Journal of Alzheimer's Disease - Volume 89, issue 1

Authors: Macpherson, Helen | Brownell, Sarah | Harris, Elizabeth | Duckham, Rachel L. | O’Connell, Stella | Meyer, Barbara J. | Mirzaee, Sam | Daly, Robin M.

Article Type: Research Article

Abstract: Background: Multidomain interventions which incorporate exercise and dietary supplementation to target both cognitive and physical health domains may be an important approach to delay cognitive decline. Objective: The Protein Omega-3 aNd vitamin D Exercise Research (PONDER) study investigated the effects of a 6-month multifaceted intervention in community-dwelling older adults with subjective memory impairment on cognition (primary outcome), physical function, and body composition with a further 6-month follow up for cognition (secondary outcomes). Methods: Single-center, community-based, parallel-group, randomized, double-blind placebo-controlled trial involving a 6-month multifaceted intervention with a further follow-up at 12 months. A total of 147 …participants [mean age 70.2 years (SD 6.1), 70% female] were randomized to a multimodal exercise program consisting of twice-weekly supervised resistance and aerobic training, combined with a daily omega-3 (900 mg EPA, 600 mg DHA), vitamin D (1000 IU) and protein (20 g) supplement (n  = 73), or a control condition (n  = 74) comprising stretching/flexibility sessions combined with a placebo. The primary outcome was a composite CogState measure and Trail-Making Test B-A. Results: There were no significant between-group differences in the change of cognition at 6 or 12 months or physical function outcomes at 6 months, but the intervention significantly improved total lean mass compared to controls [0.72 kg (95% CI 0.26–1.19), p  = 0.001]. Conclusion: A multi-faceted intervention including an omega-3, vitamin D and protein-enriched supplement with twice-weekly exercise training did not provide any benefits to cognitive or physical function in older adults with subjective memory impairment, despite improvements in lean mass. Show more

Keywords: Cognition, dietary proteins, exercise, fatty acids, omega-3, vitamin D, white matter hyperintensities, white matter lesions

DOI: 10.3233/JAD-220234

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 247-263, 2022

Authors: Heal, Mackenzie | McFall, G. Peggy | Vergote, David | Jhamandas, Jack H. | Westaway, David | Dixon, Roger A.

Article Type: Research Article

Abstract: Background: A promising risk loci for sporadic Alzheimer’s disease (AD), Bridging Integrator 1 (BIN1 ), is thought to operate through the tau pathology pathway. Objective: We examine BIN1 risk for a moderating role with vascular health (pulse pressure; PP) and sex in predictions of episodic memory trajectories in asymptomatic aging adults. Methods: The sample included 623 participants (Baseline Mean age = 70.1; 66.8% female) covering a 44-year longitudinal band (53–97 years). With an established memory latent variable arrayed as individualized trajectories, we applied Mplus 8.5 to determine the best fitting longitudinal growth model. Main analyses were …conducted in three sequential phases to investigate: 1) memory trajectory prediction by PP, 2) moderation by BIN1 genetic risk, and 3) stratification by sex. Results: We first confirmed that good vascular health (lower PP) was associated with higher memory level and shallower decline and males were more severely affected by worsening PP in both memory performance and longitudinal decline. Second, the PP prediction of memory trajectories was significant for BIN1 C/C and C/T carriers but not for persons with the highest AD risk (T/T homozygotes). Third, when further stratified by sex, the BIN1 moderation of memory prediction by PP was selective for females. Conclusion: We observed a novel interaction whereby BIN1 (linked with tauopathy in AD) and sex sequentially moderated a benchmark PP prediction of differential memory decline in asymptomatic aging. This multi-modal biomarker interaction approach, disaggregated by sex, can be an effective method for enhancing precision of AD genetic risk assessment. Show more

Keywords: Bridging integrator 1, memory trajectories, pulse pressure, sex differences, Victoria Longitudinal Study

DOI: 10.3233/JAD-220334

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 265-281, 2022

Authors: Huffels, Christiaan F.M. | van Dijk, Roland E. | Karst, Henk | Meye, Frank J. | Hol, Elly M. | Middeldorp, Jinte

