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  • 1
    Online Resource
    Online Resource
    Diagnosis of Alzheimer Disease and Tauopathies on Whole-Slide Histopathology Images Using a Weakly Supervised Deep Learning Algorithm
    Elsevier BV ; 2023
    In:  Laboratory Investigation Vol. 103, No. 6 ( 2023-06), p. 100127-
    Details
    In: Laboratory Investigation, Elsevier BV, Vol. 103, No. 6 ( 2023-06), p. 100127-
    Type of Medium: Online Resource
    ISSN: 0023-6837
    URL: Article
    DOI: 10.1016/j.labinv.2023.100127
    RVK:
    WA 15000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
    detail.hit.zdb_id: 2041329-4
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  • 2
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    Cancer in pathologically confirmed multiple system atrophy
    Springer Science and Business Media LLC ; 2023
    In:  Clinical Autonomic Research Vol. 33, No. 4 ( 2023-08), p. 451-458
    Details
    In: Clinical Autonomic Research, Springer Science and Business Media LLC, Vol. 33, No. 4 ( 2023-08), p. 451-458
    Type of Medium: Online Resource
    ISSN: 0959-9851 , 1619-1560
    URL: Article
    DOI: 10.1007/s10286-023-00946-w
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2081578-5
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  • 3
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    Creutzfeldt–Jakob Disease Misdiagnosed as Multiple System Atrophy
    Wiley ; 2023
    In:  Movement Disorders Clinical Practice Vol. 10, No. 3 ( 2023-03), p. 496-500
    Details
    In: Movement Disorders Clinical Practice, Wiley, Vol. 10, No. 3 ( 2023-03), p. 496-500
    Abstract: Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by various combinations of autonomic failure, parkinsonism, and cerebellar syndromes. Although consensus criteria have been widely used to diagnose MSA, accurate clinical diagnosis remains challenging. Other neurodegenerative disorders, such as Lewy body disease, can mimic MSA. Objectives We described clinical and neuropathologic findings of two patients with Creutzfeldt–Jakob disease (CJD) who had antemortem clinical diagnoses of MSA. Methods The brain bank for neurodegenerative disorders was queried for cases with a clinical diagnosis of MSA, but neuropathologic findings of CJD. Results Case 1 was a 55‐year‐old man with a 6‐month history of orthostatic hypotension, parkinsonism, cerebellar ataxia, bradyphrenia, and memory impairment. Case 2 was a 65‐year‐old man who had a 5‐year history of cerebellar ataxia, parkinsonism, and cognitive impairment, as well as a 7‐year history of dream enactment behavior. Neither case had characteristic α‐synuclein immunoreactive neuronal or glial inclusions typical of MSA. Instead, they had spongiform encephalopathy with neuronal loss and gliosis with prion protein‐immunoreactive kuru‐like plaques. Genetic analyses in case 1 had wild‐type PRNP , whereas case 2 revealed a 4‐octapeptide repeat insertion in PRNP . Conclusions Even when clinical features suggest MSA, CJD should also be considered if the progression is rapid or the disease course is atypical, such as the absence of autonomic dysfunction for an extended period.
