume and index lesion-related severity correlated with EDSS and cognitive performance. Volumetric cortical/subcortical GM correlated less than lesion metrics to cognitive outcomes. Conclusion: Despite early aggressive course in pathologically confirmed MS, its long-term course was comparable to typical MS in our study. Cognitive impairment in this group seemed to correlate strongest to index lesion severity and total lesion volume. It remains to be established how the aggressive nature of the lesion, biopsy, and treatment affect clinical/cognitive outcomes.

BACKGROUND: Twenty-five single nucleotide polymorphisms (SNPs) are associated with adult diffuse glioma risk. We hypothesized that the inclusion of these 25 SNPs with age at diagnosis and sex could estimate risk of glioma as well as identify glioma subtypes. METHODS: Case-control design and multinomial logistic regression were used to develop models to estimate the risk of glioma development while accounting for histologic and molecular subtypes. Case-case design and logistic regression were used to develop models to predict isocitrate dehydrogenase (IDH) mutation status. A total of 1273 glioma cases and 443 controls from Mayo Clinic were used in the discovery set, and 852 glioma cases and 231 controls from UCSF were used in the validation set. All samples were genotyped using a custom Illumina OncoArray. RESULTS: Patients in the highest 5% of the risk score had more than a 14-fold increase in relative risk of developing an IDH mutant glioma. Large differences in lifetime absolute risk were observed at the extremes of the risk score percentile. For both IDH mutant 1p/19q non-codeleted glioma and IDH mutant 1p/19q codeleted glioma, the lifetime risk increased from almost null to 2.3% and almost null to 1.7%, respectively. The SNP-based model that predicted IDH mutation status had a validation concordance index of 0.85. CONCLUSIONS: These results suggest that germline genotyping can provide new tools for the initial management of newly discovered brain lesions. Given the low lifetime risk of glioma, risk scores will not be useful for population screening; however, they may be useful in certain clinically defined high-risk groups.

Background and ObjectivesThe goal of this work was to compare clinical characteristics across immunopathologic subtypes of patients with multiple sclerosis.MethodsImmunopathologic subtyping was performed on specimens from 547 patients with biopsy- or autopsy-confirmed CNS demyelination.ResultsThe frequency of immunopathologic subtypes was 23% for pattern I, 56% for pattern II, and 22% for pattern III. Immunopatterns were similar in terms of age at autopsy/biopsy (median age 41 years, range 4–83 years, p = 0.16) and proportion female (54%, p = 0.71). Median follow-up after symptom onset was 2.3 years (range 0–38 years). In addition to being overrepresented among autopsy cases (45% vs 19% in biopsy cohort, p < 0.001), index attack-related disability was higher in pattern III vs II (median Expanded Disability Status Scale score 4 vs 3, p = 0.02). Monophasic clinical course was more common in patients with pattern III than pattern I or II (59% vs 33% vs 32%, p < 0.001). Similarly, patients with pattern III pathology were likely to have progressive disease compared to patients with patterns I or II when followed up for ≥5 years (24% overall, p = 0.49), with no differences in long-term survival, despite a more fulminant attack presentation.ConclusionAll 3 immunopatterns can be detected in active lesions, although they are found less frequently later into the disease due to the lower number of active lesions. Pattern III is associated with a more fulminant initial attack than either pattern I or II. Biopsied patients appear to have similar long-term outcomes regardless of their immunopatterns. Progressive disease is less associated with the initial immunopattern and suggests convergence into a final common pathway related to the chronically denuded axon.

