Journal of Alzheimer's Disease - Volume 87, issue 3

Authors: Kawarabayashi, Takeshi | Nakamura, Takumi | Sato, Kaoru | Seino, Yusuke | Ichii, Sadanobu | Nakahata, Naoko | Takatama, Masamitsu | Westaway, David | George-Hyslop, Peter St. | Shoji, Mikio

Article Type: Research Article

Abstract: Background: Amyloid-β (Aβ) oligomers induce the overproduction of phosphorylated tau and neurodegeneration. These cascades gradually cause cognitive impairment in Alzheimer’s disease (AD). While each pathological event in AD has been studied in detail separately, the spatial and temporal relationships between pathological events in AD remain unclear. Objective: We demonstrated that lipid rafts function as a common platform for the pathological cascades of AD. Methods: Cellular and synaptosomal lipid rafts were prepared from the brains of Aβ amyloid model mice (Tg2576 mice) and double transgenic mice (Tg2576 x TgTauP301L mice) and longitudinally analyzed. Results: Aβ …dimers, the cellular prion protein (PrPc ), and Aβ dimer/PrPc complexes were detected in the lipid rafts. The levels of Fyn, the phosphorylated NR2B subunit of the N-methyl-D-aspartate receptor, glycogen synthase kinase 3β, total tau, phosphorylated tau, and tau oligomers increased with Aβ dimer accumulation in both the cellular and synaptosomal lipid rafts. Increases in the levels of these molecules were first seen at 6 months of age and corresponded with the early stages of Aβ accumulation in the amyloid model mice. Conclusion: Lipid rafts act as a common platform for the progression of AD pathology. The findings of this study suggest a novel therapeutic approach to AD, involving the modification of lipid raft components and the inhibition of their roles in the sequential pathological events of AD. Show more

Keywords: Alzheimer’s disease, Aβ oligomers, Fyn, lipid rafts, NMDA receptors, phosphorylated tau, platform, PrPc , synaptosome, tau oligomers

DOI: 10.3233/JAD-215662

Citation: Journal of Alzheimer's Disease, vol. 87, no. 3, pp. 1189-1203, 2022

Authors: Wong, Hiu Yi | Zhong, Huan | Zhong, Mingqian | Zhou, Xiaopu | Chan, Phillip Y.C. | Kwok, Timothy C.Y. | Mok, Kin | Hardy, John | Ip, Fanny C.F. | Fu, Amy K.Y. | Ip, Nancy Y.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common cause of dementia in the elderly population. However, epidemiological studies on the demographics of AD in Hong Kong population are lacking. Objective: We investigated the demographics, comorbidities, mortality rates, and medication use of patients with AD in Hong Kong to understand how the disease has been managed locally. Methods: This was a collaborative study of The Hong Kong University of Science and Technology and the Hospital Authority Data Collaboration Lab. We analyzed the demographic data, clinical records, diagnoses, and medication records of patients with AD under the care …of the Hospital Authority between January 1, 2007 and December 31, 2017. Results: We identified 23,467 patients diagnosed with AD. The median age at diagnosis was 84 years old, and 71% of patients were female. The most common comorbidity was hypertension (52.6%). 39.9% of patients received medications for dementia; of those, 68.4% had taken those medications for > 1 year. Compared to nonusers, long-term AD medication users had a significantly younger age of AD onset and were taking more lipid-regulating medication, diabetes medication, or antidepressants. Surprisingly, the use of antipsychotics in patients with AD was quite common; 50.7% of patients had received any type of antipsychotic during disease progression. Conclusion: This study provides detailed information on the demographics and medication use of patients with AD in Hong Kong. The data from this AD cohort will aid our future research aiming to identify potential AD risk factors and associations between AD and other diseases. Show more

Keywords: Alzheimer’s disease, demographics, epidemiological study, medication use

DOI: 10.3233/JAD-215312

Citation: Journal of Alzheimer's Disease, vol. 87, no. 3, pp. 1205-1213, 2022

Authors: Zhang, Ying | Wang, Jing | Sun, Tingting | Wang, Luchun | Li, Tao | Li, Huizi | Zheng, Yaonan | Fan, Zili | Zhang, Ming | Tu, Lihui | Yu, Xin | Wang, Huali

