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  • 1
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    Convergent effects of a functional C3 variant on brain atrophy, demyelination, and cognitive impairment in multiple sclerosis
    SAGE Publications ; 2019
    In:  Multiple Sclerosis Journal Vol. 25, No. 4 ( 2019-04), p. 532-540
    Details
    In: Multiple Sclerosis Journal, SAGE Publications, Vol. 25, No. 4 ( 2019-04), p. 532-540
    Abstract: Complement system activation products are present in areas of neuroinflammation, demyelination, and neurodegeneration in brains of patients with multiple sclerosis (MS). C3 is a central element in the activation of complement cascades. A common coding variant in the C3 gene (rs2230199, C3R102G) affects C3 activity. Objectives: To assess the effects of rs2230199 on MS severity using clinical, cognitive, and imaging measures. Methods: In total, 161 relapse-onset MS patients (Expanded Disability Status Scale (EDSS) ≤ 6) underwent physical assessments, cognitive tests (Paced Auditory Serial Addition Test (PASAT), Symbol Digit Modalities Test (SDMT), and California Verbal Learning Test (CVLT)), and magnetic resonance imaging (MRI). Lesion volumes were quantified semi-automatically. Voxel-wise analyses were performed to assess the effects of rs2230199 genotype on gray matter (GM) atrophy ( n = 155), white matter (WM) fractional anisotropy (FA; n = 105), and WM magnetization transfer ratio (MTR; n = 90). Results: While rs2230199 minor-allele dosage (C3-102G) showed no significant effect on EDSS and Multiple Sclerosis Functional Composite (MSFC), it was associated with worse cognitive performance ( p = 0.02), lower brain parenchymal fraction ( p = 0.003), and higher lesion burden ( p = 0.02). Moreover, voxel-wise analyses showed lower GM volume in subcortical structures and insula, and lower FA and MTR in several WM areas with higher copies of rs2230199 minor allele. Conclusion: C3-rs2230199 affects white and GM damage as well as cognitive impairment in MS patients. Our findings support a causal role for complement system activity in the pathophysiology of MS.
    Type of Medium: Online Resource
    ISSN: 1352-4585 , 1477-0970
    URL: Article
    DOI: 10.1177/1352458518760715
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2019
    detail.hit.zdb_id: 2008225-3
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  • 2
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    Young versus older subject diffusion magnetic resonance imaging data for virtual white matter lesion tractography
    Wiley ; 2023
    In:  Human Brain Mapping Vol. 44, No. 10 ( 2023-07), p. 3943-3953
    Details
    In: Human Brain Mapping, Wiley, Vol. 44, No. 10 ( 2023-07), p. 3943-3953
    Abstract: White matter hyperintensity (WMH) lesions on T2 fluid‐attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) and changes in adjacent normal‐appearing white matter can disrupt computerized tract reconstruction and result in inaccurate measures of structural brain connectivity. The virtual lesion approach provides an alternative strategy for estimating structural connectivity changes due to WMH. To assess the impact of using young versus older subject diffusion MRI data for virtual lesion tractography, we leveraged recently available diffusion MRI data from the Human Connectome Project (HCP) Lifespan database. Neuroimaging data from 50 healthy young (39.2 ± 1.6 years) and 46 healthy older (74.2 ± 2.5 years) subjects were obtained from the publicly available HCP‐Aging database. Three WMH masks with low, moderate, and high lesion burdens were extracted from the WMH lesion frequency map of locally acquired FLAIR MRI data. Deterministic tractography was conducted to extract streamlines in 21 WM bundles with and without the WMH masks as regions of avoidance in both young and older cohorts. For intact tractography without virtual lesion masks, 7 out of 21 WM pathways showed a significantly lower number of streamlines in older subjects compared to young subjects. A decrease in streamline count with higher native lesion burden was found in corpus callosum, corticostriatal tract, and fornix pathways. Comparable percentages of affected streamlines were obtained in young and older groups with virtual lesion tractography using the three WMH lesion masks of increasing severity. We conclude that using normative diffusion MRI data from young subjects for virtual lesion tractography of WMH is, in most cases, preferable to using age‐matched normative data.