Background and ObjectiveThere are few studies comparing lesion evolution across different CNS demyelinating diseases, yet knowledge of this may be important for diagnosis and understanding differences in disease pathogenesis. We sought to compare MRI T2 lesion evolution in myelin oligodendrocyte glycoprotein immunoglobulin G (IgG)–associated disorder (MOGAD), aquaporin 4 IgG–positive neuromyelitis optica spectrum disorder (AQP4-IgG-NMOSD), and multiple sclerosis (MS).MethodsIn this descriptive study, we retrospectively identified Mayo Clinic patients with MOGAD, AQP4-IgG-NMOSD, or MS and (1) brain or myelitis attack; (2) available attack MRI within 6 weeks; and (3) follow-up MRI beyond 6 months without interval relapses in that region. Two neurologists identified the symptomatic or largest T2 lesion for each patient (index lesion). MRIs were then independently reviewed by 2 neuroradiologists blinded to diagnosis to determine resolution of T2 lesions by consensus. The index T2 lesion area was manually outlined acutely and at follow-up to assess variation in size.ResultsWe included 156 patients (MOGAD, 38; AQP4-IgG-NMOSD, 51; MS, 67) with 172 attacks (brain, 81; myelitis, 91). The age (median [range]) differed between MOGAD (25 [2–74]), AQP4-IgG-NMOSD (53 [10–78]), and MS (37 [16–61]) (p < 0.01) and female sex predominated in the AQP4-IgG-NMOSD (41/51 [80%]) and MS (51/67 [76%]) groups but not among those with MOGAD (17/38 [45%]). Complete resolution of the index T2 lesion was more frequent in MOGAD (brain, 13/18 [72%]; spine, 22/28 [79%]) than AQP4-IgG-NMOSD (brain, 3/21 [14%]; spine, 0/34 [0%]) and MS (brain, 7/42 [17%]; spine, 0/29 [0%]) (p < 0.001). Resolution of all T2 lesions occurred most often in MOGAD (brain, 7/18 [39%]; spine, 22/28 [79%]) than AQP4-IgG-NMOSD (brain, 2/21 [10%]; spine, 0/34 [0%]) and MS (brain, 2/42 [5%]; spine, 0/29 [0%]) (p < 0.01). There was a larger median (range) reduction in T2 lesion area in mm2 on follow-up axial brain MRI with MOGAD (213 [55–873]) than AQP4-IgG-NMOSD (104 [0.7–597]) (p = 0.02) and MS (36 [0–506]) (p < 0.001) and the reductions in size on sagittal spine MRI follow-up in MOGAD (262 [0–888]) and AQP4-IgG-NMOSD (309 [0–1885]) were similar (p = 0.4) and greater than in MS (23 [0–152]) (p < 0.001).DiscussionThe MRI T2 lesions in MOGAD resolve completely more often than in AQP4-IgG-NMOSD and MS. This has implications for diagnosis, monitoring disease activity, and clinical trial design, while also providing insight into pathogenesis of CNS demyelinating diseases.

This cohort study reports outcomes of long-term follow-up in patients with myelin oligodendrocyte glycoprotein antibody–associated disorder.

Western-style diets cause disruptions in myelinating cells and astrocytes within the mouse CNS. Increased CD38 expression is present in the cuprizone and experimental autoimmune encephalomyelitis models of demyelination and CD38 is the main nicotinamide adenine dinucleotide (NAD(+))-depleting enzyme in the CNS. Altered NAD(+) metabolism is linked to both high fat consumption and multiple sclerosis (MS). Here, we identify increased CD38 expression in the male mouse spinal cord following chronic high fat consumption, after focal toxin [lysolecithin (LL)]-mediated demyelinating injury, and in reactive astrocytes within active MS lesions. We demonstrate that CD38 catalytically inactive mice are substantially protected from high fat-induced NAD(+) depletion, oligodendrocyte loss, oxidative damage, and astrogliosis. A CD38 inhibitor, 78c, increased NAD(+) and attenuated neuroinflammatory changes induced by saturated fat applied to astrocyte cultures. Conditioned media from saturated fat-exposed astrocytes applied to oligodendrocyte cultures impaired myelin protein production, suggesting astrocyte-driven indirect mechanisms of oligodendrogliopathy. In cerebellar organotypic slice cultures subject to LL-demyelination, saturated fat impaired signs of remyelination effects that were mitigated by concomitant 78c treatment. Significantly, oral 78c increased counts of oligodendrocytes and remyelinated axons after focal LL-induced spinal cord demyelination. Using a RiboTag approach, we identified a unique in vivo brain astrocyte translatome profile induced by 78c-mediated CD38 inhibition in mice, including decreased expression of proinflammatory astrocyte markers and increased growth factors. Our findings suggest that a high-fat diet impairs oligodendrocyte survival and differentiation through astrocyte-linked mechanisms mediated by the NAD(+)ase CD38 and highlights CD38 inhibitors as potential therapeutic candidates to improve myelin regeneration. SIGNIFICANCE STATEMENT Myelin disturbances and oligodendrocyte loss can leave axons vulnerable, leading to permanent neurologic deficits. The results of this study suggest that metabolic disturbances, triggered by consumption of a diet high in fat, promote oligodendrogliopathy and impair myelin regeneration through astrocyte-linked indirect nicotinamide adenine dinucleotide (NAD(+))-dependent mechanisms. We demonstrate that restoring NAD(+) levels via genetic inactivation of CD38 can overcome these effects. Moreover, we show that therapeutic inactivation of CD38 can enhance myelin regeneration. Together, these findings point to a new metabolic targeting strategy positioned to improve disease course in multiple sclerosis and other conditions in which the integrity of myelin is a key concern.