Article Type: Research Article

Abstract: Background: It is crucial for older adults, especially those with mild cognitive impairment (MCI), to make profitable decisions routinely. However, the results regarding decision-making (DM) remain inconsistent. Objective: The present study assessed DM profiles under uncertainty conditions in individuals with MCI and their associations with multi-domain cognitive performance. Method: Fifty-three patients with MCI and forty-two age-, gender-, and education level-matched healthy controls (HCs) were administered a comprehensive neuropsychological battery test. The Iowa Gambling Task (IGT) and Game of Dice Task (GDT) were used to assess DM competence in conditions involving ambiguity and risk, respectively. In addition, …Spearman’s correlations were used to examine relationships between GDT and multi-domain cognitive performance. Result: The final capital (FC) and frequency of utilization of negative feedback (FUNF) and positive feedback (FUPF) in the GDT were lower in MCI patients than in HCs. In addition, the number of shifts between safe and risky alternatives was significantly different across groups. However, IGT performance was comparable across groups. In the MCI patients, risky DM performance was associated with language, whereas in HCs was correlated with memory and executive functions. Besides, in MCI, performance on IGT was significantly correlated with social cognition. Conclusion: Individuals with mild cognitive impairment have difficulty utilizing feedback to make optimal decisions under risky situations. The association between decision-making performance and cognitive function is divergent regarding situational uncertainty and individuals’ cognitive status. In mild cognitive impairment and normal aging, decision-making under ambiguity needs further investigation. Show more

Keywords: Ambiguous situation, cognitive function, decision-making, mild cognitive impairment, risky situation, situational uncertainty

DOI: 10.3233/JAD-215440

Citation: Journal of Alzheimer's Disease, vol. 87, no. 3, pp. 1215-1227, 2022

Authors: Rippon, Brady | Palta, Priya | Tahmi, Mouna | Sherwood, Greysi | Soto, Luisa | Cespedes, Sandino | Mesen, Yanette | He, Hengda | Laing, Krystal | Moreno, Herman | Teresi, Jeanne | Razlighi, Qolamreza | Brickman, Adam M. | Zetterberg, Henrik | Luchsinger, José A.

Article Type: Research Article

Abstract: Background: Determining amyloid positivity is possible with cerebrospinal fluid and brain imaging of amyloid, but these methods are invasive and expensive. Objective: To relate plasma amyloid-β (Aβ), measured using Single-molecule array (Simoatrademark) assays, to in vivo brain Aβ, measured using positron emission tomography (PET), examine the accuracy of plasma Aβ to predict brain Aβ positivity, and the relation of APOE ɛ4 with plasma Aβ. Methods: We performed a cross-sectional analysis in a cohort of 345 late middle-aged Hispanic men and women (age 64 years, 72% women). Our primary plasma variable was Aβ42 /Aβ40 …ratio measured with Simoa. Brain Aβ burden was measured as global SUVR with 18 F-Florbetaben PET examined continuously and categorically. Results: Plasma Aβ42 /Aβ40 ratio was inversely associated with global Aβ SUVR (β= –0.13, 95% Confidence Interval (CI): –0.23, –0.03; p  = 0.013) and Aβ positivity (Odds Ratio: 0.59, 95% CI: 0.38, 0.91; p  = 0.016), independent of demographics and APOE ɛ4. ROC curves (AUC = 0.73, 95% CI: 0.64, 0.82; p  < 0.0001) showed that the optimal threshold for plasma Aβ42 /Aβ40 ratio in relation to brain Aβ positivity was 0.060 with a sensitivity of 82.4% and specificity of 62.8%. APOE ɛ4 carriers had lower Aβ42 /Aβ40 ratio and a higher Aβ positivity determined with the Aβ42 /Aβ40 ratio threshold of 0.060. Conclusion: Plasma Aβ42 /Aβ40 ratio assayed using Simoa is weakly correlated with in vivo brain amyloid and has limited accuracy in screening for amyloid positivity and for studying risk factors of brain amyloid burden when in vivo imaging is not feasible. Show more

Keywords: Alzheimer’s disease, amyloid, brain, hispanics, middle age, plasma, positron emission tomography

DOI: 10.3233/JAD-210391

Citation: Journal of Alzheimer's Disease, vol. 87, no. 3, pp. 1229-1238, 2022

Authors: Andriuta, Daniela | Si-Ahmed, Cherifa | Roussel, Martine | Constans, Jean-Marc | Makki, Malek | Aarabi, Ardalan | Basille, Damien | Andrejak, Claire | Godefroy, Olivier

