Comparative Analysis of Low Molecular Weight Fraction of Conditioned Media Derived from Starvation-Dormant and Anaerobically-Dormant Mycobacterium Avium Subsp. Paratuberculosis

Johne\u27s disease (JD) caused by Mycobacterium avium subsp. paratuberculosis (MAP) is a contagious chronic enteritis affecting all ruminants and causing economic loss of at least $250 million annually in the US dairy industry. One of the major limitations in the diagnosis of JD is the low sensitivity of fecal culture in animals with no clinical signs of the disease, but who are actively shedding MAP. Persistence of MAP in the host with no apparent signs of infection is attributed to its ability to enter a dormant state wherein the bacterium is viable, but is not able to replicate until conditions become favorable. In vitro studies have shown that addition of culture media from starvation-dormant cells (SDCM) to growth media enhances the recovery of dormant cells. Resuscitative activity has been noted in the fraction of SDCM containing molecules equal to or smaller than 5kDa in size; the ability of this fraction to resuscitate was resistant to heat and enzyme treatment. In this study we sought to further investigate the composition of low molecular weight fraction of SDCM in order to identify the nature of the molecules with resuscitative effect. Starvation-dormant MAP cells were grouped into three distinct phenotypes based on acid-fast staining properties, and fractions of SDCM were obtained from cultures of similar phenotype. Only higher dilutions of fractions pooled from cultures with preserved acid-fastness had a resuscitative effect, which disappeared with higher concentration of the fraction. Fractions derived from cultures with complete or partial loss of acid-fastness either had no effect or inhibitory effect on MAP recovery. The concentrates of resuscitative fractions were comparatively analyzed with non-resuscitative fractions of SDCM, fractions of ADCM and growth media for protein/peptide concentration and lipid profile using BCA assay, SDS-PAGE gel electrophoresis, and thin layer chromatography. No proteins of 5kDa or smaller were detected in any of the samples. Resuscitative fractions of SDCM had a different mycolic acid profile compared to non-resuscitative, ADCM fractions, and cell-wall bound mycolic acids from exponentially growing MAP. Further analysis of lipid composition and lipid purification are needed in order to test whether lipids are involved in resuscitation of the MAP cells from the dormancy

Comparison of MRI lesion evolution in different central nervous system demyelinating disorders

Background and Objective: There are few studies that compare 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-IgG-associated disorder (MOGAD), aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4-IgG-NMOSD), and multiple sclerosis (MS). Methods: In 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 two 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. Results: We 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 MS (23[0-152]) (p<0.001)

Variability of cerebrospinal fluid findings by attack phenotype in myelin oligodendrocyte glycoprotein-IgG-associated disorder

Background: The variability in cerebrospinal fluid (CSF) findings of myelin oligodendrocyte glycoprotein-IgG-associated disorder (MOGAD) is not fully elucidated. Objective and Methods: We retrospectively analyzed 203 attack-associated CSFs from Mayo Clinic patients (2000-2019) with MOGAD. Results: White-blood-cell (>5/mm3) elevation was less with clinically isolated optic neuritis (23%), compared to myelitis, brain/brainstem attacks, or combinations thereof (>70%), p<0.0001. CSF pleocytosis in optic neuritis was more common in patients with coexisting asymptomatic brain and/or spine MRI T2-lesions (53%) than in those without (16%), p=0.005. Abnormal CSF oligoclonal bands ranged from 1% (optic neuritis) to 18% (brain/brainstem attacks). CSF pleocytosis was less common after immunotherapy. Conclusions: CSF findings in MOGAD vary by attack phenotype and preceding treatment

Lewy Body Disease is a Contributor to Logopenic Progressive Aphasia Phenotype

Objective: The objective of this study was to describe clinical features, [18 F]-fluorodeoxyglucose (FDG)-positron emission tomography (PET) metabolism and digital pathology in patients with logopenic progressive aphasia (LPA) and pathologic diagnosis of diffuse Lewy body disease (DLBD) and compare to patients with LPA with other pathologies, as well as patients with classical features of probable dementia with Lewy bodies (pDLB). Methods: This is a clinicopathologic case-control study of 45 patients, including 20 prospectively recruited patients with LPA among whom 6 were diagnosed with LPA-DLBD. We analyzed clinical features and compared FDG-PET metabolism in LPA-DLBD to an independent group of patients with clinical pDLB and regional α-synuclein burden on digital pathology to a second independent group of autopsied patients with DLBD pathology and antemortem pDLB (DLB-DLBD). Results: All patients with LPA-DLBD were men. Neurological, speech, and neuropsychological characteristics were similar across LPA-DLBD, LPA-Alzheimer's disease (LPA-AD), and LPA-frontotemporal lobar degeneration (LPA-FTLD). Genetic screening of AD, DLBD, and FTLD linked genes were negative with the exception of APOE ε4 allele present in 83% of LPA-DLBD patients. Seventy-five percent of the patients with LPA-DLBD showed a parietal-dominant pattern of hy pometabolism; LPA-FTLD - temporal-dominant pattern, whereas LPA-AD showed heterogeneous patterns of hypometabolism. LPA-DLBD had more asymmetrical hypometabolism affecting frontal lobes, with relatively spared occipital lobe in the nondominantly affected hemisphere, compared to pDLB. LPA-DLBD had minimal atrophy on gross brain examination, higher cortical Lewy body counts, and higher α-synuclein burden in the middle frontal and inferior parietal cortices compared to DLB-DLBD. Interpretation: Whereas AD is the most frequent underlying pathology of LPA, DLBD can also be present and may contribute to the LPA phenotype possibly due to α-synuclein-associated functional impairment of the dominant parietal lobe

A molecular pathology, neurobiology, biochemical, genetic and neuroimaging study of progressive apraxia of speech

Progressive apraxia of speech (PAOS) is a neurodegenerative syndrome of multiple etiologies which affects spoken communication. Here, the authors characterized the molecular pathology, biochemistry, genetics and longitudinal neuroimaging of 32 autopsy-confirmed patients with PAOS who were followed over 10 years