    Type of Medium: Online Resource
    ISSN: 1065-9471 , 1097-0193
    URL: Issue
    URL: Article
    DOI: 10.1002/hbm.v44.10
    DOI: 10.1002/hbm.26326
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 1492703-2
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  • 3
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    Genome‐wide variant by serum urate interaction in Parkinson's disease
    Wiley ; 2015
    In:  Annals of Neurology Vol. 78, No. 5 ( 2015-11), p. 731-741
    Details
    In: Annals of Neurology, Wiley, Vol. 78, No. 5 ( 2015-11), p. 731-741
    Abstract: Serum urate levels have been associated with risk for and progression of Parkinson's disease (PD). Urate‐related compounds are therapeutic candidates in neuroprotective efforts to slow PD progression. A urate‐elevating agent is currently under investigation as a potential disease‐modifying strategy in people with PD. However, PD is a heterogeneous disorder, and genetic variation may explain divergence in disease severity and progression. Methods We conducted a genome‐wide association study to identify gene variant × serum urate interaction effects on the striatal 123 I‐ioflupane (DaTscan) binding ratio measured using single photon emission computed tomography in patients with possible PD from the Parkinson's Progression Markers Initiative (PPMI, n = 360). Follow‐up analyses were conducted to assess gene variant × serum urate interaction effects on magnetic resonance imaging–derived regional brain volumes and clinical status. We then attempted to replicate our primary analysis in patients who entered the Parkinson Research Examination of CEP‐1347 Trial (PRECEPT) with a clinical diagnosis of PD (n = 349). Results Rs1109303 (T 〉 G) variant within the INPP5K gene on chromosome 17p13.3 demonstrated a genome‐wide significant interaction with serum urate level to predict striatal dopamine transporter density among all PPMI participants (n = 359) with possible PD ( p = 2.01 × 10 −8 ; after excluding participants with SWEDD [scan without evidence of dopaminergic deficit]: p = 1.12 × 10 −9 ; n = 316). Independent of striatal dopamine transporter density, similar effects on brain atrophy, bradykinesia, anxiety, and depression were observed. No effect was present in the PRECEPT sample at baseline; however, in non‐SWEDD PD participants in PRECEPT (n = 309), we observed a significant longitudinal genotype × serum urate interaction effect, consistent in direction with the PPMI sample, on progression of striatal dopamine transporter density over the 22‐month follow‐up. Interpretation Genetic profile combined with serum urate level can be used to predict disease severity and potential disease progression in patients with PD. These results may be relevant to therapeutic efforts targeting the urate pathway. Ann Neurol 2015;78:Ann Neurol 2015;78:679–696
    Type of Medium: Online Resource
    ISSN: 0364-5134 , 1531-8249
    URL: Issue
    URL: Article
    DOI: 10.1002/ana.v78.5
    DOI: 10.1002/ana.24504
    Language: English
    Publisher: Wiley
    Publication Date: 2015
    detail.hit.zdb_id: 2037912-2
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  • 4
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    Associations of phosphorylated tau pathology with whole‐hemisphere ex vivo morphometry in 7 tesla MRI
    Wiley ; 2023
    In:  Alzheimer's & Dementia Vol. 19, No. 6 ( 2023-06), p. 2355-2364
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 19, No. 6 ( 2023-06), p. 2355-2364
    Abstract: Neurodegenerative disorders are associated with different pathologies that often co‐occur but cannot be measured specifically with in vivo methods. Methods Thirty‐three brain hemispheres from donors with an Alzheimer's disease (AD) spectrum diagnosis underwent T2‐weighted magnetic resonance imaging (MRI). Gray matter thickness was paired with histopathology from the closest anatomic region in the contralateral hemisphere. Results Partial Spearman correlation of phosphorylated tau and cortical thickness with TAR DNA‐binding protein 43 (TDP‐43) and α‐synuclein scores, age, sex, and postmortem interval as covariates showed significant relationships in entorhinal and primary visual cortices, temporal pole, and insular and posterior cingulate gyri. Linear models including Braak stages, TDP‐43 and α‐synuclein scores, age, sex, and postmortem interval showed significant correlation between Braak stage and thickness in the parahippocampal gyrus, entorhinal cortex, and Broadman area 35. Conclusion We demonstrated an association of measures of AD pathology with tissue loss in several AD regions despite a limited range of pathology in these cases. Highlights Neurodegenerative disorders are associated with co‐occurring pathologies that cannot be measured specifically with in vivo methods. Identification of the topographic patterns of these pathologies in structural magnetic resonance imaging (MRI) may provide probabilistic biomarkers. We demonstrated the correlation of the specific patterns of tissue loss from ex vivo brain MRI with underlying pathologies detected in postmortem brain hemispheres in patients with Alzheimer's disease (AD) spectrum disorders. The results provide insight into the interpretation of in vivo structural MRI studies in patients with AD spectrum disorders.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v19.6