Western-style diets cause disruptions in myelinating cells and astrocytes within the mouse CNS. CD38 has increased expression in the cuprizone and EAE demyelination models and is the main NAD+ depleting enzyme in CNS tissue. Altered NAD+ metabolism has been linked to both high fat consumption and Multiple Sclerosis (MS). We identified increased CD38 expression in the male mouse spinal cord following chronic high fat consumption or focal lysolecithin-induced demyelinating injury as well as in reactive astrocytes within an active MS lesion. CD38-catalytically inactive mice are significantly protected from high fat-induced NAD+ depletion, oligodendrocyte loss, oxidative damage, and astrogliosis. 78c, a CD38 inhibitor, increased NAD+ and attenuated neuroinflammatory changes in astrocytes induced by saturated fat. Conditioned media from saturated fat-treated astrocytes impaired oligodendrocyte differentiation pointing to indirect mechanisms of oligodendrogliopathy. Combined saturated fat and lysolecithin demyelination in cerebellar slices resulted in additional deficits in myelin proteins that were mitigated by concomitant 78c treatment. Importantly, oral 78c increased counts of oligodendrocytes and remyelinated axons after focal demyelination. Our findings suggest high fat diet impairs oligodendrocyte survival and differentiation through astrocyte-linked mechanisms mediated by the NAD+ase CD38, and highlight the use of CD38 inhibitors as potential therapeutic candidates to improve myelin regeneration.

We report the neuropathological findings of a patient who died from complications of COVID-19. The decedent was initially hospitalized for surgical management of underlying coronary artery disease. He developed post-operative complications and was evaluated with chest imaging studies. The chest computed tomography (CT) imaging results were indicative of COVID-19 and he was subsequently tested for SARS-CoV-2, which was positive. His condition worsened and he died after more than 2 weeks of hospitalization and aggressive treatment. The autopsy revealed a range of neuropathological lesions, with features resembling both vascular and demyelinating etiologies. Hemorrhagic white matter lesions were present throughout the cerebral hemispheres with surrounding axonal injury and macrophages. The subcortical white matter had scattered clusters of macrophages, a range of associated axonal injury, and a perivascular acute disseminated encephalomyelitis (ADEM)-like appearance. Additional white matter lesions included focal microscopic areas of necrosis with central loss of white matter and marked axonal injury. Rare neocortical organizing microscopic infarcts were also identified. Imaging and clinical reports have demonstrated central nervous system complications in patients’ with COVID-19, but there is a gap in our understanding of the neuropathology. The lesions described in this case provide insight into the potential parainfectious processes affecting COVID-19 patients, which may direct clinical management and ongoing research into the disease. The clinical course of the patient also illustrates that during prolonged hospitalizations neurological complications of COVID may develop, which are particularly difficult to evaluate and appreciate in the critically ill.

