Journal of Alzheimer's Disease - Volume 94, issue 1

Authors: Querry, Manon | Blanc, Frédéric | Bousiges, Olivier | Philippi, Nathalie | Cretin, Benjamin | Demuynck, Catherine | Muller, Candice | Botzung, Anne

Article Type: Research Article

Abstract: Background: Dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD) are likely to induce memory impairments from the prodromal stage but, to our knowledge, no longitudinal study of these patients’ memory profile has been conducted to date. Objective: The aim of our study was to describe the characteristics and the evolution of the long-term memory profile of patients with prodromal and mild DLB and AD. Methods: We collected verbal (RL/RI-16) and visual (DMS48) memory scores from 91 DLB patients, 28 AD patients, 15 patients with both conditions (DLB/AD), and 18 healthy control subjects at their inclusion …visit and at 12, 24, and 48 months. Results: On the RL/RI-16, DLB patients performed better than AD patients in terms of total recall (p  < 0.001), delayed total recall (p  < 0.001), recognition (p  = 0.031), and loss of information over time (p  = 0.023). On the DMS48, differences between these two groups were not significant (p  > 0.05). Longitudinally, the memory performance of DLB patients was stable over 48 months, unlike that of AD patients. Conclusion: Four indicators were relevant to distinguish between DLB and AD patients in terms of memory performance: DLB patients benefitted greatly from semantic cueing, their recognition and consolidation abilities were well-preserved, and both their verbal and visual memory performance remained remarkably stable over four years. However, no performance differences between DLB and AD patients were found regarding visual memory, either qualitatively (memory profile) or quantitatively (severity of impairment), indicating the lesser relevance of this test in distinguishing between these two diseases. Show more

Keywords: Alzheimer’s disease, dementia with Lewy bodies, diagnosis, DMS48, Lewy body disease, memory, mild cognitive impairment, RL/RI-16

DOI: 10.3233/JAD-221243

Citation: Journal of Alzheimer's Disease, vol. 94, no. 1, pp. 147-162, 2023

Authors: Buawangpong, Nida | Pinyopornpanish, Kanokporn | Phinyo, Phichayut | Jiraporncharoen, Wichuda | Angkurawaranon, Chaisiri | Soontornpun, Atiwat

Article Type: Research Article

Abstract: Background: There is a verified association between comorbidity and survival in patients with dementia. Objective: To describe the ten-year survival probability of patients with dementia and to identify the impact of comorbidity. Methods: The prognostic retrospective cohort study was conducted using data from adults with dementia who had visited the outpatient departments at Maharaj Nakorn Chiang Mai hospital between 2006 and 2012. Dementia was verified in accordance with standard practice guidelines. Secondary data detailing about patient age, gender, date of dementia diagnosis and death, types of dementia, and comorbidities at the time of dementia diagnosis was …obtained from electronic medical records. The association between comorbidity, patients’ underlying disease at dementia diagnosis, and overall survival were analyzed using a multivariable Cox proportional hazard model adjusted for age, gender, types of dementia, and other comorbidities. Results: Of the 702 patients, 56.9% were female. Alzheimer’s disease (39.6%) was the most prevalent type of dementia. Median overall survival was 6.0 years (95% CI 5.5– 6.7). The comorbidities associated with a high risk of mortality included liver disease (aHR 2.70, 95% CI 1.46– 5.00), atrial fibrillation (aHR 2.15, 95% CI 1.29– 3.58), myocardial infarction (aHR 1.55, 95% CI 1.07– 2.26), and type 2 diabetes mellitus (aHR 1.40, 95% CI 1.13– 1.74). Conclusion: Overall survival rate of patients with dementia in Thailand was comparable to previous studies. Several comorbidities were associated with a ten-year survival. The prognosis of patients with dementia may be improved by appropriate care of comorbidities. Show more