Article Type: Research Article

Abstract: Background: Neurocognitive disorders (NCDs) are a part of the post-acute coronavirus disease (COVID-19) syndrome. No study has specifically evaluated NCDs in post-acute COVID-19 patients with cognitive complaints or their MRI determinants. Objective: To characterize NCDs in post-acute COVID-19 patients with cognitive complaints. The secondary objectives were to assess their clinical and MRI determinants. Methods: We included 46 patients with a post-acute COVID-19 cognitive complaint referred to the Amiens University Hospital Memory Center. They underwent a neuropsychological assessment and 36 had cerebral MRI. The G3 overall summary score was the sum of the mean z scores for …the executive function, language, and action speed domains. Neuropsychological profiles were compared in a general linear model. Clinical determinants were analyzed by stepwise linear regression. White matter hyperintensities (WMH) masks were analyzed using parcel-based WMH symptom mapping to identify the locations of WMHs associated with cognitive performance. Results: Repeated ANOVA showed a group effect (p  = 0.0001) due to overall lower performance for patients and a domain effect (p  = 0.0001) due to a lower (p  = 0.007) action speed score. The G3 overall summary score was significantly associated with solely the requirement for oxygen (R2  = 0.319, p  = 0.031). WHMs were associated with the G3 overall summary score in the following structures, all right-sided (p  < 0.01): superior frontal region, postcentral region, cingulum, cortico-spinal tract, inferior longitudinal fasciculus, internal capsule, and posterior segment of the arcuate fasciculus. Conclusion: Post-acute COVID-19 patients with cognitive complaints had NCD, with prominent action slowing, significantly associated with the acute phase oxygen requirement and a right-sided WMH structure pattern. Show more

Keywords: COVID-19, neurocognitive disorders, post-acute COVID-19, white matter hyperintensities

DOI: 10.3233/JAD-215506

Citation: Journal of Alzheimer's Disease, vol. 87, no. 3, pp. 1239-1250, 2022

Authors: Ramsden, Christopher E. | Keyes, Gregory S. | Calzada, Elizabeth | Horowitz, Mark S. | Zamora, Daisy | Jahanipour, Jahandar | Sedlock, Andrea | Indig, Fred E. | Moaddel, Ruin | Kapogiannis, Dimitrios | Maric, Dragan

Article Type: Research Article

Abstract: Background: Sporadic Alzheimer’s disease (sAD) lacks a unifying hypothesis that can account for the lipid peroxidation observed early in the disease, enrichment of ApoE in the core of neuritic plaques, hallmark plaques and tangles, and selective vulnerability of entorhinal-hippocampal structures. Objective: We hypothesized that 1) high expression of ApoER2 (receptor for ApoE and Reelin) helps explain this anatomical vulnerability; 2) lipid peroxidation of ApoE and ApoER2 contributes to sAD pathogenesis, by disrupting neuronal ApoE delivery and Reelin-ApoER2-Dab1 signaling cascades. Methods: In vitro biochemical experiments; Single-marker and multiplex fluorescence-immunohistochemistry (IHC) in postmortem specimens from 26 individuals …who died cognitively normal, with mild cognitive impairment or with sAD. Results: ApoE and ApoER2 peptides and proteins were susceptible to attack by reactive lipid aldehydes, generating lipid-protein adducts and crosslinked ApoE-ApoER2 complexes. Using in situ hybridization alongside IHC, we observed that: 1) ApoER2 is strongly expressed in terminal zones of the entorhinal-hippocampal ‘perforant path’ projections that underlie memory; 2) ApoE, lipid aldehyde-modified ApoE, Reelin, ApoER2, and the downstream Reelin-ApoER2 cascade components Dab1 and Thr19-phosphorylated PSD95 accumulated in the vicinity of neuritic plaques in perforant path terminal zones in sAD cases; 3) several ApoE/Reelin-ApoER2-Dab1 pathway markers were higher in sAD cases and positively correlated with histological progression and cognitive deficits. Conclusion: Results demonstrate derangements in multiple ApoE/Reelin-ApoER2-Dab1 axis components in perforant path terminal zones in sAD and provide proof-of-concept that ApoE and ApoER2 are vulnerable to aldehyde-induced adduction and crosslinking. Findings provide the foundation for a unifying hypothesis implicating lipid peroxidation of ApoE and ApoE receptors in sAD. Show more

