Authors: Dugger, Brittany N. | Hidalgo, Jose A. | Chiarolanza, Glenn | Mariner, Monica | Henry-Watson, Jonette | Sue, Lucia I. | Beach, Thomas G.
Article Type: Research Article
Abstract: Abnormal phosphorylation of the microtubule-associated protein tau develops in selected brain regions in normal aging and becomes widespread throughout the brain in Alzheimer's disease (AD). Braak and others have described the distribution of neurofibrillary tangles and deposition of abnormally phosphorylated tau (p-tau) and correlated this with the progressive cognitive dysfunction in AD. However, to date there have been no comprehensive studies examining abnormally phosphorylated tau deposition in the spinal cord as part of normal aging or AD. We investigated, using immunohistochemical methods, the presence of p-tau in the spinal cord of 46 cases with a clinicopathological diagnosis of AD as …well as 37 non-demented aged (ND) individuals lacking any defined central nervous system-related clinicopathological diagnosis. We found the cervical cord segments to be the most frequently affected subdivision (96% AD versus 43% ND), followed by thoracic (69% AD versus 37% ND), lumbar (65% AD versus 27% ND), and sacral (53% AD versus 13% ND). The spinal cord was often affected at early-stage brain disease, with p-tau spinal cord immunoreactivity in 40% of subjects at Braak neurofibrillary stage I; however, there were no cases having spinal cord p-tau that did not have p-tau within the brain. As p-tau immunoreactivity is present within the spinal cords of ND as well as AD subjects, it is likely that the phosphorylation of spinal cord tau occurs in the preclinical stage of AD, prior to dementia. The presence of significant spinal cord p-tau-immunoreactive pathology has important implications for both the pathogenesis and clinical manifestations of AD. Show more
Keywords: Aging, autopsy, neurofibrillary tangle, pathology, peripheral nervous system, senile dementia, systemic disorder
DOI: 10.3233/JAD-121864
Citation: Journal of Alzheimer's Disease, vol. 34, no. 2, pp. 529-536, 2013
Authors: Dugger, Brittany N. | Whiteside, Charisse M. | Maarouf, Chera L. | Walker, Douglas G. | Beach, Thomas G. | Sue, Lucia I. | Garcia, Angelica | Dunckley, Travis | Meechoovet, Bessie | Reiman, Eric M. | Roher, Alex E.
Article Type: Correction
DOI: 10.3233/JAD-169007
Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 1249-1249, 2016
Authors: Beach, Thomas G. | Sue, Lucia I. | Walker, Douglas G. | Sabbagh, Marwan N. | Serrano, Geidy | Dugger, Brittany N. | Mariner, Monica | Yantos, Kim | Henry-Watson, Jonette | Chiarolanza, Glenn | Hidalgo, Jose A. | Souders, Leslie
Article Type: Research Article
Abstract: Amyloid imaging may revolutionize Alzheimer's disease (AD) research and clinical practice but is critically limited by an inadequate correlation between cerebral cortex amyloid plaques and dementia. Also, amyloid imaging does not indicate the extent of neurofibrillary tangle (NFT) spread throughout the brain. Currently, the presence of dementia as well as a minimal brain load of both plaques and NFTs is required for the diagnosis of AD. Autopsy studies suggest that striatal amyloid plaques may be mainly restricted to subjects in higher Braak NFT stages that meet clinicopathological diagnostic criteria for AD. Striatal plaques, which are readily identified by amyloid imaging, …might therefore be used to predict the presence of a higher Braak NFT stage and clinicopathological AD in living subjects. This study determined the sensitivity and specificity of striatal plaques for predicting a higher Braak NFT stage and clinicopathological AD in a postmortem series of 211 elderly subjects. Subjects included 87 clinicopathologically classified as non-demented elderly controls and 124 with AD. A higher striatal plaque density score (moderate or frequent) had 95.8% sensitivity, 75.7% specificity for Braak NFT stage V or VI and 85.6% sensitivity, 86.2% specificity for the presence of dementia and clinicopathological AD (National Institute on Aging – Reagan Institute “intermediate” or “high”). Amyloid imaging of the striatum may be useful as a predictor, in living subjects, of Braak NFT stage and the presence or absence of dementia and clinicopathological AD. Validation of this hypothesis will require autopsy studies of subjects that had amyloid imaging during life. Show more
Keywords: Alzheimer's disease, amyloid imaging, amyloid plaques, asymptomatic, autopsy, diagnosis, preclinical, striatum, therapy
DOI: 10.3233/JAD-2011-111340
Citation: Journal of Alzheimer's Disease, vol. 28, no. 4, pp. 869-876, 2012
Authors: Dugger, Brittany N. | Whiteside, Charisse M. | Maarouf, Chera L. | Walker, Douglas G. | Beach, Thomas G. | Sue, Lucia I. | Garcia, Angelica | Dunckley, Travis | Meechoovet, Bessie | Reiman, Eric M. | Roher, Alex E.