    Type of Medium: Online Resource
    ISSN: 2330-1619 , 2330-1619
    URL: Issue
    URL: Article
    DOI: 10.1002/mdc3.v10.3
    DOI: 10.1002/mdc3.13654
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2772809-2
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  • 4
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    Lysosomal polygenic risk is associated with the severity of neuropathology in Lewy body disease
    Oxford University Press (OUP) ; 2023
    In:  Brain Vol. 146, No. 10 ( 2023-10-03), p. 4077-4087
    Details
    In: Brain, Oxford University Press (OUP), Vol. 146, No. 10 ( 2023-10-03), p. 4077-4087
    Abstract: Intraneuronal accumulation of misfolded α-synuclein is the pathological hallmark of Parkinson’s disease and dementia with Lewy bodies, often co-occurring with variable degrees of Alzheimer’s disease related neuropathology. Genetic association studies have successfully identified common variants associated with disease risk and phenotypic traits in Lewy body disease, yet little is known about the genetic contribution to neuropathological heterogeneity. Using summary statistics from Parkinson’s disease and Alzheimer’s disease genome-wide association studies, we calculated polygenic risk scores and investigated the relationship with Lewy, amyloid-β and tau pathology. Associations were nominated in neuropathologically defined samples with Lewy body disease from the Netherlands Brain Bank (n = 217) and followed up in an independent sample series from the Mayo Clinic Brain Bank (n = 394). We also generated stratified polygenic risk scores based on single-nucleotide polymorphisms annotated to eight functional pathways or cell types previously implicated in Parkinson’s disease and assessed for association with Lewy pathology in subgroups with and without significant Alzheimer’s disease co-pathology. In an ordinal logistic regression model, the Alzheimer’s disease polygenic risk score was associated with concomitant amyloid-β and tau pathology in both cohorts. Moreover, both cohorts showed a significant association between lysosomal pathway polygenic risk and Lewy pathology, which was more consistent than the association with a general Parkinson’s disease risk score and specific to the subset of samples without significant concomitant Alzheimer’s disease related neuropathology. Our findings provide proof of principle that the specific risk alleles a patient carries for Parkinson’s and Alzheimer’s disease also influence key aspects of the underlying neuropathology in Lewy body disease. The interrelations between genetic architecture and neuropathology are complex, as our results implicate lysosomal risk loci specifically in the subset of samples without Alzheimer’s disease co-pathology. Our findings hold promise that genetic profiling may help predict the vulnerability to specific neuropathologies in Lewy body disease, with potential relevance for the further development of precision medicine in these disorders.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awad183
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 1474117-9
    SSG: 12
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  • 5
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    Old age amyotrophic lateral sclerosis and limbic TDP‐43 pathology
    Wiley ; 2022
    In:  Brain Pathology Vol. 32, No. 6 ( 2022-11)
    Details
    In: Brain Pathology, Wiley, Vol. 32, No. 6 ( 2022-11)
    Abstract: This study aimed to assess and compare the burden of transactive response DNA‐binding protein of 43 kDa (TDP‐43) pathology and clinical features of amyotrophic lateral sclerosis (ALS) in three age groups. All cases were from the Mayo Clinic brain bank for neurodegenerative disorders and most were followed longitudinally in the ALS Clinic. Cases with moderate‐to‐severe Alzheimer's disease neuropathological change were excluded. The 55 cases included in the study were divided into three groups by age at death: 75 years or older (old‐ALS, n  = 8), 64–74 years (middle‐ALS, n  = 23), and 63 years or younger (young‐ALS, n  = 24). Clinical features, including disease duration, initial symptoms, and ALS Cognitive Behavior Score (ALS‐CBS), were summarized. Sections of paraffin‐embedded tissue from the motor cortex, basal forebrain, medial temporal lobe, and middle frontal gyrus were processed for phospho‐TDP‐43 immunohistochemistry. The burden of TDP‐43 pathology was analyzed using digital image analysis. The TDP‐43 burden in the limbic system (i.e., amygdala, dentate gyrus and CA1 sector of the hippocampus, subiculum, and entorhinal cortex) was greater in old‐ALS than in young‐ALS and middle‐ALS. TDP‐43 burden in the middle frontal gyrus was sparse and did not differ between the three groups. The average of ALS‐CBS was not different between the three groups. The present study shows that the amygdala and hippocampus are vulnerable to TDP‐43 pathology in older patients with ALS. We discuss the evidence for and against this pathology being related to concurrent limbic‐predominant, age‐related TDP‐43 encephalopathy neuropathologic change.
