%0 Journal Article %J J Alzheimers Dis %D 2023 %T Cerebral Gray and White Matter Monogalactosyl Diglyceride Levels Rise with the Progression of Alzheimer's Disease. %A Blusztajn, Jan Krzysztof %A Aytan, Nurgul %A Rajendiran, Thekkelnaycke %A Mellott, Tiffany J %A Soni, Tanu %A Burant, Charles F %A Serrano, Geidy E %A Beach, Thomas G %A Lin, Honghuang %A Stein, Thor D %X

BACKGROUND: Multiple studies have reported brain lipidomic abnormalities in Alzheimer's disease (AD) that affect glycerophospholipids, sphingolipids, and fatty acids. However, there is no consensus regarding the nature of these abnormalities, and it is unclear if they relate to disease progression.

OBJECTIVE: Monogalactosyl diglycerides (MGDGs) are a class of lipids which have been recently detected in the human brain. We sought to measure their levels in postmortem human brain and determine if these levels correlate with the progression of the AD-related traits.

METHODS: We measured MGDGs by ultrahigh performance liquid chromatography tandem mass spectrometry in postmortem dorsolateral prefrontal cortex gray matter and subcortical corona radiata white matter samples derived from three cohorts of participants: the Framingham Heart Study, the Boston University Alzheimer's Disease Research Center, and the Arizona Study of Aging and Neurodegenerative Disorders/Brain and Body Donation Program (total n = 288).

RESULTS: We detected 40 molecular species of MGDGs (including diacyl and alkyl/acyl compounds) and found that the levels of 29 of them, as well as total MGDG levels, are positively associated with AD-related traits including pathologically confirmed AD diagnosis, clinical dementia rating, Braak and Braak stage, neuritic plaque score, phospho-Tau AT8 immunostaining density, levels of phospho-Tau396 and levels of Aβ40. Increased MGDG levels were present in both gray and white matter, indicating that they are widespread and likely associated with myelin-producing oligodendrocytes-the principal cell type of white matter.

CONCLUSIONS: Our data implicate the MGDG metabolic defect as a central correlate of clinical and pathological progression in AD.

%B J Alzheimers Dis %V 95 %P 1623-1634 %8 2023 Oct 10 %G eng %N 4 %R 10.3233/JAD-230543 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Sirtuin 3 Mediates Tau Deacetylation. %A Li, Shiping %A Yin, Junxiang %A Nielsen, Megan %A Beach, Thomas G %A Guo, Li %A Shi, Jiong %X

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.

%B J Alzheimers Dis %V 69 %P 355-362 %8 2019 May 21 %G eng %N 2 %R 10.3233/JAD-190014 %0 Journal Article %J J Alzheimers Dis %D 2019 %T Transcriptome Changes in the Alzheimer's Disease Middle Temporal Gyrus: Importance of RNA Metabolism and Mitochondria-Associated Membrane Genes. %A Piras, Ignazio S %A Krate, Jonida %A Delvaux, Elaine %A Nolz, Jennifer %A Mastroeni, Diego F %A Persico, Antonio M %A Jepsen, Wayne M %A Beach, Thomas G %A Huentelman, Matthew J %A Coleman, Paul D %X

We used Illumina Human HT-12 v4 arrays to compare RNA expression of middle temporal gyrus (MTG; BA21) in Alzheimer's disease (AD = 97) and non-demented controls (ND = 98). A total of 938 transcripts were highly differentially expressed (adj p < 0.01; log2 FC ≥ |0.500|, with 411 overexpressed and 527 underexpressed in AD. Our results correlated with expression profiling in neurons from AD and ND obtained by laser capture microscopy in MTG from an independent dataset (log2 FC correlation: r = 0.504; p = 2.2e-16). Additionally, selected effects were validated by qPCR. ANOVA analysis yielded no difference between genders in response to AD, but some gender specific genes were detected (e.g., IL8 and AGRN in males, and HSPH1 and GRM1 in females). Several transcripts were associated with Braak staging (e.g., AEBP1 and DNALI1), antemortem MMSE (e.g., AEBP1 and GFAP), and tangle density (e.g., RNU1G2, and DNALI1). At the pathway level, we detected enrichment of synaptic vesicle processes and GABAergic transmission genes. Finally, applying the Weighted Correlation Network Analysis, we identified four expression modules enriched for neuronal and synaptic genes, mitochondria-associated membrane, chemical stimulus and olfactory receptor and non-coding RNA metabolism genes. Our results represent an extensive description of MTG mRNA profiling in a large sample of AD and ND. These data provide a list of genes associated with AD, and correlated to neurofibrillary tangles density. In addition, these data emphasize the importance of mitochondrial membranes and transcripts related to olfactory receptors in AD.