Article Type: Research Article
Abstract: Tau becomes excessively phosphorylated in Alzheimer’s disease (AD) and is widely studied within the brain. Further examination of the extent and types of tau present in peripheral tissues and their relation to AD is warranted given recent publications on pathologic spreading. Cases were selected based on the presence of pathological tau spinal cord deposits (n = 18). Tissue samples from sigmoid colon, scalp, abdominal skin, liver, and submandibular gland were analyzed by western blot and enzyme-linked immunosorbent assays (ELISAs) for certain tau species; frontal cortex gray matter was used for comparison. ELISAs revealed brain to have the highest total tau levels, …followed by submandibular gland, sigmoid colon, liver, scalp, and abdominal skin. Western blots with antibodies recognizing tau phosphorylated at threonine 231(pT231), serine 396 and 404 (PHF-1), and an unmodified total human tau between residues 159 and 163 (HT7) revealed multiple banding patterns, some of which predominated in peripheral tissues. As submandibular gland had the highest levels of peripheral tau, a second set of submandibular gland samples were analyzed (n = 36; 19 AD, 17 non-demented controls). ELISAs revealed significantly lower levels of pS396 (p = 0.009) and pT231 (p = 0.005) in AD cases but not total tau (p = 0.18). Furthermore, pT231 levels in submandibular gland inversely correlated with Braak neurofibrillary tangle stage (p = 0.04), after adjusting for age at death, gender, and postmortem interval. These results provide evidence that certain tau species are present in peripheral tissues. Of potential importance, submandibular gland pT231 is progressively less abundant with increasing Braak neurofibrillary tangle stage. Show more
Keywords: Braak NFT stage, colon, HT7, liver, PHF-1, propagation, skin, spread, submandibular gland, T231
DOI: 10.3233/JAD-150859
Citation: Journal of Alzheimer's Disease, vol. 51, no. 2, pp. 345-356, 2016
Authors: Filshtein, Teresa Jenica | Dugger, Brittany N. | Jin, Lee-Way | Olichney, John M. | Farias, Sarah T. | Carvajal-Carmona, Luis | Lott, Paul | Mungas, Dan | Reed, Bruce | Beckett, Laurel A. | DeCarli, Charles
Article Type: Research Article
Abstract: Our nation is becoming increasingly diverse; however, few autopsy studies examine multiple ethnoracial groups, especially Hispanics. We examined differences in neuropathological diagnoses of 423 deceased participants with dementia from three ethnoracial groups (35 Black, 28 Hispanic, and 360 non-Hispanic White) evaluated at the University of California Davis Alzheimer’s Disease Center. We used novel applications of bootstrap resampling and logistic regression standardization to project neuropathological diagnostic rates for non-Hispanic Whites to minority sample characteristics to improve inference of findings. Alzheimer’s disease (AD) without significant cerebrovascular disease (CVD) or other dementia-related pathologies (AD (non-mixed)) was present in 15 Black (43%), 4 Hispanic …(14%), and 156 (43%) non-Hispanic Whites. CVD sufficient to contribute to dementia was confirmed in 14 Black (40%), 15 Hispanic (54%), and 101 (28%) non-Hispanic White decedents. The observed CVD prevalence of 40% in Blacks exceeded the predicted 29% [95% CI: 22%-36%]. Despite being outside the 95% confidence interval, the difference between observed and predicted was not statistically significant after bootstrap testing. Conversely, for Hispanics, the observed proportion at 54% exceeded significantly the predicted prevalence of 24% from non-Hispanic Whites [95% CI: 16%-34%], avg. p = 0.008). An identical analysis using AD (non-mixed) as the outcome predicted AD (non-mixed) in Blacks averaging 41% [95% CI: 34%-48%], nearly equal to observed prevalence. For Hispanics, however, the observed proportion at 14%, was well below predictions (mean = 42%, 95% CI: 32%-53%], avg. p = 0.008). We conclude mixed diagnoses and CVD are more common in Hispanic and Black decedents than Non-Hispanic Whites with dementia in our cohort. The increased prevalence of vascular co-morbidity may be a potential opportunity to intervene more effectively in dementia treatment of those individuals. Show more
Keywords: Alzheimer’s disease, autopsy, brain, cognitive aging, cohort studies, dementia, minority groups, neuropathology, vascular
DOI: 10.3233/JAD-180992
Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 145-158, 2019
Authors: Huie, Emily Z. | Escudero, Anthony | Saito, Naomi | Harvey, Danielle | Nguyen, My-Le | Lucot, Katherine L. | LaGrande, Jayne | Mungas, Dan | DeCarli, Charles | Lamar, Melissa | Schneider, Julie A. | Kapasi, Alifiya | Rissman, Robert A. | Teich, Andrew F. | Dugger, Brittany N.