Keywords: Alzheimer’s disease, comorbidity, dementia, survival time

DOI: 10.3233/JAD-221259

Citation: Journal of Alzheimer's Disease, vol. 94, no. 1, pp. 163-175, 2023

Authors: Mori, Hiroaki | Yoshino, Yuta | Iga, Jun-ichi | Ochi, Shinichiro | Funahashi, Yu | Yamazaki, Kiyohiro | Kumon, Hiroshi | Ozaki, Yuki | Ueno, Shu-ichi

Article Type: Research Article

Abstract: Background: We explored the gene expression levels in the brain of 3xTg-AD model mice to elucidate the molecular pathological changes from the early to end stages of Alzheimer’s disease (AD). Objective: We re-analyzed our previously published microarray data obtained from the hippocampus of 3xTg-AD model mice at 12 and 52 weeks of age. Methods: Functional annotation and network analyses of the up- and downregulated differentially expressed genes (DEGs) in mice aged 12 to 52 weeks were performed. Validation tests for gamma-aminobutyric acid (GABA)-related genes were also performed by quantitative polymerase chain reaction (qPCR). Results: …In total, 644 DEGs were upregulated and 624 DEGs were downregulated in the hippocampus of both the 12- and 52-week-old 3xTg-AD mice. In the functional analysis of the upregulated DEGs, 330 gene ontology biological process terms, including immune response, were found, and they interacted with each other in the network analysis. In the functional analysis of the downregulated DEGs, 90 biological process terms, including several terms related to membrane potential and synapse function, were found, and they also interacted with each other in the network analysis. In the qPCR validation test, significant downregulation was seen for Gabrg3 at the ages of 12 (p  = 0.02) and 36 (p  = 0.005) weeks, Gabbr1 at the age of 52 weeks (p  = 0.001), and Gabrr2 at the age of 36 weeks (p  = 0.02). Conclusion: Changes in immune response and GABAergic neurotransmission may occur in the brain of 3xTg mice from the early to end stages of AD. Show more

Keywords: Alzheimer’s disease, GABA, gene expression, microarrays, 3xTg-AD model mice

DOI: 10.3233/JAD-230078

Citation: Journal of Alzheimer's Disease, vol. 94, no. 1, pp. 177-188, 2023

Authors: Bollinger, Rebecca M. | Gabel, Matthew | Coble, Dean W. | Chen, Szu-Wei | Keleman, Audrey A. | Doralus, Jeff | Chin, Erin | Lingler, Jennifer H. | Grill, Joshua D. | Stark, Susan L. | Edwards, Dorothy F.

Article Type: Research Article

Abstract: Background: Study partners are required for all participants at Alzheimer’s Disease Research Centers (ADRCs). Study partners’ attitudes and beliefs may contribute to missed visits and negatively impact retention of participants in longitudinal AD studies. Objective: Study partners (N = 212) of participants (Clinical Dementia Rating® [CDR]≤2) at four ADRCs were randomly surveyed to examine their facilitators and barriers to continued participation in AD studies. Methods: Reasons for participation were analyzed with factor analysis and regression analysis. Effects of complaints and goal fulfillment on attendance were estimated with fractional logistic models. Open-ended responses were characterized with a Latent …Dirichlet Allocation topic model. Results: Study partners participated for personal benefit and altruism. They emphasized personal benefits more when their participants had a CDR > 0 than when they had a CDR = 0. This difference declined with participant age. The majority of study partners rated their ADRC participation as positive and meeting their goals. Although half reported at least one complaint, very few regretted participating. Those who reported that ADRC participation fulfilled their goals or had fewer complaints were more likely to have perfect attendance. Study partners requested more feedback about test results and better management of study visits. Conclusion: Study partners are motivated by both personal and altruistic goals. The salience of each goal depends on their trust in researchers and the participant’s cognitive status and age. Retention may improve with perceived goal fulfillment and fewer complaints. Potential areas for improving retention are providing more information about the participant’s test results and better management of study visits. Show more

Keywords: Adult children, Alzheimer’s disease, barriers, facilitators, spouse

DOI: 10.3233/JAD-230079

Citation: Journal of Alzheimer's Disease, vol. 94, no. 1, pp. 189-199, 2023

Authors: Peavy, Guerry M.

