Journal of Alzheimer's Disease - Volume 91, issue 3

Authors: Parker, Daniel C. | Kraus, William E. | Whitson, Heather E. | Kraus, Virginia B. | Smith, Patrick J. | Cohen, Harvey Jay | Pieper, Carl F. | Faldowski, Richard A. | Hall, Katherine S. | Huebner, Janet L. | Ilkayeva, Olga R. | Bain, James R. | Newby, L. Kristin | Huffman, Kim M.

Article Type: Research Article

Abstract: Background: The kynurenine pathway (KP) comprises a family of tryptophan-derived metabolites that some studies have reported are associated with poorer cognitive performance and an increased risk of Alzheimer’s disease and related dementias (ADRD). Objective: The objective of this study was to determine the associations of plasma KP metabolites (kynurenine [KYN], kynurenic acid [KA], and tryptophan [TRP]) with a panel of plasma ADRD biomarkers (Aβ42 / β40 ratio, pTau-181, glial fibrillary acidic protein [GFAP], and neurofilament light [NfL]) and cognitive performance in a subset of older adults drawn from the Duke Physical Performance Across the LifeSpan (PALS) study. …Methods: The Montreal Cognitive Assessment (MoCA) was used to assess cognitive performance. We used multivariate multiple regression to evaluate associations of the KYN/TRP and KA/KYN ratios with MoCA score and plasma ADRD biomarkers at baseline and over two years (n  = 301; Age = 74.8±8.7). Results: Over two years, an increasing KYN/TRP ratio was associated with increasing plasma concentrations of plasma p-Tau181 (β= 6.151; 95% CI [0.29, 12.01]; p  = 0.040), GFAP (β= 11.12; 95% CI [1.73, 20.51 ]; p  = 0.020), and NfL (β= 11.13; 95% CI [2.745, 19.52 ]; p  = 0.009), but not MoCA score or the Aβ42 /Aβ40 ratio. There were no significant associations of KA/KYN with MoCA score or plasma ADRD biomarkers. Conclusion: Our findings provide evidence that greater concentrations of KP metabolites are associated longitudinally over two years with greater biomarker evidence of neurofibrillary tau pathology (pTau-181), neuroinflammation (GFAP), and neurodegeneration (NfL), suggesting that dysregulated KP metabolism may play a role in ADRD pathogenesis. Show more

Keywords: Alzheimer’s disease and related dementias, biomarkers, cognition, kynurenines, tryptophan

DOI: 10.3233/JAD-220906

Citation: Journal of Alzheimer's Disease, vol. 91, no. 3, pp. 1141-1150, 2023

Authors: Canário, Nádia S. | Jorge, Lília P. | Santana, Isabel J. | Castelo-Branco, Miguel S.

Article Type: Research Article

Abstract: Background: Investigation of neural response patterns along the entire network of functionally defined object recognition ventral stream regions in Alzheimer’s disease (AD) is surprisingly lacking. Objective: We aimed to investigate putative functional reorganization along a wide-ranging network of known regions in the ventral visual stream in mild AD. Methods: Overall we investigated 6 regions of interest (5 of which were not investigated before), in 19 AD patients and 19 controls, in both hemispheres along the ventral visual stream: Fusiform Face Area, Fusiform Body Area, Extrastriate Body Area, Lateral Occipital Cortex, Parahippocampal Place Area, and Visual Word …Form Area, while assessing object recognition performance. Results: We found group differences in dprime measures for all object categories, corroborating generalized deficits in object recognition. Concerning neural responses, we found region dependent group differences respecting a priori expected Hemispheric asymmetries. Patients showed significantly decreased BOLD responses in the right hemisphere-biased Fusiform Body Area, and lower left hemisphere responses in the Visual Word Form Area (with a priori known left hemispheric bias), consistent with deficits in body shape and word/pseudoword processing deficits. This hemispheric dominance related effects were preserved when controlling for performance differences. Whole brain analysis during the recognition task showed enhanced activity in AD group of left dorsolateral prefrontal cortex, left cingulate gyrus, and in the posterior cingulate cortex— a hotspot of amyloid-β accumulation. Conclusion: These findings demonstrate region dependent respecting hemispheric dominance patterns activation changes in independently localized selective regions in mild AD, accompanied by putative compensatory activity of frontal and cingular networks. Show more

Keywords: Alzheimer’s disease, fMRI, recognition, ventral visual stream

DOI: 10.3233/JAD-220055

Citation: Journal of Alzheimer's Disease, vol. 91, no. 3, pp. 1151-1164, 2023

Authors: Schäfer, Simona | Mallick, Elisa | Schwed, Louisa | König, Alexandra | Zhao, Jian | Linz, Nicklas | Bodin, Timothy Hadarsson | Skoog, Johan | Possemis, Nina | ter Huurne, Daphne | Zettergren, Anna | Kern, Silke | Sacuiu, Simona | Ramakers, Inez | Skoog, Ingmar | Tröger, Johannes