Article Type: Research Article

Abstract: Background: Aging is characterized by systemic alterations and forms an important risk factor for Alzheimer’s disease (AD). Recently, it has been indicated that blood-borne factors present in the systemic milieu contribute to the aging process. Exposing young mice to aged blood plasma results in impaired neurogenesis and synaptic plasticity in the dentate gyrus, as well as impaired cognition. Vice versa, treating aged mice with young blood plasma rescues impairments associated with aging. Objective: Whether blood-borne factors are sufficient to drive impairments outside the dentate gyrus, how they impact neurophysiology, and how the functional outcome compares to impairments found …in mouse models for AD is still unclear. Methods: Here, we treated adult mice with blood plasma from aged mice and assessed neurophysiological parameters in the hippocampal CA1. Results: Mice treated with aged blood plasma show significantly impaired levels of long-term potentiation (LTP), similar to those present in APP/PS1 mice. These impaired levels of LTP in plasma-treated mice are associated with alterations in basic properties of glutamatergic transmission and the enhanced activity of voltage-gated Ca2+ channels. Conclusion: Together, the data presented in this study show that blood-borne factors are sufficient to drive neurophysiological impairments in the hippocampal CA1. Show more

Keywords: Aging, Alzheimer’s disease, calcium, calcium channels, hippocampus, neuronal plasticity, plasma

DOI: 10.3233/JAD-220337

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 283-297, 2022

Authors: Cerami, Chiara | Perdixi, Elena | Meli, Claudia | Marcone, Alessandra | Zamboni, Michele | Iannaccone, Sandro | Dodich, Alessandra

Article Type: Research Article

Abstract: Background: The Frontal Behavioral Inventory (FBI) is a questionnaire designed to quantify behavioral changes in frontotemporal dementia (FTD). Literature showed heterogeneous FBI profiles in FTD versus Alzheimer’s disease (AD) with variable occurrence of positive and negative symptoms. Objective: In this study, we constructed a short FBI version (i.e., mini-FBI) with the aim to provide clinicians with a brief tool for the identification of early behavioral changes in behavioral variant of FTD (bvFTD), also facilitating the differential diagnosis with AD. Methods: 40 bvFTD and 33 AD patients were enrolled. FBI items were selected based on internal consistency …and exploratory factor analysis. Convergent validity of mini-FBI was also assessed. A behavioral index (i.e., B-index) representing the balance between positive and negative mini-FBI symptoms was computed in order to analyze its distribution in bvFTD through a cluster analysis and to compare performance among patient groups. Results: The final version of the mini-FBI included 12 items, showing a significant convergent validity with the Neuropsychiatric Inventory scores (rp  = 0.61, p  < 0.001). Cluster analysis split patients in four clusters. bvFTD were included in three different clusters characterized by prevalent positive symptoms, both positive and negative symptoms, or prevalent negative behavioral alterations, similar to a subset of AD patients. A fourth cluster included only AD patients showing no positive symptoms. Conclusion: The mini-FBI is a valuable easily administrable questionnaire able to early identify symptoms effectively contributing to the bvFTD behavioral syndrome, aiding clinician in diagnosis and management. Show more

Keywords: Accuracy, Alzheimer’s disease, behavioral disorders, behavioral variant of frontotemporal dementia, diagnosis, frontal syndrome, frontotemporal dementia

DOI: 10.3233/JAD-220173

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 299-308, 2022

Authors: Luo, Wendy | Pryzbyl, Katherine J. | Bigio, Eileen H. | Weintraub, Sandra | Mesulam, M.-Marsel | Redei, Eva E.

