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Authors: Beach, Thomas G.

Article Type: Review Article

Abstract: Medical science is currently perceived as underperforming. This is because of the relatively slow recent rate of development of new disease treatments. This has been blamed on cultural, regulatory, and economic factors that generate a so-called “Valley of Death”, hindering new drug candidates from being moved into clinical trials and eventually approved for use. We propose, however, that for neurodegenerative diseases, a relative decline of human brain tissue research is also a contributor. The present pharmacological agents for treating Alzheimer's disease (AD) were identified through direct examination of postmortem human brain tissue more than 30 years ago. Since that time …the percentage of research grants awarded to human brain tissue-using projects has dropped precipitously and publication rates have stagnated. As human brain tissue research has played a central and often initiating role in identifying most of the targets that have gone to AD clinical trials, it is proposed that the rate of discovery of new targets has been curtailed. Additionally, the continued rejection of cortical biopsy as a diagnostic method for AD has most probably depressed the perceived effect sizes of new medications and contributed to the high Phase II clinical trial failure rates. Despite the relative lack of funding, human brain discovery research has continued to make important contributions to our understanding of neurodegenerative disease, and brain banks have played an essential role. It is likely that the pace of discovery will dramatically accelerate over the coming decades as increasingly powerful tools including genomics, epigenetics, transcriptomics, regulatory RNA, gene expression profiling, proteomics, and metabolomics are applied. To optimize the promise of these new technologies, however, it is critical that brain banks are rejuvenated by enhanced governmental and/or private support. Show more

Keywords: Alzheimer's disease, autopsy, brain, clinical trials, human, neuropathology, postmortem

DOI: 10.3233/JAD-2012-129020

Citation: Journal of Alzheimer's Disease, vol. 33, no. s1, pp. S219-S233, 2013

Authors: Beach, Thomas G. | Malek-Ahmadi, Michael

Article Type: Research Article

Abstract: Background: Clinicopathological studies have demonstrated that Alzheimer’s disease dementia (ADD) is often accompanied by clinically undetectable comorbid neurodegenerative and cerebrovascular disease that alter the rate of cognitive decline. Aside from causing increased variability in clinical response, it is possible that the major ADD comorbidities may not respond to ADD-specific molecular therapeutics. Objective: As most reports have focused on comorbidity in the oldest-old, its extent in younger age groups that are more likely to be involved in clinical trials is largely unknown; our objective is to provide this information. Methods: We conducted a survey of neuropathological comorbidities in sporadic ADD using …data from the US National Alzheimer’s Coordinating Center. Subject data was restricted to those with dementia and meeting National Institute on Aging-Alzheimer’s Association intermediate or high AD Neuropathological Change levels, excluding those with known autosomal dominant AD-related mutations. Results: Highly prevalent ADD comorbidities are not restricted to the oldest-old but are common even in early-onset ADD. The percentage of cases with ADD as the sole major neuropathological diagnosis is highest in the under-60 group, where “pure” ADD cases are still in the minority at 44%. After this AD as a sole major pathology in ADD declines to roughly 20%in the 70s and beyond. Lewy body disease is the most common comorbidity at younger ages but actually is less common at later ages, while for most others, their prevalence increases with age. Conclusion: Alzheimer’s disease neuropathological comorbidities are highly prevalent even in the younger-old. Show more

Keywords: Cerebrovascular, infarct, Lewy bodies, TDP-43, tau, white matter

DOI: 10.3233/JAD-201213

Citation: Journal of Alzheimer's Disease, vol. 79, no. 1, pp. 389-400, 2021

Authors: Beach, Thomas G. | Thal, Dietmar Rudolf | Zanette, Michelle | Smith, Adrian | Buckley, Christopher

Article Type: Research Article

Abstract: Amyloid imaging is limited by an inconsistent relationship between cerebral cortex amyloid- β (Aβ) plaques and dementia. Autopsy studies suggest that Aβ plaques first appear in the cerebral cortex while subcortical plaques are present only later in the disease course. The presence of abundant plaques in both cortex and striatum is more strongly correlated with the presence of dementia than cortical Aβ plaques alone. Additionally, detection of striatal plaques may allow, for the first time, pathology-based clinical staging of AD. Striatal plaques are reportedly identifiable by amyloid imaging but the accuracy and reliability of striatal amyloid imaging has never been …tested against postmortem histopathology. To determine this, we correlated the presence of histopathologically-demonstrated striatal Aβ deposits with a visually positive panel consensus decision of a positive [18 F]flutemetamol striatal PET signal in 68 subjects that later came to autopsy. The sensitivity of [18 F]flutemetamol PET striatal amyloid imaging, for several defined density levels of histological striatal Aβ deposits, ranged between 69% and 87% while the specificity ranged between 96% and 100%. Sensitivity increased with higher histological density thresholds while the reverse was found for specificity. In general, as compared with PET alone, PET with CT had slightly higher sensitivities but slightly lower specificities. In conclusion, amyloid imaging of the striatum with [18 F]flutemetamol PET has reasonable accuracy for the detection of histologically-demonstrated striatal Aβ plaques when present at moderate or frequent densities. Amyloid imaging of the cerebral cortex and striatum together may allow for a more accurate clinicopathological diagnosis of AD and enable pathology-based clinical staging of AD. Show more