Keywords: Alzheimer’s disease, ApoE, ApoER2, disabled homolog 1, lipid peroxidation, perforant path, polyunsaturated, pyrrole crosslink, reelin, Thr19-phosphorylated PSD95

DOI: 10.3233/JAD-220071

Citation: Journal of Alzheimer's Disease, vol. 87, no. 3, pp. 1251-1290, 2022

Authors: Fang, Yuan | Doyle, Margaret F. | Alosco, Michael L. | Mez, Jesse | Satizabal, Claudia L. | Qiu, Wei Qiao | Lunetta, Kathryn L. | Murabito, Joanne M.

Article Type: Research Article

Abstract: Background: Peripheral inflammation is associated with increased risk for dementia. Neutrophil to lymphocyte ratio (NLR), red cell distribution width (RDW), and mean platelet volume (MPV), are easily measured circulating blood cell phenotypes reflecting chronic peripheral inflammation, but their association with dementia status is unclear. Objective: We sought to investigate the cross-sectional association of these inflammatory measures with neuropsychological (NP) test performance, and brain magnetic resonance imaging (MRI) measures in the Framingham Heart Study (FHS) Offspring, Third-generation, and Omni cohorts. Methods: We identified FHS participants who attended an exam that included a complete blood cell count (CBC) …and underwent NP testing (n  = 3,396) or brain MRI (n  = 2,770) within five years of blood draw. We investigated the association between NLR, RDW, and MPV and NP test performance and structural MRI-derived volumetric measurements using linear mixed effect models accounting for family relationships and adjusting for potential confounders. Results: Participants were on average 60 years old, 53% female, and about 80% attended some college. Higher NLR was significantly associated with poorer performance on visual memory, and visuospatial abilities, as well as with larger white matter hyperintensity volume. We also observed associations for higher RDW with poorer executive function and smaller total cerebral brain volume. Conclusion: Chronic peripheral inflammation as measured by NLR and RDW was associated with worse cognitive function, reduced brain volume, and greater microvascular disease in FHS participants. If confirmed in other samples, CBC may provide informative and cost-effective biomarkers of abnormal brain aging in the community. Show more

Keywords: Biomarkers, cognitive aging, complete blood count, inflammation

DOI: 10.3233/JAD-215533

Citation: Journal of Alzheimer's Disease, vol. 87, no. 3, pp. 1291-1305, 2022

Authors: Schwertner, Emilia | Pereira, Joana B. | Xu, Hong | Secnik, Juraj | Winblad, Bengt | Eriksdotter, Maria | Nägga, Katarina | Religa, Dorota

Article Type: Research Article

Abstract: Background: The majority of individuals with dementia will suffer from behavioral and psychological symptoms of dementia (BPSD). These symptoms contribute to functional impairment and caregiver burden. Objective: To characterize BPSD in Alzheimer’s disease (AD), vascular dementia (VaD), mixed (Mixed) dementia, Parkinson’s disease dementia (PDD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and unspecified dementia in individuals residing in long-term care facilities. Methods: We included 10,405 individuals with dementia living in long-term care facilities from the Swedish registry for cognitive/dementia disorders (SveDem) and the Swedish BPSD registry. BPSD was assessed with the Neuropsychiatric Inventory - Nursing …Home Version (NPI-NH). Multivariate logistic regression models were used to evaluate the associations between dementia diagnoses and different BPSDs. Results: The most common symptoms were aberrant motor behavior, agitation, and irritability. Compared to AD, we found a lower risk of delusions (in FTD, unspecified dementia), hallucinations (FTD), agitation (VaD, PDD, unspecified dementia), elation/euphoria (DLB), anxiety (Mixed, VaD, unspecified dementia), disinhibition (in PDD), irritability (in DLB, FTD, unspecified dementia), aberrant motor behavior (Mixed, VaD, unspecified dementia), and sleep and night-time behavior changes (unspecified dementia). Higher risk of delusions (DLB), hallucinations (DLB, PDD), apathy (VaD, FTD), disinhibition (FTD), and appetite and eating abnormalities (FTD) were also found in comparison to AD. Conclusion: Although individuals in our sample were diagnosed with different dementia disorders, they all exhibited aberrant motor behavior, agitation, and irritability. This suggests common underlying psychosocial or biological mechanisms. We recommend prioritizing these symptoms while planning interventions in long-term care facilities. Show more