Article Type: Research Article

Abstract: Background: Major depressive disorder (MDD) is a risk factor for dementia including that caused by Alzheimer’s disease (AD). Both MDD and AD have a higher prevalence in women than men, and estrogen-related processes have been implicated in this sex difference. Objective: To identify if enhanced oxidative stress and decreased expression of the memory enhancer insulin-like growth factor 2 (IGF2 ), each implicated separately in MDD and AD, are exaggerated in individuals with both AD and MDD compared to those with AD. Methods: Expression of target genes are determined by qPCR in postmortem hippocampus (Hip) and anterior …cingulate cortex (ACC) of individuals with dementia and autopsy confirmed AD and those of AD+MDD. Results: Transcript levels of the antioxidant enzymes catalase (CAT ) and superoxide dismutase 1 (SOD1 ), as well as IGF2 and its receptor (IGF2R ) were significantly lower in the Hip and ACC of individuals with both AD and MDD compared to those with AD and no MDD. Expressions of Progestin and AdipoQ Receptor Family Member 7 (PAQR7, alias progesterone receptor alpha, mPRa ) and PAQR8 (mPR β), receptors that bind neurosteroids, were also lower in the Hip and ACC of AD+MDD samples compared to those of AD without MDD. Correlations among these transcripts revealed that estrogen receptor 2 (ESR2 ) and mPR β are direct or indirect regulators of the expression of the antioxidant enzymes and IGF2R. Conclusion: Reduced levels of antioxidant enzymes, decreased IGF2 expression, and diminished estrogen or membrane progesterone receptor-dependent processes might be more pronounced in the subpopulation of individuals with AD and MDD than without MDD. Show more

Keywords: Antioxidant enzymes, depression, insulin like growth factor 2, membrane progesterone receptor, molecular vulnerability, sex/gender differences

DOI: 10.3233/JAD-220574

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 309-321, 2022

Authors: Yen, Fu-Shun | Wei, James Cheng-Chung | Yip, Hei-Tung | Hwu, Chii-Min | Hsu, Chih-Cheng

Article Type: Research Article

Abstract: Background: Type 2 diabetes (T2D) and hypertension (HTN) are well-known modifiable risk factors for dementia, but their intricate attributes accounting for dementia development has not been clearly delineated. Objective: We conducted this study to investigate and compare the effects of T2D and HTN on dementia risk. Methods: We screened data of matched pairs of patients with T2D or HTN between January 1, 2000 and December 31, 2017 from Taiwan’s National Health Insurance Research Database. Fine and Gray’s subdistribution hazard models were used for calculating the risk of dementia. Results: Patients with T2D and subsequent …HTN were associated with significantly higher risks of all-cause dementia (aHR 1.51, 95% CI 1.25–1.83) and vascular dementia (aHR 2.30, 95% CI 1.71–3.13) compared with those without subsequent HTN. Patients with HTN and subsequent T2D were associated with significantly higher risks of all-cause dementia (aHR 1.15, 95% CI 1.08–1.21), vascular dementia (aHR 1.25, 95% CI 1.62–1.34), and other dementia (aHR 1.31, 95% CI 1.03–1.66) compared with those without subsequent HTN. The subgroups of male and female patients, age of 50–69 and 70–90 years with subsequent comorbidity were associated with significantly higher risks of all-cause dementia and vascular dementia than those without subsequent comorbidity. Conclusion: This nationwide cohort study demonstrated that patients with T2D and subsequent HTN had association with higher risks of all-cause dementia and vascular dementia, and those with HTN and subsequent T2D were associated with higher risks of all-cause dementia, vascular dementia, and other dementia. Show more

Keywords: All-cause dementia, Alzheimer’s disease, other dementia, vascular dementia

DOI: 10.3233/JAD-220207

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 323-333, 2022

Authors: Zhang, Yangyang | Yang, Yin | Hu, Zhengtao | Zhu, Manyi | Qin, Shuangying | Yu, Pengpeng | Li, Bo | Xu, Jitian | Ondrejcak, Tomas | Klyubin, Igor | Rowan, Michael J. | Hu, Neng-Wei