Background: Tumor necrosis factor alpha (TNF-alpha) inhibitors, such as infliximab, are commonly used to treat rheumatoid arthritis (RA) and other immune-mediated disorders. Objective: To determine whether infliximab-associated central nervous system (CNS) demyelination can be differentiated from multiple sclerosis (MS). Methods: We present a case of pathologically proven CNS demyelination in a patient treated with infliximab and describe clinical–radiographic–neuropathological findings. Putative mechanisms of TNF-alpha inhibitor-associated CNS demyelination are described. Results and conclusion: Infliximab treatment is associated with CNS inflammatory demyelinating activity, which is histopathologically indistinguishable from MS.

ObjectiveTo describe paraneoplastic neuronal intermediate filament (NIF) autoimmunity.MethodsArchived patient and control serum and CSF specimens were evaluated by tissue-based indirect immunofluorescence assay (IFA). Autoantigens were identified by Western blot and mass spectrometry. NIF specificity was confirmed by dual tissue section staining and 5 recombinant NIF-specific HEK293 cell-based assays (CBAs, for α-internexin, neurofilament light [NfL], neurofilament medium, or neurofilament heavy chain, and peripherin). NIF–immunoglobulin Gs (IgGs) were correlated with neurologic syndromes and cancers.ResultsAmong 65 patients, NIF-IgG-positive by IFA and CBAs, 33 were female (51%). Median symptom onset age was 62 years (range 18–88). Patients fell into 2 groups, defined by the presence of NfL-IgG (21 patients, who mostly had ≥4 NIF-IgGs detected) or its absence (44 patients, who mostly had ≤2 NIF-IgGs detected). Among NfL-IgG-positive patients, 19/21 had ≥1 subacute onset CNS disorders: cerebellar ataxia (11), encephalopathy (11), or myelopathy (2). Cancers were detected in 16 of 21 patients (77%): carcinomas of neuroendocrine lineage (10) being most common (small cell [5], Merkel cell [3], other neuroendocrine [2]). Two of 257 controls (0.8%, both with small cell carcinoma) were positive by both IFA and CBA. Five of 7 patients with immunotherapy data improved. By comparison, the 44 NfL-IgG-negative patients had findings of unclear significance: diverse nervous system disorders (p= 0.006), as well as limited (p= 0.003) and more diverse (p< 0.0001) cancer accompaniments.ConclusionsNIF-IgG detection by IFA, with confirmatory CBA testing that yields a profile including NfL-IgG, defines a paraneoplastic CNS disorder (usually ataxia or encephalopathy) accompanying neuroendocrine lineage neoplasia.

A 50-year-old woman with a history of systemic lupus erythematosus (SLE) treated with methotrexate and hydroxychloroquine presented to the emergency department for evaluation of numbness and weakness of the left hand that began 12 hours earlier.