Keywords: Aberrant motor behavior, aging, agitation, Alzheimer’s disease, behavioral problem, behavioral and psychological symptoms of dementia, dementia, irritability, Neuropsychiatric Inventory, nursing homes

DOI: 10.3233/JAD-215198

Citation: Journal of Alzheimer's Disease, vol. 87, no. 3, pp. 1307-1318, 2022

Authors: Sheng, Can | Yang, Kun | He, Beiqi | Li, Taoran | Wang, Xiaoqi | Du, Wenying | Hu, Xiaochen | Jiang, Jiehui | Jiang, Xueyan | Jessen, Frank | Han, Ying

Article Type: Research Article

Abstract: Background: Subjective cognitive decline (SCD) is considered as the first symptomatic manifestation of Alzheimer’s disease (AD), which is also affected by different cultural backgrounds. Establishing cross-cultural prediction models of SCD is challenging. Objective: To establish prediction models of SCD available for both the Chinese and European populations. Methods: In this project, 330 SCD from China and 380 SCD from Germany are intended to be recruited. For all participants, standardized assessments, including clinical, neuropsychological, apolipoprotein E (APOE ) genotype, blood, and multi-parameter magnetic resonance imaging (MRI) at baseline will be conducted. Participants will voluntarily undergo amyloid positron …emission tomography (PET) and are classified into amyloid-β (Aβ) positive SCD (SCD+) and Aβ negative SCD (SCD-). First, baseline data of all SCD individuals between the two cohorts will be compared. Then, key features associated with brain amyloidosis will be extracted in SCD+ individuals, and the diagnosis model will be established using the radiomics method. Finally, the follow-up visits will be conducted every 12 months and the primary outcome is the conversion to mild cognitive impairment or dementia. After a 4-year follow-up, we will extract factors associated with the conversion risk of SCD using Cox regression analysis. Results: At present, 141 SCD from China and 338 SCD from Germany have been recruited. Initial analysis showed significant differences in demographic information, neuropsychological tests, and regional brain atrophy in SCD compared with controls in both cohorts. Conclusion: This project may be of great value for future implications of SCD studies in different cultural backgrounds. Trial registration: ClinicalTrials.gov, NCT04696315. Registered 3 January 2021. Show more

Keywords: Alzheimer’s disease, amyloid, cross-cultural, magnetic resonance imaging, radiomics, subjective cognitive decline

DOI: 10.3233/JAD-215452

Citation: Journal of Alzheimer's Disease, vol. 87, no. 3, pp. 1319-1333, 2022

Authors: Classon, Elisabet | van den Hurk, Wobbie | Lyth, Johan | Johansson, Maria M.

Article Type: Research Article

Abstract: Background: The Montreal Cognitive Assessment (MoCA) is sensitive to cognitive impairment; however, it is also sensitive to demographic and socio-cultural factors. This necessitates reliable sub-population norms, but these are often lacking for older adults. Objective: To present demographically adjusted regression-based MoCA norms for cognitively healthy Swedish older adults. Methods: A pseudo-random sample of community-dwelling 80- to 94-year-olds, stratified by age and gender, was invited to the study. Initial telephone interviews and medical records searches (n  = 218) were conducted to screen for cognitive impairment. N  = 181 eligible participants were administered a protocol including the Swedish version of …the MoCA and assessments of global cognition (Mini-Mental State Examination, MMSE) and depression (Patient Health Questionnaire-9, PHQ-9). Individuals scoring in the range of possible cognitive impairment on the MMSE or more than mild depression on the PHQ-9 were excluded (n  = 23); three discontinued the test-session. Results: Norms were derived from the remaining n  = 158. They were evenly distributed by gender, on average 85 years old, and with a mean education of 11 years. MoCA scores were independently influenced by age and education, together explaining 17.2% of the total variance. Higher age and lower education were associated with lower performance and 46% performed below the original cut-off (< 26/30). Conclusion: The negative impact of increasing age on MoCA performance continues linearly into the nineties in normal aging. Demographic factors should be considered when interpreting MoCA performance and a tool for computing demographically corrected standard scores is provided. Show more

Keywords: Cognitive aging, healthy volunteers, neuropsychological tests, regression analyses

