The Distribution of Phosphorylated Tau in Spinal Cords of Alzheimer's Disease and Non-Demented Individuals
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
Antemortem-Postmortem Correlation of Florbetapir ( 18F) PET Amyloid Imaging with Quantitative Biochemical Measures of Aβ 42 but not Aβ 40
Authors: Beach, Thomas G. | Maarouf, Chera L. | Intorcia, Anthony | Sue, Lucia I. | Serrano, Geidy E. | Lu, Ming | Joshi, Abhinay | Pontecorvo, Michael J. | Roher, Alex E.
Article Type: Research Article
Abstract: Amyloid imaging demonstrates the in vivo presence of amyloid-β (Aβ) deposits in the aging human brain but it is still unknown which structural forms and modifications of Aβ are detected. In Alzheimer’s disease, most amyloid deposits are predominantly composed of Aβ ending at amino acid residues Val40 or Ala42. It has been reported that Aβ40 is largely restricted to neuritic plaques while Aβ42 may be deposited in amyloid plaques of all types, and is often the sole component of diffuse plaques. The distinction is important as it is mainly the neuritic plaques that correlate with cognitive impairment while diffuse plaques …may be the initial type of Aβ deposited. Whether PET amyloid ligands such as florbetapir-18 F (Amyvid) are partially or wholly selective for brain deposits of Aβ40 or Aβ42 is currently unknown. We compared antemortem florbetapir PET cortical/cerebellar signal intensity (SUVr) of 55 subjects with postmortem biochemical (ELISA) measurements employing specific antibodies against Aβ40 and Aβ42 . Spearman’s univariable correlations were significant for both Aβ40 and Aβ42 , but were much stronger for Aβ42 . Multiple linear regression showed significance only for Aβ42 . These results suggest that florbetapir binds only weakly, if at all, to Aβ40 . This may be in part due to the higher likelihood for Aβ42 to be present in a β-pleated sheet tertiary structure, or to differences between Aβ40 and Aβ42 in β-pleated sheet tertiary or quaternary structure. Show more
Keywords: Alzheimer’s disease, autopsy, diagnosis, diffuse plaque, neuritic plaque
DOI: 10.3233/JAD-170762
Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1509-1516, 2018
The Presence of Select Tau Species in Human Peripheral Tissues and Their Relation to Alzheimer’s Disease
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
Positive Florbetapir PET Amyloid Imaging in a Subject with Frequent Cortical Neuritic Plaques and Frontotemporal Lobar Degeneration with TDP43-Positive Inclusions
Authors: Serrano, Geidy E. | Sabbagh, Marwan N. | Sue, Lucia I. | Hidalgo, Jose A. | Schneider, Julie A. | Bedell, Barry J. | Van Deerlin, Vivianna M. | Suh, Eunran | Akiyama, Haruhiko | Joshi, Abhinay D. | Pontecorvo, Michael J. | Mintun, Mark A. | Beach, Thomas G.