Article Type: Research Article

Abstract: Background: Modern prodromal Alzheimer’s disease (AD) clinical trials might extend outreach to a general population, causing high screen-out rates and thereby increasing study time and costs. Thus, screening tools that cost-effectively detect mild cognitive impairment (MCI) at scale are needed. Objective: Develop a screening algorithm that can differentiate between healthy and MCI participants in different clinically relevant populations. Methods: Two screening algorithms based on the remote ki:e speech biomarker for cognition (ki:e SB-C) were designed on a Dutch memory clinic cohort (N  = 121) and a Swedish birth cohort (N  = 404). MCI classification was each evaluated on …the training cohort as well as on the unrelated validation cohort. Results: The algorithms achieved a performance of AUC  0.73 and AUC  0.77 in the respective training cohorts and AUC  0.81 in the unseen validation cohorts. Conclusion: The results indicate that a ki:e SB-C based algorithm robustly detects MCI across different cohorts and languages, which has the potential to make current trials more efficient and improve future primary health care. Show more

Keywords: Alzheimer’s disease, biomarker, clinical trial, machine learning, mild cognitive impairment, screening

DOI: 10.3233/JAD-220762

Citation: Journal of Alzheimer's Disease, vol. 91, no. 3, pp. 1165-1171, 2023

Authors: Sakai, Kenji | Noguchi-Shinohara, Moeko | Tanaka, Hidetomo | Ikeda, Tokuhei | Hamaguchi, Tsuyoshi | Kakita, Akiyoshi | Yamada, Masahito | Ono, Kenjiro

Article Type: Research Article

Abstract: Background: Cerebrospinal fluid (CSF) biomarkers in patients with cerebral amyloid angiopathy-related inflammation (CAA-ri) have demonstrated inconsistent results. Objective: We investigated the relationship between CSF amyloid-β protein (Aβ) and vascular pathological findings to elucidate the mechanisms of Aβ elimination from the brain in CAA-ri. Methods: We examined Aβ40 and Aβ42 levels in CSF samples in 15 patients with CAA-ri and 15 patients with Alzheimer’s disease and cerebral amyloid angiopathy (AD-CAA) using ELISA as a cross-sectional study. Furthermore, we pathologically examined Aβ40 and Aβ42 depositions on the leptomeningeal blood vessels (arteries, arterioles, and veins) …using brain biopsy samples from six patients with acute CAA-ri and brain tissues of two autopsied patients with CAA-ri. Results: The median Aβ40 and Aβ42 levels in the CSF showed no significant difference between pre-treatment CAA-ri (Aβ40, 6837 pg/ml; Aβ42 , 324 pg/ml) and AD-CAA (Aβ40 , 7669 pg/ml, p  = 0.345; Aβ42 , 355 pg/ml, p  = 0.760). Aβ40 and Aβ42 levels in patients with post-treatment CAA-ri (Aβ40, 1770 pg/ml, p  = 0.056; Aβ42 , 167 pg/ml, p  = 0.006) were lower than those in patients with pre-treatment CAA-ri. Regarding Aβ40 and Aβ42 positive arteries, acute CAA-ri cases showed a higher frequency of partially Aβ-deposited blood vessels than postmortem CAA-ri cases (Aβ40 , 20.8% versus 3.9%, p  = 0.0714; Aβ42 , 27.4% versus 2.0%, p  = 0.0714, respectively). Conclusion: Lower levels of CSF Aβ40 and Aβ42 could be biomarkers for the cessation of inflammation in CAA-ri reflecting the recovery of the intramural periarterial drainage pathway and vascular function. Show more

Keywords: Amyloid-β protein-related angiitis, amyloid-related imaging abnormalities, biomarker, cerebral amyloid angiopathy-related inflammation, cerebrospinal fluid, diagnosis, elimination, pathology, vasculitis

DOI: 10.3233/JAD-220838

Citation: Journal of Alzheimer's Disease, vol. 91, no. 3, pp. 1173-1183, 2023

Authors: Downer, Brian | Li, Chih-Ying | Al Snih, Soham

Article Type: Research Article

Abstract: Background: Evidence from predominately non-Hispanic White populations indicates that emergency room (ER) admissions and hospitalizations by older adults with and without dementia are associated with caregiver stress and depressive symptoms. These results may not generalize to Hispanic populations because of cultural differences in caregiving roles, responsibilities, and perspectives about care burden. Objective: Investigate the association between ER admissions and hospitalizations by Mexican American older adults with and without dementia and symptoms of depression and stress among family caregivers. Methods: Data came from the 2010/11 wave of the Hispanic Established Populations for the Epidemiologic Study of the …Elderly and Medicare claims files. The final sample included 326 older adults and their caregivers. Negative binomial regression was used to model the association between hospitalizations and ER admissions by older adults in the previous two years and caregivers’ depressive symptoms and stress in 2010/11. Results: The number of older adult ER admissions and hospitalizations was not associated with caregiver depressive symptoms. Two or more ER admissions (incident rate ratio [IRR] = 1.26, 95% CI = 1.05–1.51) and two or more hospitalizations (IRR = 1.32, 95% CI = 1.07–1.61) were associated with significantly higher caregiver stress. Additionally, ER admissions and hospitalizations for a circulatory disease or injury and poisoning were associated with significantly higher caregiver stress. These associations were not modified by the care recipient’s dementia status. Conclusion: Hospitalizations and ER admissions by older Mexican Americans were associated with greater caregiver stress but not depressive symptoms. These associations were similar for caregivers to older adults with and without dementia. Show more