%B J Alzheimers Dis %V 70 %P 691-713 %8 2019 Aug 3 %G eng %N 3 %R 10.3233/JAD-181113 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Antemortem-Postmortem Correlation of Florbetapir (18F) PET Amyloid Imaging with Quantitative Biochemical Measures of Aβ42 but not Aβ40. %A Beach, Thomas G %A Maarouf, Chera L %A Intorcia, Anthony %A Sue, Lucia I %A Serrano, Geidy E %A Lu, Ming %A Joshi, Abhinay %A Pontecorvo, Michael J %A Roher, Alex E %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Amyloid beta-Peptides %K Amyloidosis %K Aniline Compounds %K Autopsy %K Brain %K Ethylene Glycols %K Humans %K Linear Models %K Peptide Fragments %K Plaque, Amyloid %K Positron-Emission Tomography %X

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-18F (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.

%B J Alzheimers Dis %V 61 %P 1509-1516 %8 2018 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/29376867?dopt=Abstract %R 10.3233/JAD-170762 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Detection of Striatal Amyloid Plaques with [18F]flutemetamol: Validation with Postmortem Histopathology. %A Beach, Thomas G %A Thal, Dietmar Rudolf %A Zanette, Michelle %A Smith, Adrian %A Buckley, Christopher %X

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 [18F]flutemetamol striatal PET signal in 68 subjects that later came to autopsy. The sensitivity of [18F]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 [18F]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.

%B J Alzheimers Dis %V 52 %P 863-73 %8 2016 Mar 31 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27031469?dopt=Abstract %R 10.3233/JAD-150732 %0 Journal Article %J J Alzheimers Dis %D 2016 %T The Presence of Select Tau Species in Human Peripheral Tissues and Their Relation to Alzheimer's Disease. %A Dugger, Brittany N %A Whiteside, Charisse M %A Maarouf, Chera L %A Walker, Douglas G %A Beach, Thomas G %A Sue, Lucia I %A Garcia, Angelica %A Dunckley, Travis %A Meechoovet, Bessie %A Reiman, Eric M %A Roher, Alex E %K Aged %K Aged, 80 and over %K Aging %K Alzheimer Disease %K Blotting, Western %K Colon %K Enzyme-Linked Immunosorbent Assay %K Female %K Frontal Lobe %K Gray Matter %K Humans %K Immunohistochemistry %K Liver %K Male %K Neurofibrillary Tangles %K Phosphorylation %K Severity of Illness Index %K Sex Characteristics %K Skin %K Submandibular Gland %K tau Proteins %X

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.

%B J Alzheimers Dis %V 51 %P 345-56 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26890756?dopt=Abstract %R 10.3233/JAD-150859 %0 Journal Article %J Alzheimers Dement %D 2012 %T National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease. %A Hyman, Bradley T %A Phelps, Creighton H %A Beach, Thomas G %A Bigio, Eileen H %A Cairns, Nigel J %A Carrillo, Maria C %A Dickson, Dennis W %A Duyckaerts, Charles %A Frosch, Matthew P %A Masliah, Eliezer %A Mirra, Suzanne S %A Nelson, Peter T %A Schneider, Julie A %A Thal, Dietmar Rudolf %A Thies, Bill %A Trojanowski, John Q %A Vinters, Harry V %A Montine, Thomas J %K Alzheimer Disease %K Brain %K Consensus Development Conferences, NIH as Topic %K Humans %K National Institute on Aging (U.S.) %K Practice Guidelines as Topic %K Societies, Medical %K United States %X

A consensus panel from the United States and Europe was convened recently to update and revise the 1997 consensus guidelines for the neuropathologic evaluation of Alzheimer's disease (AD) and other diseases of brain that are common in the elderly. The new guidelines recognize the pre-clinical stage of AD, enhance the assessment of AD to include amyloid accumulation as well as neurofibrillary change and neuritic plaques, establish protocols for the neuropathologic assessment of Lewy body disease, vascular brain injury, hippocampal sclerosis, and TDP-43 inclusions, and recommend standard approaches for the workup of cases and their clinico-pathologic correlation.

%B Alzheimers Dement %V 8 %P 1-13 %8 2012 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/22265587?dopt=Abstract %R 10.1016/j.jalz.2011.10.007