Abstract
Progressive apraxia of speech is a neurodegenerative syndrome affecting spoken communication. Molecular pathology, biochemistry, genetics, and longitudinal imaging were investigated in 32 ...autopsy-confirmed patients with progressive apraxia of speech who were followed over 10 years. Corticobasal degeneration and progressive supranuclear palsy (4R-tauopathies) were the most common underlying pathologies. Perceptually distinct speech characteristics, combined with age-at-onset, predicted specific 4R-tauopathy; phonetic subtype and younger age predicted corticobasal degeneration, and prosodic subtype and older age predicted progressive supranuclear palsy. Phonetic and prosodic subtypes showed differing relationships within the cortico-striato-pallido-nigro-luysial network. Biochemical analysis revealed no distinct differences in aggregated 4R-tau while tau H1 haplotype frequency (69%) was lower compared to 1000+ autopsy-confirmed 4R-tauopathies. Corticobasal degeneration patients had faster rates of decline, greater cortical degeneration, and shorter illness duration than progressive supranuclear palsy. These findings help define the pathobiology of progressive apraxia of speech and may have consequences for development of 4R-tau targeting treatment.
There 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).
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 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.
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) (
< 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%) (
< 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%) (
< 0.01). There was a larger median (range) reduction in T2 lesion area in mm
on follow-up axial brain MRI with MOGAD (213 55-873) than AQP4-IgG-NMOSD (104 0.7-597) (
= 0.02) and MS (36 0-506) (
< 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 (
= 0.4) and greater than in MS (23 0-152) (
< 0.001).
The 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.
Alzheimer's disease is characterized by the presence of amyloid-β and tau deposition in the brain, hippocampal atrophy and increased rates of hippocampal atrophy over time. Another protein, TAR DNA ...binding protein 43 (TDP-43) has been identified in up to 75% of cases of Alzheimer's disease. TDP-43, tau and amyloid-β have all been linked to hippocampal atrophy. TDP-43 and tau have also been linked to hippocampal atrophy in cases of primary age-related tauopathy, a pathological entity with features that strongly overlap with those of Alzheimer's disease. At present, it is unclear whether and how TDP-43 and tau are associated with early or late hippocampal atrophy in Alzheimer's disease and primary age-related tauopathy, whether either protein is also associated with faster rates of atrophy of other brain regions and whether there is evidence for protein-associated acceleration/deceleration of atrophy rates. We therefore aimed to model how these proteins, particularly TDP-43, influence non-linear trajectories of hippocampal and neocortical atrophy in Alzheimer's disease and primary age-related tauopathy. In this longitudinal retrospective study, 557 autopsied cases with Alzheimer's disease neuropathological changes with 1638 ante-mortem volumetric head MRI scans spanning 1.0-16.8 years of disease duration prior to death were analysed. TDP-43 and Braak neurofibrillary tangle pathological staging schemes were constructed, and hippocampal and neocortical (inferior temporal and middle frontal) brain volumes determined using longitudinal FreeSurfer. Bayesian bivariate-outcome hierarchical models were utilized to estimate associations between proteins and volume, early rate of atrophy and acceleration in atrophy rates across brain regions. High TDP-43 stage was associated with smaller cross-sectional brain volumes, faster rates of brain atrophy and acceleration of atrophy rates, more than a decade prior to death, with deceleration occurring closer to death. Stronger associations were observed with hippocampus compared to temporal and frontal neocortex. Conversely, low TDP-43 stage was associated with slower early rates but later acceleration. This later acceleration was associated with high Braak neurofibrillary tangle stage. Somewhat similar, but less striking, findings were observed between TDP-43 and neocortical rates. Braak stage appeared to have stronger associations with neocortex compared to TDP-43. The association between TDP-43 and brain atrophy occurred slightly later in time (∼3 years) in cases of primary age-related tauopathy compared to Alzheimer's disease. The results suggest that TDP-43 and tau have different contributions to acceleration and deceleration of brain atrophy rates over time in both Alzheimer's disease and primary age-related tauopathy.
Background:
Progressive motor impairment anatomically attributable to prominent, focally atrophic lateral column spinal cord lesions (“critical lesions”) can be seen in multiple sclerosis (MS), for ...example, progressive hemiparetic MS.
Objective:
The aim of this study was to investigate whether similar spinal cord lesions are more frequent in long-standing MS patients with secondary progressive motor impairment (secondary progressive MS (SPMS)) versus those maintaining a relapsing-remitting course (relapsing-remitting MS (RRMS)).
Methods:
We retrospectively identified Olmsted County (MN, USA) residents on 31 December 2011 with (1) RRMS or SPMS for ⩾25 years, and (2) available brain and spine magnetic resonance imaging (MRI). A blinded neuroradiologist determined demyelinating lesion burden and presence of potential critical lesions (prominent focally atrophic spinal cord lateral column lesions).
Results:
In total, 32 patients were included: RRMS, 18; SPMS, 14. Median (range) disease duration (34 (27–53) vs. 39 (29–47) years) and relapse number (4 (1–10) vs. 3 (1–15)) were similar. In comparison to RRMS, SPMS patients more commonly showed potential critical spinal cord lesions (8/18 (44%) vs. 14/14 (100%)), higher spinal cord (median (range) 4 (1–7) vs. 7.5 (3–12)), and brain infratentorial (median (range) 1 (0–12) vs. 2.5 (1–13)) lesion number; p < 0.05. By multivariate analysis, only the presence of potential critical lesions independently associated with motor progression (p = 0.02).
Conclusion:
Critical spinal cord lesions may be important contributors to motor progression in MS.