    DOI: 10.1002/alz.12884
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2201940-6
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  • 5
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    Surgical complications of endoscopic approach to skull base: analysis of 584 consecutive patients
    Springer Science and Business Media LLC ; 2022
    In:  European Archives of Oto-Rhino-Laryngology Vol. 279, No. 6 ( 2022-06), p. 3189-3199
    Details
    In: European Archives of Oto-Rhino-Laryngology, Springer Science and Business Media LLC, Vol. 279, No. 6 ( 2022-06), p. 3189-3199
    Type of Medium: Online Resource
    ISSN: 0937-4477 , 1434-4726
    URL: Article
    DOI: 10.1007/s00405-022-07256-3
    RVK:
    XA 26650
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 1459042-6
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  • 6
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    Molecular Detection of Epstein–Barr Virus, Human Herpes Virus 6, Cytomegalovirus, and Hepatitis B Virus in Patients with Multiple Sclerosis
    Maad Rayan Publishing Company ; 2020
    In:  Middle East Journal of Digestive Diseases Vol. 12, No. 3 ( 2020-07-19), p. 171-177
    Details
    In: Middle East Journal of Digestive Diseases, Maad Rayan Publishing Company, Vol. 12, No. 3 ( 2020-07-19), p. 171-177
    Abstract: BACKGROUND Multiple sclerosis (MS) is a chronic disease with significant morbidity. A wide spectrum of risk factors has been suggested that triggers the development of MS. Among them, several viral infections have been implicated to play a role in MS pathogenesis. We aimed to evaluate the relationship between viral diseases, including Epstein–Barr virus (EBV), human herpes virus 6 (HHV-6), cytomegalovirus (CMV), and hepatitis B virus (HBV) and MS in the present case-control study. METHODS About 100 patients with confirmed MS and age- and sex-matched individuals were selected as case and control groups, respectively. The patients were randomly selected from individuals diagnosed by neurologists based on the clinical signs and symptoms and imaging procedures. RESULTS More than 100 patients with MS and patients who were referred for other causes were analyzed for the presence of DNA of EBV, HHV6, CMV, and HBV separately. 9.37% of the control group had a positive test for the DNA of EBV in a real-time polymerase chain reaction (PCR), while the frequency of positive test result was zero in the case group (p = 0.0012). HBV DNA was not detected in both the case and control groups. The prevalence of CMV was 0.88 and zero in the control and case groups, respectively (p = 0.3410). For HHV6, 9.73 % of the control group had a positive result, while this test was positive in 5.88% of the patients with MS (p = 0.2959). CONCLUSION We detected a significantly higher number of individuals with DNA of EBV in their blood among the control group compared with the case group. In conclusion, the results suggest a surprisingly adverse association between MS and EBV, and no association was found between the presence of DNA of HBV, CMV, and HHV6 and MS.
    Type of Medium: Online Resource
    ISSN: 2008-5249
    URL: Article
    DOI: 10.34172/mejdd.2020.179
    Language: English
    Publisher: Maad Rayan Publishing Company
    Publication Date: 2020
    detail.hit.zdb_id: 2623796-9
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  • 7
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    Associations between cortical microinfarcts and MRI markers of neurodegeneration and cerebrovascular disease in aging
    Wiley ; 2021
    In:  Alzheimer's & Dementia Vol. 17, No. S4 ( 2021-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 17, No. S4 ( 2021-12)
    Abstract: Cortical microinfarcts (CMI) are associated with cognitive impairment in both healthy aging and dementia, though the mechanisms underlying CMIs remain uncertain. Here we assessed correlations between CMIs and medial temporal lobe (MTL) cortical thickness, white matter hyperintensity (WMH) volume, and cerebral blood flow (CBF) in older subjects. Method Neuroimaging data from 55 cognitively intact older subjects scanned using a hybrid 7T/3T protocol were analyzed. CMIs were manually identified on T1‐weighted MP2RAGE data (0.7mm isotropic resolution) obtained at 7T (Figure 1). Cortical thickness, WMH volume and whole brain CBF were obtained with T1‐weighted, FLAIR and 3D background suppressed arterial spin labeling (ASL) imaging, all acquired at 3T and were available from N=39, 49 and 48 subjects of the N=55 subjects respectively. Spearman’s bivariate nonparametric test was used for statistical analyses. Result Cohort demographics and imaging results are summarized in Table 1. 