Keywords: Alzheimer’s disease, amyloid imaging, autopsy, diagnosis, [18F]flutemetamol, preclinical, staging

DOI: 10.3233/JAD-150732

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 863-873, 2016

Authors: Li, Shiping | Yin, Junxiang | Nielsen, Megan | Beach, Thomas G. | Guo, Li | Shi, Jiong

Article Type: Research Article

Abstract: Background: Emerging evidence shows tau acetylation has been observed in Alzheimer’s disease (AD) brain at early Braak stages and is involved in regulating tau early accumulation. However, the effects of deacetylase Sirtuin 3 (Sirt3) on tau acetylation and its aggregations are unclear. Objective: We studied the effects of Sirt3 on tau acetylation and its aggregations. Methods: We investigated the protein levels of Sirt3 and tangle tau in human postmortem brains slices from AD, mild cognitive impairment, and age- and education-matched cognitively normal subjects, and AD model mice. We also measured tau acetylation levels in hippocampal HT22 cells after Sirt3 knockdown …or overexpression. Results: The level of Sirt3 was inversely related with tau protein in brain slices from both human being and AD model mice. Mechanistically, tau acetylation decreased dramatically with Sirt3 overexpression, while tau acetylation increased after Sirt3 knockdown in hippocampal HT22 cells. Conclusions: Sirt3 may play a role in tau acetylation and could be a potential target for novel therapy to alleviate tau accumulation. Show more

Keywords: Acetylation, Alzheimer’s disease, Sirtuin, tau

DOI: 10.3233/JAD-190014

Citation: Journal of Alzheimer's Disease, vol. 69, no. 2, pp. 355-362, 2019

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: Tharp, William G. | Lee, Yong-Ho | Greene, Shane M. | Vincellete, Elise | Beach, Thomas G. | Pratley, Richard E.

Article Type: Research Article

Abstract: Enzymatic cleavage of amyloid-β protein precursor (AβPP) produces amyloid-β (Aβ) peptides which form the insoluble cortical plaques characteristic of Alzheimer's disease (AD). AβPP is post-transcriptionally processed into three major isoforms with differential cellular and tissue expression patterns. Changes in AβPP isoform expression may be indicative of disease pathogenesis in AD, but accurately measuring AβPP gene isoforms has been difficult to standardize, reproduce, and interpret. In light of this, we developed a set of isoform specific absolute quantification real time PCR standards that allow for quantification of transcript copy numbers for total AβPP and all three major isoforms (AβPP695, AβPP751, and …AβPP770) in addition to glyceraldehyde-3-dehydrogenase (GAPDH) and examined expression patterns in superior frontal gyrus (SFG) and cerebellar samples from patients with (n = 12) and without AD (n = 10). Both total AβPP and AβPP695 transcripts were significantly decreased in SFG of patients with AD compared to control (p = 0.037 and p = 0.034, respectively). AβPP751 and AβPP770 transcripts numbers were not significantly different between AD and control (p > 0.15). There was trend for decreased percentage AβPP695 (p = 0.051) and increased percentage AβPP770 (p = 0.013) expression in SFG of patients with AD. GAPDH transcripts levels were also decreased significantly in the SFG of patients with AD compared to control (p = 0.005). Decreasing total AβPP and AβPP695 copy number was associated with increased plaque burden and decreased cognitive function. In this study we describe a simple procedure for measuring AβPP isoform transcripts by real-time PCR and confirm previous studies showing altered AβPP isoform expression patterns in AD. Show more

Keywords: Alternative splicing, Alzheimer's disease (AD), amyloid-β (Aβ), amyloid-β protein precursor (AβPP), dementia, kunitz, polymerase chain reaction

DOI: 10.3233/JAD-2011-111337

Citation: Journal of Alzheimer's Disease, vol. 29, no. 2, pp. 449-457, 2012

Authors: Valla, Jon | Yaari, Roy | Wolf, Andrew B. | Kusne, Yael | Beach, Thomas G. | Roher, Alex E. | Corneveaux, Jason J. | Huentelman, Matthew J. | Caselli, Richard J. | Reiman, Eric M.