Article Type: Article Commentary

Abstract: Alzheimer’s disease (AD) clinical research depends on engaging and enrolling appropriate research participants to address specific scientific questions. Investigators, however, are beginning to recognize the importance of participant study partners who contribute to AD research in multiple ways, including their contributions to the diagnostic process through observations of participant cognition and daily functioning. These contributions justify increased efforts to understand factors that impede or facilitate their willingness to remain in this role in longitudinal studies and clinical trials. Study partners, including those from diverse, underrepresented communities, are stakeholders significantly invested in AD research that benefits all living with the disease.

Keywords: Alzheimer’s disease, diversity, recruitment, retention, study partner

DOI: 10.3233/JAD-230455

Citation: Journal of Alzheimer's Disease, vol. 94, no. 1, pp. 201-203, 2023

Authors: Paik, Woo Hyun | Jang, Dong Kee | Cho, Soyoung | Choi, Jin Ho | Kim, Min Kyu | Cho, In Rae | Ryu, Ji Kon | Kim, Yong-Tae | Han, Kyung-Do | Lee, Sang Hyub

Article Type: Research Article

Abstract: Background: Diabetes is a major risk factor for the development of dementia, which has been proven to be associated with systemic inflammation. Acute pancreatitis, also a local and systemic inflammatory disease, is the most common gastrointestinal disease requiring acute hospitalization. Objective: The effect of acute pancreatitis on dementia was investigated in type 2 diabetic patients. Methods: Data was collected from the Korean National Health Insurance Service. The study sample included type 2 diabetes patients who received general health examination from 2009 to 2012. Cox proportional hazard regression analysis was used to evaluate the association between acute …pancreatitis and dementia with adjustment of confounders. Stratified subgroup analysis by age, sex, smoking, alcohol consumption, hypertension, dyslipidemia, and body mass index was conducted. Results: Among the 2,328,671 participants in total, 4,463 patients had a history of acute pancreatitis before the health examination. During a median follow-up of 8.1 (IQR, 6.7–9.0) years, 194,023 participants (8.3%) developed all-cause dementia. Previous history of acute pancreatitis was a significant risk factor for dementia after adjustment of confounding variables (HR 1.39 [95% CI 1.26–1.53]). In the subgroup analysis, patient characteristics such as age under 65 years, male, current smoker, and alcohol consumption were significant risk factors for dementia in patients with a history of acute pancreatitis. Conclusion: The history of acute pancreatitis was associated with the development of dementia in patients with diabetes. Because the risk of dementia increases with alcohol consumption and smoking in diabetic patients with history of acute pancreatitis, abstinence from alcohol and smoking should be recommended. Show more

Keywords: Alzheimer’s disease, big data, dementia, diabetes mellitus, pancreatitis

DOI: 10.3233/JAD-220353

Citation: Journal of Alzheimer's Disease, vol. 94, no. 1, pp. 205-216, 2023

Authors: Gonzalez, Christopher | Mimmack, Kayden J. | Amariglio, Rebecca E. | Becker, J. Alex | Chhatwal, Jasmeer P. | Fitzpatrick, Colleen D. | Gatchel, Jennifer R. | Johnson, Keith A. | Katz, Zoe S. | Kuppe, Madeline K. | Locascio, Joseph J. | Udeogu, Onyinye J. | Papp, Kathryn V. | Premnath, Pranitha | Properzi, Michael J. | Rentz, Dorene M. | Schultz, Aaron P. | Sperling, Reisa A. | Vannini, Patrizia | Wang, Sharon | Marshall, Gad A.