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a central nervous system inflammatory syndrome predominantly affecting the brainstem, cerebellum, and spinal cord. Following its initial description, the salient features of CLIPPERS have been confirmed and expanded upon, but the lack of formalized diagnostic criteria has led to reports of patients with dissimilar features purported to have CLIPPERS. We evaluated clinical, radiological and pathological features of patients referred for suspected CLIPPERS and propose diagnostic criteria to discriminate CLIPPERS from non-CLIPPERS aetiologies. Thirty-five patients were evaluated for suspected CLIPPERS. Clinical and neuroimaging data were reviewed by three neurologists to confirm CLIPPERS by consensus agreement. Neuroimaging and neuropathology were reviewed by experienced neuroradiologists and neuropathologists, respectively, both of whom were blinded to the clinical data. CLIPPERS was diagnosed in 23 patients (18 male and five female) and 12 patients had a non-CLIPPERS diagnosis. CLIPPERS patients' median age of onset was 58 years (interquartile range, 24-72) and were followed a median of 44 months (interquartile range 38-63). Non-CLIPPERS patients' median age of onset was 52 years (interquartile range, 39-59) and were followed a median of 27 months (interquartile range, 14-47). Clinical symptoms of gait ataxia, diplopia, cognitive impairment, and facial paraesthesia did not discriminate CLIPPERS from non-CLIPPERS. Marked clinical and radiological corticosteroid responsiveness was observed in CLIPPERS (23/23), and clinical worsening occurred in all 12 CLIPPERS cases when corticosteroids were discontinued. Corticosteroid responsiveness was common but not universal in non-CLIPPERS [clinical improvement (8/12); radiological improvement (2/12); clinical worsening on discontinuation (3/8)]. CLIPPERS patients had brainstem predominant perivascular gadolinium enhancing lesions on magnetic resonance imaging that were discriminated from non-CLIPPERS by: homogenous gadolinium enhancing nodules3 mm in diameter without ring-enhancement or mass effect, and homogenous T2 signal abnormality not significantly exceeding the T1 enhancement. Brain neuropathology on 14 CLIPPERS cases demonstrated marked CD3-positive T-lymphocyte, mild B-lymphocyte and moderate macrophage infiltrates, with perivascular predominance as well as diffuse parenchymal infiltration (14/14), present in meninges, white and grey matter, associated with variable tissue destruction, astrogliosis and secondary myelin loss. Clinical, radiological and pathological feature define CLIPPERS syndrome and are differentiated from non-CLIPPERS aetiologies by neuroradiological and neuropathological findings.

Pathogenic autoantibodies associated with neuromyelitis optica (NMO) induce disease by targeting aquaporin-4 (AQP4) water channels enriched on astrocytic endfeet at blood–brain interfaces. AQP4 is also expressed at cerebrospinal fluid (CSF)–brain interfaces, such as the pial glia limitans and the ependyma and at the choroid plexus blood–CSF barrier. However, little is known regarding pathology at these sites in NMO. Therefore, we evaluated AQP4 expression, microglial reactivity, and complement deposition at pial and ependymal surfaces and in the fourth ventricle choroid plexus in 23 autopsy cases with clinically and/or pathologically confirmed NMO or NMO spectrum disorder. These findings were compared to five cases with multiple sclerosis, five cases of choroid plexus papilloma, and five control cases without central nervous system disease. In the NMO cases, AQP4 immunoreactivity was reduced relative to control levels in the pia (91%; 21/23), ependyma (56%; 9/16), and choroid plexus epithelium (100%; 12/12). AQP4 immunoreactivity was normal in MS cases in these regions. Compared to MS, NMO cases also showed a focal pattern of pial and ependymal complement deposition and more pronounced microglial reactivity. In addition, AQP4 loss, microglial reactivity, and complement deposition colocalized along the pia and ependyma only in NMO cases. Within the choroid plexus, AQP4 loss was coincident with C9neo immunoreactivity on epithelial cell membranes only in NMO cases. These observations demonstrate that NMO immunopathology extends beyond perivascular astrocytic foot processes to include the pia, ependyma, and choroid plexus, suggesting that NMO IgG-induced pathological alterations at CSF–brain and blood–CSF interfaces may contribute to the occurrence of ventriculitis, leptomeningitis, and hydrocephalus observed among NMO patients. Moreover, disruption of the blood–CSF barrier induced by binding of NMO IgG to AQP4 on the basolateral surface of choroid plexus epithelial cells may provide a unique portal for entry of the pathogenic antibody into the central nervous system. Electronic supplementary material The online version of this article (doi:10.1007/s00401-017-1682-1) contains supplementary material, which is available to authorized users.