    Type of Medium: Online Resource
    ISSN: 1015-6305 , 1750-3639
    URL: Issue
    URL: Article
    DOI: 10.1111/bpa.v32.6
    DOI: 10.1111/bpa.13100
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2029927-8
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  • 6
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    Clinicopathologic features of a novel star-shaped transactive response DNA-binding protein 43 (TDP-43) pathology in the oldest old
    Oxford University Press (OUP) ; 2023
    In:  Journal of Neuropathology & Experimental Neurology ( 2023-12-12)
    Details
    In: Journal of Neuropathology & Experimental Neurology, Oxford University Press (OUP), ( 2023-12-12)
    Type of Medium: Online Resource
    ISSN: 0022-3069
    URL: Article
    DOI: 10.1093/jnen/nlad105
    RVK:
    XA 55250
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 2033048-0
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  • 7
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    Discrepancy between distribution of alpha-synuclein oligomers and Lewy-related pathology in Parkinson’s disease
    Springer Science and Business Media LLC ; 2022
    In:  Acta Neuropathologica Communications Vol. 10, No. 1 ( 2022-09-06)
    Details
    In: Acta Neuropathologica Communications, Springer Science and Business Media LLC, Vol. 10, No. 1 ( 2022-09-06)
    Abstract: The pathological hallmarks of Parkinson’s disease (PD) are α-synuclein (αSYN)-positive inclusions referred to as Lewy bodies and Lewy neurites, collectively referred to as Lewy-related pathology (LRP). LRP is thought to propagate in an ascending manner throughout the brain as the disease progresses. LRP is visible with histologic methods and is thought to represent a later stage of the disease process, while αSYN oligomers, which are not visible with routine histologic methods, are considered earlier. There is increasing evidence to suggest that αSYN oligomers may be more toxic than visible LRP. Detecting αSYN oligomers requires special techniques, and their distribution and association with clinical features are important research objectives. In this report, we describe the distribution of αSYN oligomers in multiple cortical and subcortical regions of PD using a proximity ligation assay (PLA). We observe widespread distribution of αSYN oligomers with PLA and more restricted distribution of LRP with αSYN immunohistochemistry. The distribution of αSYN oligomers differed from LRP in that αSYN oligomer burden was significantly greater in the neocortex, while LRP was greater in vulnerable subcortical regions, including the brainstem. We also found that cognitive impairment was associated with αSYN oligomers in the hippocampus. These results suggest that αSYN oligomers may be widely distributed in PD early in the disease process and that they may contribute to cognitive impairment in PD.
    Type of Medium: Online Resource
    ISSN: 2051-5960
    URL: Article
    DOI: 10.1186/s40478-022-01440-6
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2715589-4
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  • 8
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    Neuropathology and molecular diagnosis of Synucleinopathies
    Springer Science and Business Media LLC ; 2021
    In:  Molecular Neurodegeneration Vol. 16, No. 1 ( 2021-12-18)
    Details
    In: Molecular Neurodegeneration, Springer Science and Business Media LLC, Vol. 16, No. 1 ( 2021-12-18)
    Abstract: Synucleinopathies are clinically and pathologically heterogeneous disorders characterized by pathologic aggregates of α-synuclein in neurons and glia, in the form of Lewy bodies, Lewy neurites, neuronal cytoplasmic inclusions, and glial cytoplasmic inclusions. Synucleinopathies can be divided into two major disease entities: Lewy body disease and multiple system atrophy (MSA). Common clinical presentations of Lewy body disease are Parkinson’s disease (PD), PD with dementia, and dementia with Lewy bodies (DLB), while MSA has two major clinical subtypes, MSA with predominant cerebellar ataxia and MSA with predominant parkinsonism. There are currently no disease-modifying therapies for the synucleinopathies, but information obtained from molecular genetics and models that explore mechanisms of α-synuclein conversion to pathologic oligomers and insoluble fibrils offer hope for eventual therapies. It remains unclear how α-synuclein can be associated with distinct cellular pathologies (e.g., Lewy bodies and glial cytoplasmic inclusions) and what factors determine neuroanatomical and cell type vulnerability. Accumulating evidence from in vitro and in vivo experiments suggests that α-synuclein species derived from Lewy body disease and MSA are distinct “strains” having different seeding properties. Recent advancements in in vitro seeding assays, such as real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA), not only demonstrate distinct seeding activity in the synucleinopathies, but also offer exciting opportunities for molecular diagnosis using readily accessible peripheral tissue samples. Cryogenic electron microscopy (cryo-EM) structural studies of α-synuclein derived from recombinant or brain-derived filaments provide new insight into mechanisms of seeding in synucleinopathies. In this review, we describe clinical, genetic and neuropathologic features of synucleinopathies, including a discussion of the evolution of classification and staging of Lewy body disease. We also provide a brief discussion on proposed mechanisms of Lewy body formation, as well as evidence supporting the existence of distinct α-synuclein strains in Lewy body disease and MSA.