DOI: 10.3233/JAD-215629

Citation: Journal of Alzheimer's Disease, vol. 87, no. 3, pp. 1335-1344, 2022

Authors: Mirabnahrazam, Ghazal | Ma, Da | Lee, Sieun | Popuri, Karteek | Lee, Hyunwoo | Cao, Jiguo | Wang, Lei | Galvin, James E. | Beg, Mirza Faisal | the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: The increasing availability of databases containing both magnetic resonance imaging (MRI) and genetic data allows researchers to utilize multimodal data to better understand the characteristics of dementia of Alzheimer’s type (DAT). Objective: The goal of this study was to develop and analyze novel biomarkers that can help predict the development and progression of DAT. Methods: We used feature selection and ensemble learning classifier to develop an image/genotype-based DAT score that represents a subject’s likelihood of developing DAT in the future. Three feature types were used: MRI only, genetic only, and combined multimodal data. We used …a novel data stratification method to better represent different stages of DAT. Using a pre-defined 0.5 threshold on DAT scores, we predicted whether a subject would develop DAT in the future. Results: Our results on Alzheimer’s Disease Neuroimaging Initiative (ADNI) database showed that dementia scores using genetic data could better predict future DAT progression for currently normal control subjects (Accuracy = 0.857) compared to MRI (Accuracy = 0.143), while MRI can better characterize subjects with stable mild cognitive impairment (Accuracy = 0.614) compared to genetics (Accuracy = 0.356). Combining MRI and genetic data showed improved classification performance in the remaining stratified groups. Conclusion: MRI and genetic data can contribute to DAT prediction in different ways. MRI data reflects anatomical changes in the brain, while genetic data can detect the risk of DAT progression prior to the symptomatic onset. Combining information from multimodal data appropriately can improve prediction performance. Show more

Keywords: Alzheimer’s disease, biomarker, early detection, machine learning, magnetic resonance imaging, risk scores, single nucleotide polymorphism

DOI: 10.3233/JAD-220021

Citation: Journal of Alzheimer's Disease, vol. 87, no. 3, pp. 1345-1365, 2022

Authors: Fefer, Gilad | Panek, Wojciech K. | Khan, Michael Z. | Singer, Matthew | Westermeyer, Hans D. | Mowat, Freya M. | Murdoch, David M. | Case, Beth | Olby, Natasha J. | Gruen, Margaret E.

Article Type: Research Article

Abstract: Background: Aging dogs may suffer from canine cognitive dysfunction syndrome (CCDS), a condition in which cognitive decline is associated with amyloid pathology and cortical atrophy. Presumptive diagnosis is made through physical examination, exclusion of systemic/metabolic conditions, and completion of screening questionnaires by owners. Objective: This study aimed to determine whether cognitive function could be quantified in aging pet dogs, and to correlate cognitive testing with validated questionnaires and plasma neurofilament light chain (pNfL) concentration. Methods: Thirty-nine dogs from fifteen breeds were recruited (9.3 to 15.3 years). Owners completed the Canine Dementia Scale (CADES) and Canine Cognitive …Dysfunction Rating scale (CCDR). Executive control and social cues were tested, and pNfL was measured with single molecule array assay. Comparisons were made between cognitive testing scores, CADES, CCDR scores, and pNfL. Results: CADES scoring classified five dogs as severe CCDS, six as moderate, ten as mild, and eighteen as normal. CCDR identified seven dogs at risk of CCDS and thirty-two as normal. Cognitive testing was possible in the majority of dogs, although severely affected dogs were unable to learn tasks. CADES score correlated with sustained attention duration (r  = –0.47, p  = 0.002), inhibitory control (r  = –0.51, p  = 0.002), detour (r  = –0.43, p  = 0.001), and pNfL (r  = 0.41, p  = 0.025). Concentration of pNfL correlated with inhibitory control (r  = –0.7, p ≤0.001). The CCDR scale correlated with performance on inhibitory control (r  = –0.46, p  = 0.005). Conclusion: Our findings suggest that a multi-dimensional approach using a combination of questionnaires, specific cognitive tests, and pNfL concentration can be used to quantify cognitive decline in aging pet dogs. Show more

Keywords: Blood biomarkers, canine cognitive dysfunction syndrome, CCDS, cognitive testing, dementia, neurofilament light chain, NfL

DOI: 10.3233/JAD-215562

Citation: Journal of Alzheimer's Disease, vol. 87, no. 3, pp. 1367-1378, 2022

Authors: Llamas-Rodríguez, Josué | Oltmer, Jan | Greve, Douglas N. | Williams, Emily | Slepneva, Natalya | Wang, Ruopeng | Champion, Samantha | Lang-Orsini, Melanie | Fischl, Bruce | Frosch, Matthew P. | van der Kouwe, André J.W. | Augustinack, Jean C.