Article Type: Research Article

Abstract: Background: Detecting clinically meaningful changes in instrumental activities of daily living (IADL) at the earliest stages of Alzheimer’s disease (AD) is critical. Objective: The objective of this exploratory study was to examine the cross-sectional relationship between a performance-based IADL test, the Harvard Automated Phone Task (APT), and cerebral tau and amyloid burden in cognitively normal (CN) older adults. Methods: Seventy-seven CN participants underwent flortaucipir tau and Pittsburgh Compound B amyloid PET. IADL were assessed using the three Harvard APT tasks: prescription refill (APT-Script), health insurance company call (APT-PCP), and bank transaction (APT-Bank). Linear regression models were …used to determine associations between each APT task and entorhinal cortex, inferior temporal, or precuneus tau with or without an interaction with amyloid. Results: Significant associations were found between APT-Bank task rate and interaction between amyloid and entorhinal cortex tau, and APT-PCP task and interactions between amyloid and inferior temporal and precuneus tau. No significant associations were found between the APT tasks and tau or amyloid alone. Conclusion: Our preliminary findings suggest an association between a simulated real-life IADL test and interactions of amyloid and several regions of early tau accumulation in CN older adults. However, some analyses were underpowered due to the small number of participants with elevated amyloid, and findings should be interpreted with caution. Future studies will further explore these associations cross-sectionally and longitudinally in order to determine whether the Harvard APT can serve as a reliable IADL outcome measure for preclinical AD prevention trials and ultimately in the clinic setting. Show more

Keywords: Alzheimer’s disease, amyloid, cognition, dementia, early detection, imaging, instrumental activities of daily living, positron emission tomography, tau

DOI: 10.3233/JAD-220885

Citation: Journal of Alzheimer's Disease, vol. 94, no. 1, pp. 217-226, 2023

Authors: Mi, Zhiping | Abrahamson, Eric E. | Ryu, Angela Y. | Malek-Ahmadi, Michael | Kofler, Julia K. | Fish, Kenneth N. | Sweet, Robert A. | Villemagne, Victor L. | Schneider, Julie A. | Mufson, Elliott J. | Ikonomovic, Milos D.

Article Type: Research Article

Abstract: Background: Altered glutamatergic neurotransmission may contribute to impaired default mode network (DMN) function in Alzheimer’s disease (AD). Among the DMN hub regions, frontal cortex (FC) was suggested to undergo a glutamatergic plasticity response in prodromal AD, while the status of glutamatergic synapses in the precuneus (PreC) during clinical-neuropathological AD progression is not known. Objective: To quantify vesicular glutamate transporter VGluT1- and VGluT2-containing synaptic terminals in PreC and FC across clinical stages of AD. Methods: Unbiased sampling and quantitative confocal immunofluorescence of cortical VGluT1- and VGluT2-immunoreactive profiles and spinophilin-labeled dendritic spines were performed in cases with no …cognitive impairment (NCI), mild cognitive impairment (MCI), mild-moderate AD (mAD), or moderate-severe AD (sAD). Results: In both regions, loss of VGluT1-positive profile density was seen in sAD compared to NCI, MCI, and mAD. VGluT1-positive profile intensity in PreC did not differ across groups, while in FC it was greater in MCI, mAD, and sAD compared to NCI. VGluT2 measures were stable in PreC while FC had greater VGluT2-positive profile density in MCI compared to sAD, but not NCI or mAD. Spinophilin measures in PreC were lower in mAD and sAD compared to NCI, while in FC they were stable across groups. Lower VGluT1 and spinophilin measures in PreC, but not FC, correlated with greater neuropathology. Conclusion: Frank loss of VGluT1 in advanced AD relative to NCI occurs in both DMN regions. In FC, an upregulation of VGluT1 protein content in remaining glutamatergic terminals may contribute to this region’s plasticity response in AD. Show more

Keywords: Alzheimer’s disease, amyloid, glutamate, plasticity, synapse, vesicular glutamate transporter

DOI: 10.3233/JAD-221063

Citation: Journal of Alzheimer's Disease, vol. 94, no. 1, pp. 227-246, 2023

Authors: Tu, Lihui | Wang, Zhijiang | Lv, Xiaozhen | Xie, Teng | Fan, Zili | Zhang, Ming | Wang, Huali | Yu, Xin

