Browsing by Author "Lowe, Val J."

Now showing 1 - 6 of 6
  • Thumbnail Image
    Item
    Blood-based gene and co-expression network levels are associated with AD/MCI diagnosis and cognitive phenotypes
    (Wiley, 2025-01-09) Chen, Xuan; Reddy, Joseph S.; Wang, Xue; Quicksall, Zachary; Nguyen, Thuy; Reyes, Denise A.; Graff-Radford, Jonathan; Jack, Clifford R., Jr.; Lowe, Val J.; Knopman, David S.; Petersen, Ronald C.; Kantarci, Kejal; Nho, Kwangsik; Allen, Mariet; Carrasquillo, Minerva M.; Saykin, Andrew J.; Ertekin-Taner, Nilüfer; Radiology and Imaging Sciences, School of Medicine
    Background: Alzheimer’s disease (AD) patients have decline in cognitive domains including memory, language, visuospatial, and/or executive function and brain pathology including amyloid‐β and tau deposition, neurodegeneration, and frequent vascular co‐pathologies detectable by neuroimaging and/or cerebrospinal fluid biomarkers. However, molecular disease mechanisms are complex and heterogeneous. It is necessary to develop cost‐effective blood‐based biomarkers reflecting brain molecular perturbations in AD. We identified blood‐based gene and co‐expression network level changes associated with AD/mild cognitive impairment (MCI) diagnosis and AD‐related phenotypes. Method: We performed differential gene expression and weighted gene co‐expression network analysis, followed by meta‐analysis, using blood transcriptome data of 391 participants from the Mayo Clinic Study of Aging and 654 participants from the Alzheimer's Disease Neuroimaging Initiative. The neuroimaging phenotypes include microhemorrhages, infarcts, amyloid burden, hippocampal volume, and white matter hyperintensities. The cognitive phenotypes include standardized cognitive subtest scores and composite scores for memory, language, visuospatial, and executive function. Result: Five out of 18 modules(M) are significantly associated with diagnosis or cognition (FDR‐adjusted p<0.05). M1 and M15 both positively associates with memory, M1 positively associated with language and M15 with visuospatial function. M1 and M15 are enriched in differentially expressed genes (DEGs) associated with language and executive function, respectively. M2 negatively associates with logical memory delayed recall scores(LMDR), memory, executive, and language functions and is enriched in DEGs for these phenotypes. M8 negatively associates with memory, language and executive functions and is enriched in DEGs for memory and language. M12 positively associates with LMDR. M1 and M15 are down‐regulated while M2 and M8 are up‐regulated in AD/MCI patients. Cell‐type enrichment analysis showed M2 is enriched in monocytes and neutrophils; M8 in monocytes; M15 in B cells (FDR <0.05). Gene ontology terms enriched in these modules indicated broad consistency with their cell types. Conclusion: We identified five modules significantly associated with AD/MCI or cognitive phenotypes using blood transcriptome data. These findings nominate blood transcriptome changes and their enriched biological processes as potential pathomechanisms in cognitive decline and AD/MCI development. We aim to investigate these blood transcripts as potential biomarkers for AD or AD‐related phenotypes and therapeutic targets through additional replication and experimental validation studies.
  • Thumbnail Image
    Item
    Global neuropathologic severity of Alzheimer's disease and locus coeruleus vulnerability influences plasma phosphorylated tau levels
    (Springer, 2022-12-27) Murray, Melissa E.; Moloney, Christina M.; Kouri, Naomi; Syrjanen, Jeremy A.; Matchett, Billie J.; Rothberg, Darren M.; Tranovich, Jessica F.; Hicks Sirmans, Tiffany N.; Wiste, Heather J.; Boon, Baayla D. C.; Nguyen, Aivi T.; Reichard, R. Ross; Dickson, Dennis W.; Lowe, Val J.; Dage, Jeffrey L.; Petersen, Ronald C.; Jack, Clifford R., Jr.; Knopman , David S.; Vemuri, Prashanthi; Graff-Radford, Jonathan; Mielke, Michelle M.; Neurology, School of Medicine