Objective
The objective of this study was to describe clinical features, 18F‐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. ANN NEUROL 2021;89:520–533
Background
Trans-active response DNA-binding protein of 43 kDa (TDP-43) can be detected in up to 63% of autopsy-confirmed Lewy body disease (LBD) cases. It is unclear whether TDP-43 is associated ...with a decreased likelihood of a clinical diagnosis of probable dementia with Lewy bodies (pDLB) during life.
Methods
In an autopsy cohort of 395 cognitively impaired patients from the Mayo Clinic Alzheimer’s Disease Research Center, we determined the presence of TDP-43 in the hippocampus hTDP-43(+) and examined associations between hTDP-43 and an antemortem pDLB clinical diagnosis with multiple regression analyses. For this study, given our specific question, we only counted transitional and diffuse Lewy body disease as LBD positive (LBD+).
Results
One-hundred forty-five cases (37%) were hTDP-43(+) and 156 (39%) were LBD+; co-pathology was noted in 63 (16%) cases. Patients with pDLB− LBD+ were more likely to be older, hTDP-43(+) and have high Braak neurofibrillary tangle (NFT) status compared to the pDLB+ LBD+ patients. After accounting for older age at death and high Braak NFT status, hTDP-43(+) status was associated with the absence of a clinical diagnosis of pDLB despite LBD+ status (
p
< 0.05).
Conclusion
The absence of a diagnosis of pDLB during life in patients with LBD is associated with older age, high Braak NFT stage and hTDP-43, each feature contributing independently to a lower likelihood of a clinical diagnosis of pDLB during life.
Objective
Determine the utility of aquaporin 4 IgG (AQP4-IgG) testing (live cell-based assay) for Neuromyelitis Optica Spectrum Disorders (NMOSD).
Methods
We included Mayo Clinic patients ...(1/1/2018-12/31/2019) tested for serum AQP4-IgG by live cell-based flow-cytometric assay. Medical records were reviewed to assess if patients fulfilled 2015 NMOSD criteria.
Results
Of 1371 patients tested, 41 were positive (3%) and all fulfilled NMOSD criteria with AQP4-IgG (specificity = 100%). Only 10/1330 testing negative met NMOSD criteria without AQP4-IgG (sensitivity = 80%) and seven of these 10 were MOG-IgG positive.
Conclusions
AQP4-IgG by live cell-based assay was highly specific and without false positives in a high throughput setting.
•Rates of anterolateral temporal lobe atrophy are faster in FTLD-TDP versus AD-TDP.•Older age is associated with slower frontal lobe atrophy in FTLD-TDP.•AD-TDP type-α showed faster medial temporal ...atrophy than type-β.•Pure-TDP was associated with slowest rates and less atrophy in all brain regions.
Transactive response DNA-binding protein of ∼43 kDa (TDP-43), a primary pathologic substrate in tau-negative frontotemporal lobar degeneration (FTLD), is also often found in the brains of elderly individuals without FTLD and is a key player in the process of neurodegeneration in brains with and without FTLD. It is unknown how rates and trajectories of TDP-43-associated brain atrophy compare between these two groups. Additionally, non-FTLD TDP-43 inclusions are not homogeneous and can be divided into two morphologic types: type-α and neurofibrillary tangle-associated type-β. Therefore, we explored whether neurodegeneration also varies due to the morphologic type. In this longitudinal retrospective study of 293 patients with 843 MRI scans spanning over ∼10 years, we used a Bayesian hierarchical linear model to quantify similarities and differences between the non-FTLD TDP-43 (type-α/type-β) and FTLD-TDP (n = 68) in both regional volume at various timepoints before death and annualized rate of atrophy. Since Alzheimer’s disease (AD) is a frequent co-pathology in non-FTLD TDP-43, we further divided types α/β based on presence/absence of intermediate-high likelihood AD: AD-TDP type-β (n = 90), AD-TDP type-α (n = 104), and Pure-TDP (n = 31, all type-α). FTLD-TDP was associated with faster atrophy rates in the inferior temporal lobe and temporal pole compared to all non-FTLD TDP-43 groups. The atrophy rate in the frontal lobe was modulated by age with younger FTLD-TDP having the fastest rates. Older FTLD-TDP showed a limbic predominant pattern of neurodegeneration. AD-TDP type-α showed faster rates of hippocampal atrophy and smaller volumes of amygdala, temporal pole, and inferior temporal lobe compared to AD-TDP type-β. Pure-TDP was associated with slowest rates and less atrophy in all brain regions. The results suggest that there are differences and similarities in longitudinal brain volume loss between FTLD-TDP and non-FTLD TDP-43. Within FTLD-TDP age plays a role in which brain regions are the most affected. Additionally, brain atrophy regional rates also vary by non-FTLD TDP-43 type.
Considerable efforts have been made to characterize active enhancer elements, which can be annotated by accessible chromatin and H3 lysine 27 acetylation (H3K27ac). However, apart from poised ...enhancers that are observed in early stages of development and putative silencers, the functional significance of cis-regulatory elements lacking H3K27ac is poorly understood. Here we show that macroH2A histone variants mark a subset of enhancers in normal and cancer cells, which we coined 'macro-Bound Enhancers', that modulate enhancer activity. We find macroH2A variants localized at enhancer elements that are devoid of H3K27ac in a cell type-specific manner, indicating a role for macroH2A at inactive enhancers to maintain cell identity. In following, reactivation of macro-bound enhancers is associated with oncogenic programs in breast cancer and their repressive role is correlated with the activity of macroH2A2 as a negative regulator of BRD4 chromatin occupancy. Finally, through single cell epigenomic profiling of normal mammary stem cells derived from mice, we show that macroH2A deficiency facilitates increased activity of transcription factors associated with stem cell activity.
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