Article Type: Research Article

Abstract: Background: Olfactory identification dysfunction (OID) might be an early sign of amnestic mild cognitive impairment (aMCI). However, odor hedonics, the ability to perceive odor pleasantness, is neglected. Also, the neural substrate of OID remains unclear. Objective: To explore the characteristics of odor identification and hedonics in aMCI and examine the potential neural correlates of OID by analyzing olfactory functional connectivity (FC) patterns in MCI. Methods: Forty-five controls and 83 aMCI patients were examined. The Chinese smell identification test was used to assess olfaction. Global cognition, memory, and social cognition were assessed. Resting-state functional networks associated with …olfactory cortex seeds were compared between the cognitively normal (CN) and aMCI groups, as well as between aMCI subgroups by the degree of OID. Results: Compared to controls, aMCI patients had a significant deficit in olfactory identification, mainly reflected in the identification of pleasant and neutral odors. aMCI patients also rated pleasant and neutral odors much lower than controls. A positive correlation between olfaction and social cognition was found in aMCI. The seed-based FC analysis found that aMCI patients had higher FC between the right orbitofrontal cortex and right frontal lobe/middle frontal gyrus than controls. Subgroup analysis showed that, compared to aMCI without OID, aMCI with severe OID had abnormal FC in the bilateral piriform region. Conclusion: Our results suggest that OID in aMCI primarily refers to the identification of pleasant and neutral odors. The FC alterations in bilateral orbitofrontal cortex and piriform cortices might contribute to the impairment in odor identification. Show more

Keywords: Alzheimer’s disease, mild cognitive impairment, odor hedonics, olfactory identification, resting-state functional magnetic resonance imaging, social cognition

DOI: 10.3233/JAD-221163

Citation: Journal of Alzheimer's Disease, vol. 94, no. 1, pp. 247-258, 2023

Authors: Jarholm, Jonas Alexander | Bjørnerud, Atle | Dalaker, Turi Olene | Akhavi, Mehdi Sadat | Kirsebom, Bjørn Eivind | Pålhaugen, Lene | Nordengen, Kaja | Grøntvedt, Gøril Rolfseng | Nakling, Arne | Kalheim, Lisa F. | Almdahl, Ina S. | Tecelão, Sandra | Fladby, Tormod | Selnes, Per

Article Type: Research Article

Abstract: Background: Atrophy of the medial temporal lobe (MTL) is a biological characteristic of Alzheimer’s disease (AD) and can be measured by segmentation of magnetic resonance images (MRI). Objective: To assess the clinical utility of automated volumetry in a cognitively well-defined and biomarker-classified multi-center longitudinal predementia cohort. Methods: We used Automatic Segmentation of Hippocampal Subfields (ASHS) to determine MTL morphometry from MRI. We harmonized scanner effects using the recently developed longitudinal ComBat. Subjects were classified according to the A/T/N system, and as normal controls (NC), subjective cognitive decline (SCD), or mild cognitive impairment (MCI). Positive or negative …values of A, T, and N were determined by cerebrospinal fluid measurements of the Aβ42/40 ratio, phosphorylated and total tau. From 406 included subjects, longitudinal data was available for 206 subjects by stage, and 212 subjects by A/T/N. Results: Compared to A–/T–/N– at baseline, the entorhinal cortex, anterior and posterior hippocampus were smaller in A+/T+orN+. Compared to NC A– at baseline, these subregions were also smaller in MCI A+. Longitudinally, SCD A+ and MCI A+, and A+/T–/N– and A+/T+orN+, had significantly greater atrophy compared to controls in both anterior and posterior hippocampus. In the entorhinal and parahippocampal cortices, longitudinal atrophy was observed only in MCI A+ compared to NC A–, and in A+/T–/N– and A+/T+orN+ compared to A–/T–/N–. Conclusion: We found MTL neurodegeneration largely consistent with existing models, suggesting that harmonized MRI volumetry may be used under conditions that are common in clinical multi-center cohorts. Show more

Keywords: Alzheimer’s disease, brain atrophy, cognitive decline, hippocampus, longitudinal studies, magnetic resonance imaging

DOI: 10.3233/JAD-221274

Citation: Journal of Alzheimer's Disease, vol. 94, no. 1, pp. 259-279, 2023