Article Type: Research Article
Abstract: Abnormal neuronal accumulation and modification of TAR DNA binding protein 43 (TDP-43) have recently been discovered to be defining histopathological features of particular subtypes of frontotemporal dementia and amyotrophic lateral sclerosis, and are also common in aging, particularly coexisting with hippocampal sclerosis and Alzheimer's disease pathology. This case report describes a 72 year old Hispanic male with no family history of neurological disease, who presented at age 59 with obsessive behavior, anxiety, agitation, and dysphasia. Positron emission tomography imaging using the amyloid ligand 18 F florbetapir (Amyvid) was positive. Postmortem examination revealed frequent diffuse and neuritic amyloid plaques throughout the …cerebral cortex, thalamus, and striatum, Braak stage II neurofibrillary degeneration, and frequent frontal and temporal cortex TDP-43-positive neurites with rare nuclear inclusions. The case is unusual and instructive because of the co-existence of frequent cortical and diencephalic amyloid plaques with extensive TDP-43-positive histopathology in the setting of early-onset dementia and because it demonstrates that a positive cortical amyloid imaging signal in a subject with dementia does not necessarily establish that Alzheimer's disease is the sole cause. Show more
Keywords: Alzheimer's disease, frontotemporal dementia, neuritic amyloid plaques, neurofibrillary degeneration
DOI: 10.3233/JAD-140162
Citation: Journal of Alzheimer's Disease, vol. 42, no. 3, pp. 813-821, 2014
Striatal Amyloid Plaque Density Predicts Braak Neurofibrillary Stage and Clinicopathological Alzheimer's Disease: Implications for Amyloid Imaging
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
Brain Lewy-Type Synucleinopathy Density Is Associated with a Lower Prevalence of Atherosclerotic Cardiovascular Disease Risk Factors in Patients with Parkinson’s Disease
Authors: Driver-Dunckley, Erika D. | Zhang, Nan | Adler, Charles H. | Serrano, Geidy E. | Sue, Lucia I. | Shill, Holly A. | Mehta, Shyamal H. | Belden, Christine M. | Zamrini, Edward Y. | Davis, Kathryn | Beach, Thomas G.
Article Type: Research Article
Abstract: Background: Some epidemiology studies suggest that atherosclerotic cardiovascular disease (ASCVD) risk factors increase the risk of developing Parkinson’s disease (PD). However, conflicting data suggest lower rates of ASCVD in PD. Objective: The objective of this study is to determine, with data from a longitudinal clinicopathological study, whether ASCVD risk factors are associated with a PD diagnosis and/or increased brain or peripheral load of Lewy-type synucleinopathy (LTS). Methods: All subjects were followed to autopsy and neuropathological examination in the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). Multivariable regression models, including age, gender, and smoking history, were used to investigate the …association of a PD diagnosis or brain or submandibular gland LTS load with ASCVD risk factors. Results: 150 subjects were included (PD n = 60, controls n = 90). Univariable comparisons and regression models showed a general trend to inverse associations. The multivariable odds ratio (OR) of brain LTS load for carotid artery disease was 0.93 (95% CI: 0.86 to 0.98; p = 0.02), for anticoagulant use 0.95 (95% CI: 0.90 to 0.99; p = 0.04) and for abnormal heart weight 0.96 (95% CI: 0.92 to 0.99; p = 0.01). Composite clinical and overall (clinical + pathology composite risk scores) composite risk scores were also significantly lower in the PD subjects (p = 0.0164 and 0.0187, respectively). Submandibular gland LTS load was not significantly related to ASCVD conditions. Conclusions: This study shows associations of higher brain LTS with lower prevalence of both clinical and pathological indices of ASCVD in PD subjects versus age-similar controls. We suggest that this is due to α -synuclein pathology-induced sympathetic denervation in PD. Show more
Keywords: α-synuclein, Parkinson’s disease, atherosclerotic cardiovascular disease, sympathetic nervous system
DOI: 10.3233/JPD-191610
Citation: Journal of Parkinson's Disease, vol. 9, no. 3, pp. 543-552, 2019
Multicenter Assessment of Immunohistochemical Methods for Pathological Alpha-Synuclein in Sigmoid Colon of Autopsied Parkinson’s Disease and Control Subjects
Authors: Beach, Thomas G. | Corbillé, Anne-Gaëlle | Letournel, Franck | Kordower, Jeffrey H. | Kremer, Thomas | Munoz, David G. | Intorcia, Anthony | Hentz, Joseph | Adler, Charles H. | Sue, Lucia I. | Walker, Jessica | Serrano, Geidy | Derkinderen, Pascal