    Background Advances in ultrasensitive detection of phosphorylated tau (p-tau) in plasma has enabled the use of blood tests to measure Alzheimer’s disease (AD) biomarker changes. Examination of postmortem brains of participants with antemortem plasma p-tau levels remains critical to understanding comorbid and AD-specific contribution to these biomarker changes. Methods We analyzed 35 population-based Mayo Clinic Study of Aging participants with plasma p-tau at threonine 181 and threonine 217 (p-tau181, p-tau217) available within 3 years of death. Autopsied participants included cognitively unimpaired, mild cognitive impairment, AD dementia, and non-AD neurodegenerative disorders. Global neuropathologic scales of tau, amyloid-β, TDP-43, and cerebrovascular disease were examined. Regional digital pathology measures of tau (phosphorylated threonine 181 and 217 [pT181, pT217]) and amyloid-β (6F/3D) were quantified in hippocampus and parietal cortex. Neurotransmitter hubs reported to influence development of tangles (nucleus basalis of Meynert) and amyloid-β plaques (locus coeruleus) were evaluated. Results The strongest regional associations were with parietal cortex for tau burden (p-tau181 R = 0.55, p = 0.003; p-tau217 R = 0.66, p < 0.001) and amyloid-β burden (p-tau181 R = 0.59, p < 0.001; p-tau217 R = 0.71, p < 0.001). Linear regression analysis of global neuropathologic scales explained 31% of variability in plasma p-tau181 (Adj. R2 = 0.31) and 59% in plasma p-tau217 (Adj. R2 = 0.59). Neither TDP-43 nor cerebrovascular disease global scales independently contributed to variability. Global scales of tau pathology (β-coefficient = 0.060, p = 0.016) and amyloid-β pathology (β-coefficient = 0.080, p < 0.001) independently predicted plasma p-tau217 when modeled together with co-pathologies, but only amyloid-β (β-coefficient = 0.33, p = 0.021) significantly predicted plasma p-tau181. While nucleus basalis of Meynert neuron count/mm2 was not associated with plasma p-tau levels, a lower locus coeruleus neuron count/mm2 was associated with higher plasma p-tau181 (R = -0.50, p = 0.007) and higher plasma p-tau217 (R = -0.55, p = 0.002). Cognitive scores (Adj. R2 = 0.25–0.32) were predicted by the global tau scale, but not by the global amyloid-β scale or plasma p-tau when modeled simultaneously. Conclusions Higher soluble plasma p-tau levels may be the result of an intersection between insoluble deposits of amyloid-β and tau accumulation in brain, and may be associated with locus coeruleus degeneration.
  • Thumbnail Image
    Item
    Lewy Body Disease is a Contributor to Logopenic Progressive Aphasia Phenotype
    (Wiley, 2021) Buciuc, Marina; Whitwell, Jennifer L.; Kasanuki, Koji; Graff-Radford, Jonathan; Machulda, Mary M.; Duffy, Joseph R.; Strand, Edythe A.; Lowe, Val J.; Graff-Radford, Neill R.; Rush, Beth K.; Franczak, Malgorzata B.; Flanagan, Margaret E.; Baker, Matthew C.; Rademakers, Rosa; Ross, Owen A.; Ghetti, Bernardino F.; Parisi, Joseph E.; Raghunathan, Aditya; Reichard, R. Ross; Bigio, Eileen H.; Dickson, Dennis W.; Josephs, Keith A.; Pathology and Laboratory Medicine, School of Medicine
    Objective: The objective of this study was to describe clinical features, [18 F]-fluorodeoxyglucose (FDG)-positron emission tomography (PET) metabolism and digital pathology in patients with logopenic progressive aphasia (LPA) and pathologic diagnosis of diffuse Lewy body disease (DLBD) and compare to patients with LPA with other pathologies, as well as patients with classical features of probable dementia with Lewy bodies (pDLB). Methods: This is a clinicopathologic case-control study of 45 patients, including 20 prospectively recruited patients with LPA among whom 6 were diagnosed with LPA-DLBD. We analyzed clinical features and compared FDG-PET metabolism in LPA-DLBD to an independent group of patients with clinical pDLB and regional α-synuclein burden on digital pathology to a second independent group of autopsied patients with DLBD pathology and antemortem pDLB (DLB-DLBD). Results: All patients with LPA-DLBD were men. Neurological, speech, and neuropsychological characteristics were similar across LPA-DLBD, LPA-Alzheimer's disease (LPA-AD), and LPA-frontotemporal lobar degeneration (LPA-FTLD). Genetic screening of AD, DLBD, and FTLD linked genes were negative with the exception of APOE ε4 allele present in 83% of LPA-DLBD patients. Seventy-five percent of the patients with LPA-DLBD showed a parietal-dominant pattern of hy pometabolism; LPA-FTLD - temporal-dominant pattern, whereas LPA-AD showed heterogeneous patterns of hypometabolism. LPA-DLBD had more asymmetrical hypometabolism affecting frontal lobes, with relatively spared occipital lobe in the nondominantly affected hemisphere, compared to pDLB. LPA-DLBD had minimal atrophy on gross brain examination, higher cortical Lewy body counts, and higher α-synuclein burden in the middle frontal and inferior parietal cortices compared to DLB-DLBD. Interpretation: Whereas AD is the most frequent underlying pathology of LPA, DLBD can also be present and may contribute to the LPA phenotype possibly due to α-synuclein-associated functional impairment of the dominant parietal lobe.