Objective We assessed the frequency and characteristics of ring-enhancing spinal cord lesions in neuromyelitis optica spectrum disorder (NMOSD) myelitis and myelitis of other cause. Methods We reviewed spinal cord MRIs for ring-enhancing lesions from 284 aquaporin-4 (AQP4)-IgG seropositive patients at Mayo Clinic from 1996 to 2014. Inclusion criteria were as follows: (1) AQP4-IgG seropositivity, (2) myelitis attack and (3) MRI spinal cord demonstrating ring-enhancement. We identified two groups of control patients with: (1) longitudinally extensive myelopathy of other cause (n=66) and (2) myelitis in the context of a concurrent or subsequent diagnosis of multiple sclerosis (MS) from a population-based cohort (n=30). Results Ring-enhancement was detected in 50 of 156 (32%) myelitis episodes in 41 patients (83% single; 17% multiple attacks). Ring-enhancement was noted on sagittal and axial images in 36 of 43 (84%) ring enhancing myelitis episodes and extended a median of two vertebral segments (range, 1–12); in 21 of 48 (44%) ring enhancing myelitis episodes, the ring extended greater than or equal to three vertebrae. Ring-enhancement was accompanied by longitudinally extensive (greater than or equal to three vertebral segments) T2-hyperintensity in 44 of 50 (88%) ring enhancing myelitis episodes. One case of a spinal cord biopsy during ring-enhancing myelitis revealed tissue vacuolation and loss of AQP4 immunoreactivity with preserved axons. The clinical characteristics of ring-enhancing myelitis episodes did not differ from non-ring-enhancing episodes. Ring-enhancing spinal cord lesions were more common in NMOSD than other causes of longitudinally extensive myelopathy (50/156 (32%) vs 0/66 (0%); p≤0.001) but did not differ between NMOSD and MS (50/156 (32%) vs 6/30 (20%); p=0.20). Conclusions Spinal cord ring-enhancement accompanies one-third of NMOSD myelitis episodes and distinguishes NMOSD from other causes of longitudinally extensive myelopathies but not from MS.

ObjectiveMyelin oligodendrocyte glycoprotein–immunoglobulin G (MOG-IgG) associated disorder (MOGAD) often manifests with recurrent CNS demyelinating attacks. The optimal treatment for reducing relapses is unknown. To help determine the efficacy of long-term immunotherapy in preventing relapse in patients with MOGAD, we conducted a multicenter retrospective study to determine the rate of relapses on various treatments.MethodsWe determined the frequency of relapses in patients receiving various forms of long-term immunotherapy for MOGAD. Inclusion criteria were history of ≥1 CNS demyelinating attacks, MOG-IgG seropositivity, and immunotherapy for ≥6 months. Patients were reviewed for CNS demyelinating attacks before and during long-term immunotherapy.ResultsSeventy patients were included. The median age at initial CNS demyelinating attack was 29 years (range 3–61 years; 33% ConclusionThis large retrospective multicenter study of patients with MOGAD suggests that maintenance immunotherapy reduces recurrent CNS demyelinating attacks, with the lowest ARR being associated with maintenance IVIG therapy. Traditional MS disease-modifying agents appear to be ineffective. Prospective randomized controlled studies are required to validate these conclusions.

Insulin resistance associates with increased risk for cognitive decline and dementia; however, the underpinning mechanisms for this increased risk remain to be fully defined. As insulin resistance impairs mitochondrial oxidative metabolism and increases ROS in skeletal muscle, we considered whether similar events occur in the brain, which - like muscle - is rich in insulin receptors and mitochondria. We show that high-fat diet-induced (HFD-induced) brain insulin resistance in mice decreased mitochondrial ATP production rate and oxidative enzyme activities in brain regions rich in insulin receptors. HFD increased ROS emission and reduced antioxidant enzyme activities, with the concurrent accumulation of oxidatively damaged mitochondrial proteins and increased mitochondrial fission. Improvement of insulin sensitivity by both aerobic exercise and metformin ameliorated HFD-induced abnormalities. Moreover, insulin-induced enhancement of ATP production in primary cortical neurons and astrocytes was counteracted by the insulin receptor antagonist S961, demonstrating a direct effect of insulin resistance on brain mitochondria. Further, intranasal S961 administration prevented exercise-induced improvements in ATP production and ROS emission during HFD, supporting that exercise enhances brain mitochondrial function by improving insulin action. These results support that insulin sensitizing by exercise and metformin restores brain mitochondrial function in insulin-resistant states.