Article Type: Research Article
Abstract: Background: Transactive Response DNA Binding Protein 43 kDa (TDP-43) pathology is frequently found in cases with Alzheimer’s disease (AD). TDP-43 pathology is associated with hippocampal atrophy and greater AD severity denoted by cognition and clinical representation. Current TDP-43 pathology studies are predominantly based on non-Hispanic White cohorts. Objective: We sought to evaluate the presence of TDP-43 pathology across ethnoracial groups utilizing the National Alzheimer’s Coordinating Center; a database containing data from over 29 institutions across the United States. Cases (N = 1135: Hispanics/Latinos = 29, African Americans/Black Americans = 51, Asians/Asian Americans = 10, American Indians/Alaskan Natives = 2, non-Hispanic …White = 1043) with intermediate/high AD having data on TDP-43 pathology in the amygdala, hippocampus, entorhinal cortex, and neocortex were included. Methods: TDP-43 pathology frequency in each neuroanatomic region among ethnoracial groups were compared using generalized linear mixed effects models with center as a random effect adjusting for age at death, education, and gender. Results: Although groups were imbalanced, there was no significant difference across ethnoracial groups based on TDP-43 pathology (p = 0.84). With respect to neuroanatomical regions evaluated, there were no significant differences across ethnoracial groups (p -values > 0.06). There were also no significant differences for age at death and gender ratios across ethnoracial groups based on TDP-43 pathology. Although not statistically significant, TDP-43 pathology was present less often in Hispanic/Latinos (34%) when compared to non-Hispanic Whites (46%). Conclusion: While this is a preliminary evaluation, it highlights the need for diverse cohorts and on TDP-43 pathology research across ethnoracial groups. This is the first study to our knowledge having a focus on the neuroanatomical distribution of TDP-43 deposits in Hispanic/Latino decedents with AD. Show more
Keywords: African American, Alzheimer’s disease, Asian, brain, cohort studies, Hispanic, Latino, minoritized groups, neuropathology
DOI: 10.3233/JAD-220558
Citation: Journal of Alzheimer's Disease, vol. 91, no. 4, pp. 1291-1301, 2023
Authors: Dugger, Brittany N. | Serrano, Geidy E. | Sue, Lucia I. | Walker, Douglas G. | Adler, Charles H. | Shill, Holly A. | Sabbagh, Marwan N. | Caviness, John N. | Hidalgo, Jose | Saxon-LaBelle, Megan | Chiarolanza, Glenn | Mariner, Monica | Henry-Watson, Jonette | Beach, Thomas G. | The Arizona Parkinson's Disease Consortium
Article Type: Research Article
Abstract: Dementia is a frequent complication of Parkinson's disease (PD). About half of PD dementia (PDD) is hypothesized to be due to progression of the underlying Lewy body pathology into limbic regions and the cerebral cortex while the other half is thought to be due to coexistent Alzheimer's disease (AD). Clinically, however, these are indistinguishable. The spread of amyloid plaques to the striatum has been reported to be a sensitive and specific indicator of dementia due to AD. The purpose of the present study was to determine if the presence of striatal plaques might also be a useful indicator of the …presence of diagnostic levels of AD pathology within PD subjects. We analyzed neuropathologically-confirmed cases of PD without dementia (PDND, N = 31), PDD without AD (PDD, N = 31) and PD with dementia meeting clinicopathological criteria for AD (PDAD, N = 40). The minimum diagnostic criterion for AD was defined as including a clinical history of dementia, moderate or frequent CERAD cortical neuritic plaque density and Braak neurofibrillary stage III-VI. Striatal amyloid plaque densities were determined using Campbell-Switzer and Thioflavine S stains. Striatal plaque densities were significantly higher in PDAD compared to PDD (p < 0.001). The presence of striatal plaques was approximately 80% sensitive and 80% specific for predicting AD. In comparison, the presence of cerebral cortex plaques alone was highly sensitive (100%) but had poor specificity (48% to 55%). The results suggest that striatal amyloid imaging may be clinically useful for making the distinction between PDD and PDAD. Show more
Keywords: Striatum, Lewy body, diagnosis, autopsy, neuropathology, biomarker
DOI: 10.3233/JPD-2012-11073
Citation: Journal of Parkinson's Disease, vol. 2, no. 1, pp. 57-65, 2012
Authors: Gupta, Harsh V. | Beach, Thomas G. | Mehta, Shyamal H. | Shill, Holly A. | Driver-Dunckley, Erika | Sabbagh, Marwan N. | Belden, Christine M. | Liebsack, Carolyn | Dugger, Brittany N. | Serrano, Geidy E. | Sue, Lucia I. | Siderowf, Andrew | Pontecorvo, Michael J. | Mintun, Mark A. | Joshi, Abhinay D. | Adler, Charles H.