Article Type: Research Article

Abstract: Background: Cognitive decline in Alzheimer’s disease (AD) correlates with the extent of tau pathology, in particular tau hyperphosphorylation, which is strongly age-associated. Although elevation of cerebrospinal fluid or blood levels of phosphorylated tau (p-Tau) at residues Thr181 (p-Tau181), Thr217 (p-Tau217), and Thr231 (p-Tau231) are proposed to be particularly sensitive markers of preclinical AD, the generation of p-Tau during brain activity is poorly understood. Objective: To study whether the expression levels of p-Tau181, p-Tau217, and p-Tau231 can be enhanced by physiological synaptic long-term depression (LTD) which has been linked to the enhancement of p-Tau in hippocampus. Methods: …In vivo electrophysiology was performed in urethane anesthetized young adult and aged male rats. Low frequency electrical stimulation (LFS) was used to induce LTD at CA3 to CA1 synapses. The expression level of p-Tau and total tau was measured in dorsal hippocampus using immunofluorescent staining and/or western blotting. Results: We found that LFS enhanced p-Tau181 and p-Tau217 in an age-dependent manner in the hippocampus of live rats. In contrast, phosphorylation at residues Thr231, Ser202/Thr205, and Ser396 appeared less sensitive to LFS. Pharmacological antagonism of either N-methyl-D-aspartate or metabotropic glutamate 5 receptors inhibited the elevation of both p-Tau181 and p-Tau217. Targeting the integrated stress response, which increases with aging, using a small molecule inhibitor ISRIB, prevented the enhancement of p-Tau by LFS in aged rats. Conclusion: Together, our data provide a novel in vivo means to uncover brain plasticity-related cellular and molecular processes of tau phosphorylation at key sites in health and aging. Show more

Keywords: Aging, Alzheimer’s disease, integrated stress response, long-term depression, tau phosphorylation

DOI: 10.3233/JAD-220351

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 335-350, 2022

Authors: Wang, Steven | Gustafson, Sara | Deckelman, Celia | Sampene, Emmanuel | Daggett, Sarah | Loosen, Julia | Robison, Raele | Pulia, Michael S. | Knigge, Molly | Thibeault, Susan | Gilmore-Bykovskyi, Andrea | Kind, Amy | Rogus-Pulia, Nicole

Article Type: Research Article

Abstract: Background: Alzheimer’s disease and related dementias (ADRD) patients who are hospitalized often develop oropharyngeal dysphagia, increasing risk for adverse outcomes, such as aspiration pneumonia. However, prevalence estimates of dysphagia are highly variable and often based on patient report or clinical testing rather than visualization of the swallow. Objective: The aims of this study were to determine prevalence and severity of dysphagia among inpatients with ADRD referred for swallowing evaluation. Methods: Electronic health record (EHR) abstraction of ADRD diagnosis and presence and severity of clinically-determined dysphagia on bedside swallow evaluation (BSE) and videofluoroscopic swallow study (VFSS). …Results: 16% (n  = 268) had an ADRD diagnosis or were taking dementia-specific medication based on the EHR. 75% (n  = 202) were diagnosed with dysphagia on the BSE. 60% subsequently underwent VFSS (n  = 122) with dysphagia confirmation in 92% (n  = 112). ADRD inpatients were significantly more likely to be diagnosed with dysphagia based on the BSE (p  < 0.0001) than those without ADRD. Additionally, dysphagia on the VFSS was more severe in the ADRD group (p  < 0.03). Discussion: ADRD individuals may be vulnerable to developing or worsening dysphagia during hospitalization. Results underscore the importance of evaluating swallowing function in hospitalized patients with ADRD in order to facilitate targeted intervention. Show more

Keywords: Alzheimer’s disease and related dementias, oropharyngeal dysphagia, swallow, videofluoroscopic

DOI: 10.3233/JAD-220402

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 351-358, 2022

Authors: Klein, Philip Charles Gerard | Huygens, Simone | Handels, Ron | Wester, Valérie | Kanters, Tim Andre

Article Type: Research Article

Abstract: Background: Disease modifying treatments (DMTs) currently under development for Alzheimer’s disease, have the potential to prevent or postpone institutionalization and more expensive care and might delay institutionalization of persons with dementia. Objective: The current study estimates costs of living in a nursing home for persons with dementia in the Netherlands to help inform economic evaluations of future DMTs. Methods: Data were collected during semi-structured interviews with healthcare professionals and from the financial administration of a healthcare organization with several nursing homes. Personnel costs were calculated using a bottom-up approach by valuing the time estimates. Non-personnel costs …were calculated using information from the financial administration of the healthcare organization. Results: Total costs of a person with dementia per 24 hours, including both care staff and other healthcare providers, were € 151 for small-scale living wards and € 147 for independent living wards. Non-personnel costs were € 37 per day. Conclusion: This study provides Dutch estimates for total healthcare costs per day for institutionalized persons with dementia. These cost estimates can be used in cost-effectiveness analyses for future DMTs in dementia. Show more