Spinal cord involvement is an important cause of disability in patients with multiple sclerosis or neuromyelitis optica spectrum disorders (NMOSDs). Multiple sclerosis and NMOSDs can be distinguished from other disorders that cause myelopathy by results from laboratory and radiological investigations. However, limitations in the sensitivity and specificity of spinal cord imaging and poor correlation with disability megasures have impeded the understanding of the relationship between spinal cord involvement and clinical manifestations. Nevertheless, studies of the pathological features of multiple sclerosis and NMOSDs have shown that quantitatively different mechanisms lead to differences in clinical course and pattern of accrual of permanent disability in the two disorders. Better understanding of these mechanisms is necessary to develop more informative clinical measures, electrophysiological methods, fluid biomarkers, and imaging techniques to detect and monitor spinal cord involvement in the diagnosis and management of patients with multiple sclerosis or NMOSDs, and as outcome measures in clinical trials.

Background: The spectrum of central nervous system–idiopathic inflammatory demyelinating disease (CNS-IIDD) in the elderly is uncertain. Objective: To describe the clinical, radiological, and pathological features of a cohort of 30 pathologically proven CNS-IIDD patients ⩾65 years. Methods: Elderly multiple sclerosis (MS)/clinically isolated syndrome (CIS) patients were compared to a cohort of 125 patients with pathologically proven MS/CIS and symptom onset Results: Median age at symptom onset was 69 years (interquartile range (IQR) = 68–75). Median follow-up was 1.9 years (IQR = 1.0–5.6). Diagnoses were MS (14/30), CIS (11/30), neuromyelitis optica (NMO; 4/30), and acute disseminated encephalomyelitis (ADEM; 1/30). Disability was higher in patients with MS/CIS ⩾65 compared to patients Conclusion: A spectrum of CNS-IIDD can develop in the elderly, with presenting symptoms similar to younger patients. Early diagnosis of CNS demyelinating disease is essential to avoid invasive and disabling procedures.

Objective Neuromyelitis optica (NMO) and its spectrum disorders (NMOSD) are inflammatory demyelinating diseases (IDDs) with a specific biomarker, aquaporin-4–immunoglobulin G (AQP4-IgG). Prior NMO/NMOSD epidemiological studies have been limited by lack of AQP4-IgG seroprevalence assessment, absence of population-based USA studies, and under-representation of blacks. To overcome these limitations, we sought to compare NMO/NMOSD seroepidemiology across 2 ethnically divergent populations. Methods We performed a population-based comparative study of the incidence (2003–2011) and prevalence (on December 31, 2011) of NMO/NMOSD and AQP4-IgG seroincidence and seroprevalence (sera collected in 80–84% of IDD cases) among patients with IDD diagnosis in Olmsted County, Minnesota (82% white [Caucasian]) and Martinique (90% black [Afro-Caribbean]). AQP4-IgG was measured by M1 isoform fluorescence-activated cell-sorting assays. Results The age- and sex-adjusted incidence (7.3 vs 0.7/1,000,000 person-years [p < 0.01]) and prevalence (10 vs 3.9/100,000 [p = 0.01]) in Martinique exceeded that in Olmsted County. The AQP4-IgG age- and sex-adjusted seroincidence (6.5 vs 0.7/1,000,000 person-years [p < 0.01]) and seroprevalence (7.9 vs 3.3/100,000 [p = 0.04]) were also higher in Martinique than Olmsted County. The ethnicity-specific prevalence was similar in Martinique and Olmsted County: 11.5 and 13/100,000 in blacks, and 6.1 and 4.0/100,000 in whites, respectively. NMO/NMOSD represented a higher proportion of IDD cases in Martinique than Olmsted County (16% vs 1.4%; p < 0.01). The onset age (median = 35–37 years) and female:male distribution (5–9:1) were similar across both populations; 60% of prevalent cases were either blind in 1 eye, dependent on a gait aid, or both. Interpretation This study reports the highest prevalence of NMO/NMOSD in any population (10/100,000 in Martinique), estimates it affects 16,000 to 17,000 in the USA (higher than previous predictions), and demonstrates it disproportionately affects blacks. Ann Neurol 2016;79:775–783