111 CMIs were detected in 43 of 55 (78%) of 7T T1‐weighted and FLAIR MRI scans (range:0‐6, 56% multiple CMIs). Age and sex were not significantly correlated with the number of CMIs. A negative correlation between the number of CMIs and mean BA36 cortical thickness was observed (r(37)= ‐0.348, p=0.03) (Figure 2). A similar trend was also observed in entorhinal and parahippocampal cortices. No significant correlation was seen between the number of CMIs and WMH volume. No significant correlation was observed between the number of CMIs and CBF in whole brain, gray matter, or white matter. Conclusion The percentage of subjects showing CMIs is higher than previous 3T studies suggesting improved sensitivity of high‐resolution 7T MRI for detection of CMIs. Contrary to prior reports the lack of correlation between the number of CMIs and either WMH volume or CBF suggests that cerebrovascular insufficiency and small vessel ischemic disease may not be the underlying pathologic mechanisms causing CMIs, at least in cognitively intact older subjects. However, the negative correlation between CMIs and MTL cortical thickness supports the possibility of a mutual underlying pathway for Alzheimer’s disease and CMIs that may be mediated by cerebral amyloid angiopathy.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v17.S4
    DOI: 10.1002/alz.057833
    Language: English
    Publisher: Wiley
    Publication Date: 2021
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  • 8
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    Associations between cortical microinfarcts, hippocampal atrophy, and cerebral small vessel disease
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S5 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S5 ( 2022-12)
    Abstract: Brain cortical microinfarcts (CMI) are negatively correlated with cognitive function in both normal aging and Alzheimer’s disease (AD). High‐field structural magnetic resonance imaging (MRI) has facilitated in vivo detection of CMIs but their significance and underlying pathological mechanism remain uncertain. Here we assessed correlations between CMIs and medial temporal lobe (MTL) cortical thickness, white matter hyperintensity (WMH) volume, and relative periventricular white matter cerebral blood flow (PVWM CBF) in healthy individuals. PVWM CBF is thought to provide a measure of cerebral small vessel function. Method 76 cognitively intact subjects age 65 ± 15 years were scanned using a hybrid 7T/3T protocol. CMIs were counted by visual inspection on T1‐weighted MP2RAGE (0.7mm 3 ) and FLAIR (0.8mm 3 ) scans obtained at 7T. T1‐weighted MPRAGE, FLAIR and 3D arterial spin labeling (ASL) data were also acquired at 3T and were used to calculate cortical thickness, WMH volume, and regional CBF. Spearman and Pearson bivariate tests were used for statistical analyses. Result 185 CMIs were detected in 63 of 76 (83%) 7T scans (range:0‐8, 66% multiple CMIs). Age and sex were not significantly correlated with CMI number. A significant positive Pearson correlation was seen between the number of CMIs and log‐transformed WMH volume (r(74)= 0.23, p=0.04) and a more significant negative correlation between the number of CMIs and PVWM CBF normalized to global CBF was also observed (r(74)= ‐0.37, p=0.003). Significant negative correlations between CMI number and mean cortical thickness in Brodmann area 35 (BA35) (r(73)= ‐0.24, p=0.04) and parahippocampal cortex (r(73)= ‐0.26, p=0.03) was observed with nonsignificant trends in BA36 and entorhinal cortex. Conclusion Significant correlations between the CMI number and both relative PVWM CBF and WMH volume suggests a contribution of small vessel ischemic disease in the development of CMIs. The negative correlation between CMIs and MTL cortical thickness supports the possibility of a mutual underlying pathway for CMIs and Alzheimer’s disease that may be mediated by cerebral amyloid angiopathy.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S5
    DOI: 10.1002/alz.065574
    Language: English
    Publisher: Wiley
    Publication Date: 2022
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  • 9
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    Deep learning pipeline for cortical gray matter segmentation and thickness analysis in Ultra High Resolution T2w 7 Tesla Ex vivo MRI across neurodegenerative diseases reveals associations with underlying neuropathology
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S5 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S5 ( 2022-12)