Article Type: Research Article

Abstract: In vivo PET imaging studies of young-adult carriers of the apolipoprotein E ε4 allele (APOEε4), the major Alzheimer's disease (AD) susceptibility gene, have demonstrated declines in glucose metabolism in brain areas later vulnerable to AD, such as posterior cingulate cortex, decades before the possible onset of symptoms. We have previously shown in postmortem studies that such metabolic declines in AD are associated with brain regional mitochondrial dysfunction. To determine whether young adult at-risk individuals demonstrate similar mitochondrial functional decline, we histochemically assessed postmortem tissues from the posterior cingulate cortex of young-adult carriers and noncarriers of APOEε4. At-risk ε4 carriers had …lower mitochondrial cytochrome oxidase activity than noncarriers in posterior cingulate cortex, particularly within the superficial cortical lamina, a pattern similar to that seen in AD patients. Except for one 34 year-old ε4 homozygote, the ε4 carriers did not have increased soluble amyloid-β, histologic amyloid-β, or tau pathology in this same region. This functional biomarker may prove useful in early detection and tracking of AD and indicates that mitochondrial mechanisms may contribute to the predisposition to AD before any evidence of amyloid or tau pathology. Show more

Keywords: Alzheimer's etiology, bioenergetics, biomarkers, cytochrome c oxidase, differential vulnerability, neocortex

DOI: 10.3233/JAD-2010-100129

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 307-313, 2010

Authors: Roher, Alex E. | Maarouf, Chera L. | Daugs, Ian D. | Kokjohn, Tyler A. | Hunter, Jesse M. | Sabbagh, Marwan N. | Beach, Thomas G.

Article Type: Research Article

Abstract: The field of Alzheimer's disease (AD) research eagerly awaits the results of a large number of Phase III clinical trials that are underway to investigate the effectiveness of anti-amyloid-β (Aβ) immunotherapy for AD. In this case report, we review the pertinent clinical history, examine the neuropathology, and characterize the Aβ profile of an AD patient who received bapineuzumab immunotherapy. The patient received four bapineuzumab infusions over a 39 week period. During the course of this treatment, there was no remarkable change in cognitive impairment as determined by MMSE scores. Forty-eight days after the fourth bapineuzumab infusion was given, MRI revealed …that the patient had developed lacunar infarcts and possible vasogenic edema, probably related to immunotherapy, but a subsequent MRI scan 38 days later demonstrated resolution of vasogenic edema. The patient expired due to acute congestive heart failure complicated by progressive AD and cerebrovascular accident 378 days after the first bapineuzumab infusion and 107 days after the end of therapy. Neuropathological and biochemical analysis did not produce evidence of lasting plaque regression or clearance of Aβ due to immunotherapy. The Aβ species profile of this case was compared with non-immunized AD cases and non-demented controls and found to be similar to non-immunized AD cases. SELDI-TOF mass spectrometric analysis revealed the presence of full-length Aβ1-42 and truncated Aβ peptides demonstrating species with and without bapineuzumab specific epitopes. These results suggest that, in this particular case, bapineuzumab immunotherapy neither resulted in detectable clearance of amyloid plaques nor prevented further cognitive impairment. Show more

Keywords: Active immunotherapy, Alzheimer's disease, amyloid-β, amyloid plaques, bapineuzumab, cerebral amyloid angiopathy, neurofibrillary tangles, passive immunotherapy

DOI: 10.3233/JAD-2011-101809

Citation: Journal of Alzheimer's Disease, vol. 24, no. 2, pp. 315-325, 2011

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

Authors: Tremblay, Cécilia | Serrano, Geidy E. | Dunckley, Nathaniel | Zhang, Nan | Fiock, Kimberly L. | Adler, Charles H. | Driver-Dunckley, Erika | Mehta, Shyamal H. | Shill, Holly A. | Beach, Thomas G.

Article Type: Research Article

Abstract: Background: Essential tremor (ET) is a common movement disorder in which cerebellar microscopic and volume alterations have been repeatedly reported although with disagreement between studies. However, pronounced heterogeneity was found with regard to cerebellar volume alterations. Objective: This study aimed to assess postmortem cerebellar volume in subjects with or without ET, as compared with subjects with multiple system atrophy (MSA), a well-established cerebellar neurodegeneration. Methods: Cases with ET (n  = 29), MSA (n  = 7), and non-demented control cases without any movement disorder (n  = 22) were selected from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND), a longitudinal clinicopathological study with …annual research-dedicated clinical assessments by neuropsychologists, subspecialist movement disorders, and cognitive/behavioral neurologists, with comprehensive neuropathological examinations after death. Group comparisons were controlled for common age-related neurodegenerative and cerebrovascular pathologies. Cerebellar volumes were calculated using digital images of slices taken at the time of autopsy, immediately after brain removal and before fixation. Results: Cerebellar volume was not reduced in ET subjects compared to controls. The two groups did not differ in terms of incidental cerebrovascular and Alzheimer’s disease neuropathology. In contrast, cerebellar volume was significantly reduced in subjects with MSA when compared to ET and control subjects. Conclusion: In a well-characterized cohort, postmortem cerebellar volume measurements suggest that there are no volume alterations in ET when compared to controls, in contrast to significant cerebellar atrophy in subjects with MSA. Show more

Keywords: Essential tremor, movement disorder, multiple system atrophy, autopsy, atrophy, Purkinje cell, neuropathology

DOI: 10.3233/JPD-225033

Citation: Journal of Parkinson's Disease, vol. 13, no. 3, pp. 333-340, 2023