Article Type: Research Article

Abstract: Background: Neurofibrillary tangle (NFT) accumulation in the entorhinal cortex (EC) precedes the transformation from cognitive controls to mild cognitive impairment and Alzheimer’s disease (AD). While tauopathy has been described in the EC before, the order and degree to which the individual subfields within the EC are engulfed by NFTs in aging and the preclinical AD stage is unknown. Objective: We aimed to investigate substructures within the EC to map the populations of cortical neurons most vulnerable to tau pathology in aging and the preclinical AD stage. Methods: We characterized phosphorylated tau (CP13) in 10 cases at …eight well-defined anterior-posterior levels and assessed NFT density within the eight entorhinal subfields (described by Insausti and colleagues) at the preclinical stages of AD. We validated with immunohistochemistry and labeled the NFT density ratings on ex vivo MRIs. We measured subfield cortical thickness and reconstructed the labels as three-dimensional isosurfaces, resulting in anatomically comprehensive, histopathologically validated tau “heat maps.” Results: We found the lateral EC subfields ELc, ECL, and ECs (lateral portion) to have the highest tau density in semi-quantitative scores and quantitative measurements. We observed significant stepwise higher tau from anterior to posterior levels (p  < 0.001). We report an age-dependent anatomically-specific vulnerability, with all cases showing posterior tau pathology, yet older individuals displaying an additional anterior tau burden. Finally, cortical thickness of each subfield negatively correlated with respective tau scores (p  < 0.05). Conclusion: Our findings indicate that posterior-lateral subfields within the EC are the most vulnerable to early NFTs and atrophy in aging and preclinical AD. Show more

Keywords: Aging, cross-sectional, entorhinal cortex, histological labeling, immunohistochemistry, neuropathology, tauopathy, temporal lobe, three-dimensional imaging, validation study

DOI: 10.3233/JAD-215567

Citation: Journal of Alzheimer's Disease, vol. 87, no. 3, pp. 1379-1399, 2022

Authors: Lei, Lauren K.S. | Lam, Bess Y.H. | Lai, Daniel W.L. | Bai, Xue | Li, Jessica | Zou, Zhi | Chan, Chetwyn C.H.

Article Type: Research Article

Abstract: Background: The Montreal Cognitive Assessment (MoCA) is a standard test for screening and monitoring cognitive functions. Objective: This study explored the two-year changes in MoCA scores in older adults. Methods: Fifty-seven participants with mild cognitive impairment (MCI) and 87 participants with normal cognition completed the baseline and two-year follow-up assessments. Apart from MoCA, tests on visuospatial judgment, memory, and motor-related executive function were administered. Results: The results identified three MCI subgroups based on the differential changes in MoCA scores. They were the consistently low, consistently high, and low-to-high between-time performances. These heterogeneous test performances …are on contrary to the significant deteriorations in executive function and finger dexterity across all subgroups. Repeated exposure to MoCA tests during the follow-up period was found to be a plausible indicator of the MCI subgroup categorization. Conclusion: Findings raise concerns over adopting brief clinical instrument for repeated testing, such as MoCA, for monitoring MCI conditions among older adults. Show more

Keywords: Aging, mild cognitive impairment, montreal cognitive assessment

DOI: 10.3233/JAD-220003

Citation: Journal of Alzheimer's Disease, vol. 87, no. 3, pp. 1401-1412, 2022

Authors: Daly, Timothy | Mastroleo, Ignacio

Article Type: Book Review

DOI: 10.3233/JAD-220185

Citation: Journal of Alzheimer's Disease, vol. 87, no. 3, pp. 1413-1414, 2022

Article Type: Correction

DOI: 10.3233/JAD-229004

Citation: Journal of Alzheimer's Disease, vol. 87, no. 3, pp. 1415-1415, 2022

Article Type: Correction

DOI: 10.3233/JAD-229005

Citation: Journal of Alzheimer's Disease, vol. 87, no. 3, pp. 1417-1417, 2022