    Abstract: Ex vivo magnetic resonance imaging (MRI) enables detailed characterization of neuroanatomy (Augustinack et al. 2013), such as hippocampal subfields in the medial temporal lobe (MTL) (Yushkevich et al. 2021, Ravikumar et al. 2021). However, automated cortical segmentation methods in ex vivo MRI are not well developed due to limited data availability and heterogeneity in scanners and acquisition. Here, we investigate a deep learning framework to parcellate the cortical mantle, compute thickness and link them with neuropathology ratings across 16 cortical regions in 7 Tesla MRIs of 38 ex vivo brain specimens spanning Alzheimer Disease and Related Dementias. Method A deep learning method, nnU‐Net (Isensee et al. 2021), was trained on manually segmented 3D image patches (Figure 1C) to obtain automated cortical segmentations across 38 subjects (Table 1). We identified 16 landmarks (Figure 1A) for localized quantitative signatures of cortical morphometry and used the pipeline in Wisse et al. 2021 to measure local thickness (Figure 1B). Associations were computed between cortical thickness from manual and automated segmentations via Pearson’s correlation and average fixed‐raters Intra‐class Correlation Coefficient (ICC) for 16 locations (Figure 3). We also correlated thickness from both automated and manual segmentations with neuropathological ratings of tau and neuronal loss in corresponding contralateral regions and global Braak staging (Figures 4 and 5). Result Figure 2 depicts cortical mantle segmentation across brain hemispheres. Figure 3 shows good agreement between ground truth and automated thickness, with 15 regions with significant associations (p 〈 0.05) and 8 regions having r 〉 0.6. We observe high ICC scores with 9 regions where ICC 〉 0.7, confirming that automated segmentations accurately measure thickness. Figure 4 shows significant correlations between thickness and Tau ratings for Brodmann Area 35 (BA35) and midfrontal regions and trends between neuronal loss and thickness in entorhinal cortex (ERC), anterior temporal pole and anterior insula. Figure 5 shows significant correlations between thickness and Braak staging in ventrolateral temporal cortex and ERC, with trends in other regions. Conclusion Our automated ex vivo neuroimaging framework accurately segments the cortical mantle, provides thickness measurements that concur with user‐supervised thickness and links morphometry with underlying neurodegeneration, thus suggesting the strengths of ex vivo MRI.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S5
    DOI: 10.1002/alz.065737
    Language: English
    Publisher: Wiley
    Publication Date: 2022
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  • 10
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    Linking histology to post‐mortem 7T MRI measures of neurodegeneration
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S5 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S5 ( 2022-12)
    Abstract: Neurodegenerative disorders are associated with different pathologies that often co‐occur and have differential contribution to the pattern of cognitive impairment. The majority of these pathologies cannot be detected or measured by in‐vivo methods; therefore, recognition of the topographic patterns of them and association with MRI findings may provide probabilistic non‐invasive biomarkers. We investigated the association of cortical and medial temporal lobe subregional thickness measured from postmortem MRI and semi‐quantitative pathologic measures in order to provide a methodological approach for linking pathological and radiological measures. Method 22 brain hemispheres from donors with Alzheimer’s disease (AD) spectrum diagnosis were included. T2‐weighted images were obtained on 7 Tesla scanner (0.28 mm isotropic) and patches of cortex around 16 anatomical locations were segmented using semi‐automated active contour segmentation in ITK‐SNAP. Immunohistochemistry evaluation was performed using previously validated antibodies to detect amyloid‐β, phosphorylated tau, phosphorylated TDP‐43 deposits and pathological conformation of α‐synuclein on contralateral hemispheres. Neuronal loss was visually assessed. Thickness measures at each location were associated with pathology measures at corresponding or closest to corresponding anatomical location. Multivariate linear models were used for statistical analyses. Result The mean age of donors at death was 80.2±10.7 years (range 63‐99) and 8 (36%) were female. The median Braak stage was 5 (range: 2‐6). Linear models including regional Tau and TDP43 scores and age showed significant relationships between increased regional tau score and reduced thickness in anterior temporal pole, entorhinal, angular and superior parietal cortices. (Table 1, Figure 1) Linear models including Braak stages, TDP43 scores and age showed significant correlation between Braak stage and thickness in anterior temporal pole and entorhinal cortices and BA35 region of medial temporal lobe. Conclusion The aim of the current study is to validate methods for development of 3D pathology maps which can be directly linked to local neurodegeneration measures. As the primary result of such an effort, the present study demonstrates an association of semi‐quantitative measures of AD pathology and with local tissue loss in several common AD regions despite limited range of pathology in these cases. These promising results provide support for future studies directly linking pathology with post‐mortem measures of structure.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S5
    DOI: 10.1002/alz.066155
    Language: English
    Publisher: Wiley
    Publication Date: 2022
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