  • Thumbnail Image
    Item
    Longitudinal Clinical, Neuropsychological, and Neuroimaging Characterization of a Kindred with a 12-Octapeptide Repeat Insertion in PRNP: The Next Generation
    (Taylor & Francis, 2020-08) Townley, Ryan A.; Polsinelli, Angelina J.; Fields, Julie A.; Machulda, Mary M.; Jones, David T.; Graff-Radford, Jonathan; Kantarci, Kejal M.; Lowe, Val J.; Rademakers, Rosa V.; Baker, Matt C.; Kumar, Neeraj; Boeve, Bradley F.; Neurology, School of Medicine
    Background: Highly penetrant inherited mutations in the prion protein gene (PRNP) offer a window to study the pathobiology of prion disorders. Method: Clinical, neuropsychological, and neuroimaging characterization of a kindred. Results: Three of four mutation carriers have progressed to a frontotemporal dementia phenotype. Declines in neuropsychological function coincided with changes in FDG-PET at the identified onset of cognitive impairment. Conclusions and relevance: Gene silencing treatments are on the horizon and when they become available, early detection will be crucial. Longitudinal studies involving familial mutation kindreds can offer important insights into the initial neuropsychological and neuroimaging changes necessary for early detection.
  • Thumbnail Image
    Item
    Neuropsychological Profiles of Patients with Progressive Apraxia of Speech and Aphasia
    (Cambridge University Press, 2022) Polsinelli, Angelina J.; Machulda, Mary M.; Martin, Peter R.; Duffy, Joseph R.; Clark, Heather M.; Butts, Alissa M.; Botha, Hugo; Lowe, Val J.; Whitwell, Jennifer L.; Josephs, Keith A.; Utiansk, Rene L.; Neurology, School of Medicine
    Objective: To characterize and compare the neuropsychological profiles of patients with primary progressive apraxia of speech (PPAOS) and apraxia of speech with progressive agrammatic aphasia (AOS-PAA). Method: Thirty-nine patients with PPAOS and 49 patients with AOS-PAA underwent formal neurological, speech, language, and neuropsychological evaluations. Cognitive domains assessed included immediate and delayed episodic memory (Wechsler Memory Scale-Third edition; Logical Memory; Visual Reproduction; Rey Auditory Verbal Learning Test), processing speed (Trail Making Test A), executive functioning (Trail Making Test B; Delis-Kaplan Executive Functioning Scale - Sorting), and visuospatial ability (Rey-Osterrieth Complex Figure copy). Results: The PPAOS patients were cognitively average or higher in the domains of immediate and delayed episodic memory, processing speed, executive functioning, and visuospatial ability. Patients with AOS-PAA performed more poorly on tests of immediate and delayed episodic memory and executive functioning compared to those with PPAOS. For every 1 unit increase in aphasia severity (e.g. mild to moderate), performance declined by 1/3 to 1/2 a standard deviation depending on cognitive domain. The degree of decline was stronger within the more verbally mediated domains, but was also notable in less verbally mediated domains. Conclusion: The study provides neuropsychological evidence further supporting the distinction of PPAOS from primary progressive aphasia and should be used to inform future diagnostic criteria. More immediately, it informs prognostication and treatment planning.
  • Thumbnail Image
    Item
    Performance of plasma phosphorylated tau 181 and 217 in the community
    (Springer Nature, 2022) Mielke, Michelle M.; Dage, Jeffrey L.; Frank, Ryan D.; Algeciras-Schimnich, Alicia; Knopman, David S.; Lowe, Val J.; Bu, Guojun; Vemuri, Prashanthi; Graff-Radford, Jonathan; Jack, Clifford R., Jr.; Petersen, Ronald C.; Neurology, School of Medicine
    Plasma phosphorylated tau 181 (P-tau181) and 217 (P-tau217) are indicators of both amyloid and tau pathology in clinical settings, but their performance in heterogeneous community-based populations is unclear. We examined P-tau181 and P-tau217 (n = 1,329, aged 30-98 years), in the population-based Mayo Clinic Study of Aging. Continuous, unadjusted plasma P-tau181 and P-tau217 predicted abnormal amyloid positron-emission tomography (PET) (area under the receiver operating characteristic curve (AUROC) = 0.81-0.86) and tau PET entorhinal cortex (AUROC > 0.80), but was less predictive of a tau PET temporal region of interest (AUROC < 0.70). Multiple comorbidities were associated with higher plasma P-tau181 and P-tau217 levels; the difference between participants with and without chronic kidney disease (CKD) was similar to the difference between participants with and without elevated brain amyloid. The exclusion of participants with CKD and other comorbidities affected the establishment of a normal reference range and cutpoints. Understanding the effect of comorbidities on P-tau181 and P-tau217 levels is important for their future interpretation in the context of clinical screening, diagnosis or prognosis at the population level.