Keywords: Caregivers, dementia, health services, Mexican Americans

DOI: 10.3233/JAD-220997

Citation: Journal of Alzheimer's Disease, vol. 91, no. 3, pp. 1185-1195, 2023

Authors: Chen, Yuzhao | Zhang, Yilin | Chen, Qiuxuan | Liu, Yuxiang | Wei, Xuemin | Wu, Meijian | Zhang, Keke | Liu, Yinghua | Wei, Wei

Article Type: Research Article

Abstract: Background: The metabotropic glutamate receptor 5 (mGluR5) is widely expressed in postsynaptic neurons and plays a vital role in the synaptic plasticity of the central nervous system. mGluR5 is a coreceptor for amyloid-β (Aβ) oligomer, and downregulation or pharmacological blockade of mGluR5 presents the therapeutic potential of Alzheimer’s disease (AD). However, the abnormality of mGluR5 in the pathogenesis of AD and its mechanism of pathology is not clear. Objective: In this study, we would like to investigate the expression of mGluR5 in the process of AD and explore the effects and the underlying mechanisms of antagonizing mGluR5 on …cognitive function, synaptic structure, and inflammation in 5xFAD mice. Methods: mGluR5 expression and interactions with PrPc in 5XFAD mice were detected using western blot and co-immunoprecipitation. The selective mGluR5 antagonist MPEP was infused into 4-month-old 5XFAD mice for 60 consecutive days. Then, cognitive function, AD-like pathology and synaptic structure were measured. Further observations were made in mGluR5 knockdown 5XFAD mice. Results: mGluR5 expression was increased with Aβ levels at 6 months in 5XFAD mice. mGluR5 antagonist rescued cognitive disorders, promoted synaptic recovery, and alleviated both the Aβ plaque load and abnormal hyperphosphorylation in 6-month-old 5XFAD mice. Meanwhile, the results were validated in mGluR5 knockdown mice. Blockade of mGluR5 efficiently alleviates AD-like pathologies by inhibiting the PI3K/AKT/mTOR pathway and activates autophagy in 5XFAD mice. Furthermore, antagonism of mGluR5 attenuated neuroinflammation by inactivating the IKK/NF-κ B pathway. Conclusion: These findings suggest that mGluR5 may be an effective drug target for AD treatment, and inhibition of the mGluR5/PI3K-AKT pathway alleviates AD-like pathology by activating autophagy and anti-neuroinflammation in 5XFAD mice. Show more

Keywords: Alzheimer’s disease, autophagy, mGluR5, MPEP, neuroinflammation

DOI: 10.3233/JAD-221058

Citation: Journal of Alzheimer's Disease, vol. 91, no. 3, pp. 1197-1214, 2023

Authors: Fleming, Victoria | Helsel, Brian C. | Ptomey, Lauren T. | Rosas, H. Diana | Handen, Benjamin | Laymon, Charles | Christian, Bradley T. | Head, Elizabeth | Mapstone, Mark | Lai, Florence | Krinsky-McHale, Sharon | Zaman, Shahid | Ances, Beau M. | Lee, Joseph H. | Hartley, Sigan L.

Article Type: Research Article

Abstract: Background: Virtually all adults with Down syndrome (DS) develop Alzheimer’s disease (AD) pathology, but research gaps remain in understanding early signs of AD in DS. Objective: The goal of the present study was to determine if unintentional weight loss is part of AD in DS. The specific aims were to: 1) examine relation between chronological age, weight, AD pathology, and AD-related cognitive decline were assessed in a large cohort of adults with DS, and 2) determine if baseline PET amyloid-β (Aβ) and tau PET status (–versus+) and/or decline in memory and mental status were associated with weight loss …prior to AD progression. Methods: Analyses included 261 adults with DS. PET data were acquired using [11 C] PiB for Aβ and [18 F] AV-1451 for tau. Body mass index (BMI) was calculated from weight and height. Direct measures assessed dementia and memory. Clinical AD status was determined using a case consensus process. Percent weight decline across 16–20 months was assessed in a subset of participants (n  = 77). Results: Polynomial regressions indicated an 0.23 kg/m2 decrease in BMI per year beginning at age 36.5 years, which occurs alongside the period during which Aβ and tau increase and memory and mental status decline. At a within-person level, elevated Aβ, decline in memory and mental status were associated with higher percent weight loss across 16–20 months. Conclusion: Unintentional weight loss occurs alongside Aβ deposition and prior to onset of AD dementia, and thus may be a useful sign of AD in DS. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, body mass index, tau, weight

DOI: 10.3233/JAD-220865

Citation: Journal of Alzheimer's Disease, vol. 91, no. 3, pp. 1215-1227, 2023

Article Type: Correction

DOI: 10.3233/JAD-229019

Citation: Journal of Alzheimer's Disease, vol. 91, no. 3, pp. 1229-1229, 2023