Article Type: Research Article
Abstract: Background: Imaging biomarkers have the potential to distinguish between different brain pathologies based on the type of ligand used with PET. AV-45 PET (florbetapir, Amyvid™) is selective for the neuritic plaque amyloid of Alzheimer’s disease (AD), while AV-133 PET (florbenazine) is selective for VMAT2, which is a dopaminergic marker. Objective: To report the clinical, AV-133 PET, AV-45 PET, and neuropathological findings of three clinically diagnosed dementia patients who were part of the Avid Radiopharmaceuticals AV133-B03 study as well as the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). Methods: Three subjects who had PET imaging with both AV-133 and AV-45 …as well as a standardized neuropathological assessment were included. The final clinical, PET scan, and neuropathological diagnoses were compared. Results: The clinical and neuropathological diagnoses were made blinded to PET scan results. The first subject had a clinical diagnosis of dementia with Lewy bodies (DLB); AV-133 PET showed bilateral striatal dopaminergic degeneration, and AV-45 PET was positive for amyloid. The final clinicopathological diagnosis was DLB and AD. The second subject was diagnosed clinically with probable AD; AV-45 PET was positive for amyloid, while striatal AV-133 PET was normal. The final clinicopathological diagnosis was DLB and AD. The third subject had a clinical diagnosis of DLB. Her AV-45 PET was positive for amyloid and striatal AV-133 showed dopaminergic degeneration. The final clinicopathological diagnosis was multiple system atrophy and AD. Conclusion: PET imaging using AV-133 for the assessment of striatal VMAT2 density may help distinguish between AD and DLB. However, some cases of DLB with less-pronounced nigrostriatal dopaminergic neuronal loss may be missed. Show more
Keywords: Alzheimer’s disease, amyloid, AV-133, dementia with Lewy bodies, synucleinopathy, VMAT2
DOI: 10.3233/JAD-200323
Citation: Journal of Alzheimer's Disease, vol. 80, no. 4, pp. 1603-1612, 2021
Authors: Beach, Thomas G. | Adler, Charles H. | Serrano, Geidy | Sue, Lucia I. | Walker, D.G. | Dugger, Brittany N. | Shill, Holly A. | Driver-Dunckley, Erika | Caviness, John N. | Intorcia, Anthony | Filon, Jessica | Scott, Sarah | Garcia, Angelica | Hoffman, Brittany | Belden, Christine M. | Davis, Kathryn J. | Sabbagh, Marwan N.
Article Type: Research Article
Abstract: Background: Clinical misdiagnosis, particularly at early disease stages, is a roadblock to finding new therapies for Lewy body disorders. Biopsy of a peripheral site might provide improved diagnostic accuracy. Previously, we reported, from both autopsy and needle biopsy, a high prevalence of submandibular gland synucleinopathy in Parkinson’s disease (PD). Here, we report on an extension of these studies to subjects with dementia with Lewy bodies (DLB) and other Lewy body disorders in 228 autopsied subjects from the Arizona Study of Aging and Neurodegenerative Disorders. Objective: To provide an estimate of the prevalence of histological synucleinopathy in the submandibular glands of …subjects with PD and other Lewy body disorders. Methods: Submandibular gland sections from autopsied subjects were stained with an immunohistochemical method for α -synuclein phosphorylated at serine 129. Included were 146 cases with CNS Lewy-type synucleinopathy (LTS), composed of 46 PD, 28 DLB, 14 incidental Lewy body disease (ILBD), 33 Alzheimer’s disease with Lewy bodies (ADLB) and 2 with progressive supranuclear palsy and Lewy bodies (PSPLB). Control subjects included 79 normal elderly, 15 AD, 12 PSP, 2 conticobasal degeneration (CBD) and 2 multiple system atrophy (MSA). Results: Submandibular gland LTS was found in 42/47 (89%) of the PD subjects, 20/28 (71%) DLB, 4/33 (12%) ADLB and 1/9 (11%) ILBD subjects but none of the 110 control subjects. Conclusions: These results provide support for further clinical trials of in vivo submandibular gland diagnostic biopsy for PD and DLB. An accurate peripheral biopsy diagnosis would assist subject selection for clinical trials and could also be used to verify other biomarkers. Show more
Keywords: Biopsy, diagnosis, clinical trial, biomarker, pathology, therapy
DOI: 10.3233/JPD-150680
Citation: Journal of Parkinson's Disease, vol. 6, no. 1, pp. 153-163, 2016