    Type of Medium: Online Resource
    ISSN: 1750-1326
    URL: Article
    DOI: 10.1186/s13024-021-00501-z
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2244557-2
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  • 9
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    Frequency of Comorbid Pathologies and Their Clinical Impact in Multiple System Atrophy
    Wiley ; 2024
    In:  Movement Disorders Vol. 39, No. 2 ( 2024-02), p. 380-390
    Details
    In: Movement Disorders, Wiley, Vol. 39, No. 2 ( 2024-02), p. 380-390
    Abstract: Mixed pathology is common at autopsy for a number of age‐associated neurodegenerative disorders; however, the frequency of comorbid pathologies in multiple system atrophy (MSA) and their clinical correlations are poorly understood. Objective We determined the frequency of comorbid pathologic processes in autopsy‐confirmed MSA and assessed their clinical correlates. Methods This study included 160 neuropathologically established MSA from the Mayo Clinic brain bank. Clinical information, including age at onset or death, clinical subtype, initial symptoms, antemortem clinical diagnosis, and cognitive dysfunction was collected. We assessed comorbid pathologies including Alzheimer's disease neuropathologic change, Lewy‐related pathology, argyrophilic grain disease, age‐related τ astrogliopathy, transactive DNA‐binding protein 43 pathology, cerebral amyloid angiopathy, and cerebrovascular small vessel disease and examined their clinical impact. Results The majority of MSA patients (62%) had no significant comorbid pathologies. There was a positive correlation between age at onset or death with the number of comorbid pathologies; however, even in the highest quartile group (average age at death 78 ± 6 years), the average number of comorbid pathologies was 〈 2. Logistic regression analysis revealed that none of the assessed variables, including sex, age at onset, and the presence or absence of each comorbid pathology, were significantly associated with cognitive dysfunction. Conclusions The majority of MSA patients do not have comorbid pathologies, even in advanced age, indicating that MSA is unique among neurodegenerative disorders in this regard. There was minimal clinical impact of comorbid pathologies in MSA. These findings warrant focusing on α‐synuclein for the treatment strategy for MSA. © 2023 International Parkinson and Movement Disorder Society.
    Type of Medium: Online Resource
    ISSN: 0885-3185 , 1531-8257
    URL: Issue
    URL: Article
    DOI: 10.1002/mds.v39.2
    DOI: 10.1002/mds.29670
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2024
    detail.hit.zdb_id: 2041249-6
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  • 10
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    Validation Study of the MDS Criteria for the Diagnosis of Multiple System Atrophy in the Mayo Clinic Brain Bank
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  Neurology
    Details
    In: Neurology, Ovid Technologies (Wolters Kluwer Health)
    Abstract: The second consensus criteria in 2008 have been used in diagnosing multiple system atrophy (MSA). The International Parkinson and Movement Disorder Society (MDS) proposed new diagnostic criteria for MSA in 2022. This study aimed to compare the diagnostic accuracy between these two criteria and validate the clinical utility of the newly proposed criteria for MSA. Methods: We conducted a retrospective autopsy cohort study of consecutive patients with a clinical or pathological diagnosis of MSA from the Mayo Clinic brain bank between 1998 and 2021. We studied 352 patients (250 pathologically-diagnosed MSA and 102 non-MSA); MDS criteria and the second consensus criteria were applied. The sensitivity, specificity, and area under the curve (AUC) of receiver operating characteristic curves were compared between these criteria. Comparison was conducted between clinical subtypes and among clinically challenging cases (those with different clinical diagnoses or those with suspected but undiagnosed MSA before death). We also employed machine learning algorithm, eXtreme Gradient Boosting, to identify clinical features contributing diagnostic performance. Results: The sensitivity and specificity of clinically established and probable MSA by the MDS criteria were 16% and 99% and 64% and 74%, respectively. The sensitivity and specificity of probable MSA and possible MSA by the second consensus criteria were 72% and 52% and 93% and 21%, respectively. The AUC of MDS clinically probable MSA was the highest (0.69). The diagnostic performance did not differ between clinical subtypes. In clinically challenging cases, MDS clinically established MSA maintained high specificity and MDS clinically probable MSA demonstrated the highest AUC (0.62). MRI findings contributed to high specificity. In addition, combining core clinical features with two or more from any of the 13 supporting features and the absence of exclusion criteria also yielded high specificity. Among supporting features, rapid progression was most important for predicting MSA pathology. Discussion: The MDS criteria showed high specificity with clinically established MSA and moderate sensitivity and specificity with clinically probable MSA. The observation that high specificity could be achieved with clinical features alone suggests that MSA diagnosis with high specificity is possible even in areas where MRI is not readily available.
    Type of Medium: Online Resource
    ISSN: 0028-3878 , 1526-632X
    URL: Article
    DOI: 10.1212/WNL.0000000000207905
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
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