Article Type: Research Article
Abstract: Background: Conflicting results from studies of Lewy-type α−synucleinopathy (LTS) in colonic biopsies of subjects with Parkinson’s disease (PD) prompted a two-part multicenter assessment. The first assessment, now published (Acta Neuropathol Commun 4 : 35, 2016), examined archived colonic biopsies and found that none of the tested methods was adequately sensitive or specific. Objective: As the amount of nervous tissue in typical colonic biopsies may be insufficient, and the clinical diagnosis of PD not completely accurate, the objective of the current study was to use instead full-thickness sections of sigmoid colon from autopsy-proven PD and normal subjects. Methods: Seven different immunohistochemical (IHC) methods …were used, employing five different primary antibodies and four different combinations of epitope exposure and signal development protocols. Specific staining was defined as being restricted to morphological features consistent with neuronal elements. Stained slides from each subject were independently categorized as being positive or negative for LTS, and their density semi-quantitatively graded, by four raters blinded to diagnosis. Results: Agreement and mean diagnostic performance varied markedly between raters. With the two most accurate raters, 5 methods achieved diagnostic accuracies of 70% or greater; one method had 100% accuracy and 100% inter-rater agreement. The submucosa had the highest prevalence of pathological LTS staining, followed by the muscularis and mucosa. Conclusions: The major conclusion of this study is that, when sufficient submucosa and LTS is present, and when specific staining is defined as being consistent with neuronal morphology, adequately-trained raters may reliably distinguish PD colon from control using suitable IHC methods. Show more
Keywords: Lewy body, gastrointestinal tract, diagnosis, pathology, biopsy, enteric nervous system
DOI: 10.3233/JPD-160888
Citation: Journal of Parkinson's Disease, vol. 6, no. 4, pp. 761-770, 2016
The Presence of Select Tau Species in Human Peripheral Tissues and Their Relation to Alzheimer’s Disease
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
Vagus Nerve and Stomach Synucleinopathy in Parkinson’s Disease, Incidental Lewy Body Disease, and Normal Elderly Subjects: Evidence Against the “Body-First” Hypothesis
Authors: Beach, Thomas G. | Adler, Charles H. | Sue, Lucia I. | Shill, Holly A. | Driver-Dunckley, Erika | Mehta, Shyamal H. | Intorcia, Anthony J. | Glass, Michael J. | Walker, Jessica E. | Arce, Richard | Nelson, Courtney M. | Serrano, Geidy E.
Article Type: Research Article
Abstract: Background: Braak and others have proposed that Lewy-type α-synucleinopathy in Parkinson’s disease (PD) may arise from an exogenous pathogen that passes across the gastric mucosa and then is retrogradely transported up the vagus nerve to the medulla. Objective: We tested this hypothesis by immunohistochemically staining, with a method specific for p-serine 129 α-synuclein (pSyn), stomach and vagus nerve tissue from an autopsy series of 111 normal elderly subjects, 33 with incidental Lewy body disease (ILBD) and 53 with PD. Methods: Vagus nerve samples were taken adjacent to the carotid artery in the neck. Stomach samples were taken from the gastric …body, midway along the greater curvature. Formalin-fixed paraffin-embedded sections were immunohistochemically stained for pSyn, shown to be highly specific and sensitive for α-synuclein pathology. Results: Median disease duration for the PD group was 13 years. In the vagus nerve none of the 111 normal subjects had pSyn in the vagus, while 12/26 ILBD (46%) and 32/36 PD (89%) subjects were pSyn-positive. In the stomach none of the 102 normal subjects had pSyn while 5/30 (17%) ILBD and 42/52 (81%) of PD subjects were pSyn-positive. Conclusion: As there was no pSyn in the vagus nerve or stomach of subjects without brain pSyn, these results support initiation of pSyn in the brain. The presence of pSyn in the vagus nerve and stomach of a subset of ILBD cases indicates that synucleinopathy within the peripheral nervous system may occur, within a subset of individuals, at preclinical stages of Lewy body disease. Show more
Keywords: Pathology, etiology, autopsy, gastrointestinal, peripheral nerve, pathogenesis
DOI: 10.3233/JPD-212733
Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1833-1843, 2021
Presence of Striatal Amyloid Plaques in Parkinson's Disease Dementia Predicts Concomitant Alzheimer's Disease: Usefulness for Amyloid Imaging
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