ObjectiveTo investigate whether aquaporin-4–immunoglobulin G (AQP4-IgG) titers and measures of complement-mediated cell killing are clinically useful to predict the occurrence of relapse, relapse severity, and/or disability in neuromyelitis optica spectrum disorder (NMOSD).MethodsWe studied 336 serial serum specimens from 82 AQP4-lgG–seropositive patients. NMOSD activity at blood draw was defined as preattack (24 [7.1%], drawn within 30 days preceding an attack), attack (108 [32.1%], drawn on attack onset or within 30 days after), or remission (199 [59.2%], drawn >90 days after attack onset and >30 days preceding a relapse). For each specimen, we documented the attack type and severity and immunotherapy status. Complement-mediated cell killing was quantitated by flow cytometry using an M23-AQP4 cell-based assay.ResultsThe estimated logarithmic means of AQP4-IgG titers in preattack, attack, and remission samples were 3.302, 3.657, and 3.458, respectively, p = 0.21. Analyses of 81 attack/remission pairs in 42 patients showed no significant titer differences (3.736 vs 3.472, p = 0.15). Analyses of 13 preattack/attack pairs in 9 patients showed no significant titer differences (3.994 vs 3.889, p = 0.67). Of 5 patients who converted to seronegative status, 2 continued to have attacks. Titers for major and minor attacks (n = 70) were not significantly different (3.905 vs 3.676, p = 0.47). Similarly, measures (titers) of complement-mediated cell killing were not significantly associated with disease course, attack severity, or disability at 5 years.Conclusions and relevanceAQP4-IgG titer and complement-mediated cell killing lack significant prognostic or predictive utility in NMOSD. Although titers may drop in the setting of immunotherapy, seroconversion to negative status does not preclude ongoing clinical attacks.Classification of evidenceThis study provides Class II evidence that in patients with NMOSD, AQP4-IgG titers and measures of complement-mediated cell killing activity do not predict relapses, relapse severity, or disability.

ObjectiveTo describe a novel antibody biomarker of neurologic paraneoplastic autoimmunity specific for phosphodiesterase 10A (PDE10A), a striatum-enriched phosphodiesterase, and to characterize the clinical phenotype of patients with PDE10A immunoglobulin G (IgG).MethodsWe describe 7 patients with autoantibodies specific for PDE10A identified in the Mayo Clinic Neuroimmunology Laboratory. Patient specimens (sera, 7; CSF, 4) produced identical basal ganglia‐predominant synaptic staining of murine brain tissue by indirect immunofluorescence. The autoantigen was identified by immunoprecipitation and mass spectrometry as PDE10A, and confirmed by antigen-specific recombinant Western blot and cell-based assays, and immune absorption experiments.ResultsThe median patient age was 70 years (range 66–76); 4 were men. Four patients with clinical information available had movement disorders (hyperkinetic in 3 [chorea, ballismus, dystonia] and parkinsonism in 1). All patients but one had cancer (lung [adenocarcinoma 1, squamous cell carcinoma 1, poorly differentiated mesenchymal carcinoma 1], renal adenocarcinoma 2, and pancreatic adenocarcinoma 1). Two of the 7 patients developed hyperkinetic movement disorders during treatment with immune checkpoint inhibitors (nivolumab and pembrolizumab), though none of 26 cancer control patients treated with immune checkpoint inhibitors harbored PDE10A IgG in their serum. MRIs from those 2 patients with hyperkinetic movement disorders demonstrated fluid-attenuated inversion recovery/T2 basal ganglia hyperintensities, and their CSF harbored unique oligoclonal bands. One of those 2 patients had substantial improvement after corticosteroids. One patient's renal adenocarcinoma expressed PDE10A by immunohistochemistry.ConclusionsPDE10A IgG defines a novel rare neurologic autoimmune syndrome and expands the spectrum of diagnosable paraneoplastic CNS disorders. The intracellular location of PDE10A suggests a T-cell-mediated pathology targeting cells displaying MHC1-bound PDE10A peptides.