Keywords: Dementia, health care economics and organizations, health resources, nursing homes

DOI: 10.3233/JAD-220416

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 359-366, 2022

Authors: Zhang, Dan-Dan | Ou, Ya-Nan | Fu, Yan | Wang, Zhi-Bo | Huang, Liang-Yu | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: A negative association between cancer and Alzheimer’s disease (AD) was revealed. Objective: We aimed to further explore the dementia risk among cancer survivors and then among cancer survivors who received cancer treatment in subsequent subgroup analyses. Methods: Databases of PubMed, Embase, and Cochrane Library were systematically searched from inception to April 1, 2021, following PRISMA and MOOSE guidelines. Relative risks (RR) of dementia were pooled by a random-effects model stratifying the data by potential confounding factors to explore the heterogeneity. This study is registered with PROSPERO, number CRD42021250654. Results: A total of 36 …studies were included in this meta-analysis, of which 16 studies were about the risk of dementia in cancer survivors, and 20 studies were about the risk of dementia in survivors who accepted cancer treatment. The pooled RR reached 0.89 ([95% CI = 0.82–0.97], I2  = 97.9%) for dementia and 0.89 ([0.83–0.95], I2  = 92.6%) for AD in cancer survivors compared with non-cancer controls. Notably, both dementia risk and AD risk significantly decreased in survivors of colon, leukemia, small intestine, and thyroid cancers (RR ranged from 0.64 to 0.92). Furthermore, prostate cancer patients treated with androgen deprivation therapy exhibited a significantly increased risk of dementia (RR:1.18 [1.09–1.27], I2  = 89.5%) and AD (RR:1.17 [1.08–1.25], I2  = 81.3%), with evidence of between-study heterogeneity. Conclusion: Currently, available evidence suggests that the risk of dementia among cancer survivors is decreased. However, large-scale prospective cohort studies are warranted to further prove the association. Show more

Keywords: Alzheimer’s disease, cancer, cancer treatment, dementia, meta-analysis

DOI: 10.3233/JAD-220436

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 367-380, 2022

Authors: Saito, Satoshi | Yamashiro, Takayuki | Yamauchi, Miho | Yamamoto, Yumi | Noguchi, Michio | Tomita, Tsutomu | Kawakami, Daisuke | Shikata, Masamitsu | Tanaka, Tomotaka | Ihara, Masafumi

Article Type: Research Article

Abstract: Background: Cerebral amyloid angiopathy is a cerebrovascular disease directly implicated in Alzheimer’s disease pathogenesis through amyloid-β deposition. Growing evidence has shown a pivotal role of chronic neuroinflammation both in cerebral amyloid angiopathy and Alzheimer’s disease. Objective: The aim of this study was to investigate whether circulating levels of the complement 3, a crucial component of the innate immune system, are increased in patients with cerebral amyloid angiopathy. Methods: Serum complement 3 levels were retrospectively measured by a sandwich enzyme-linked immunosorbent assay in a single-center cohort of patients with mild cognitive impairment. The diagnosis of cerebral amyloid …angiopathy was based on the modified Boston criteria. Logistic regression analysis was performed to identify the predictive factors for cerebral amyloid angiopathy. Results: We analyzed 55 mild cognitive impairment patients (mean age [standard deviation]: 76.3 [6.8] years; 33 [60% ] men). Complement 3 levels were significantly increased in cerebral amyloid angiopathy patients (n  = 16) compared with those without cerebral amyloid angiopathy (n  = 39) (median [interquartile range]: 0.43 [0.34–0.65] versus 0.35 [0.25–0.45], respectively; p  = 0.040). Univariate and multivariate logistic regression analysis revealed that increased complement 3 levels were significantly associated with cerebral amyloid angiopathy. After selection of the best predictive model using stepwise selection, complement 3 was preserved as a significant independent predictive factor for cerebral amyloid angiopathy (odds ratio per 0.1 unit/mL increase [95% confidence interval]: 1.407 [1.042–1.899]; p  = 0.026). Conclusion: Complement activation may play a pivotal role in cerebral amyloid angiopathy. Complement 3 may be a novel diagnostic biomarker for cerebral amyloid angiopathy. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebral amyloid angiopathy, complement 3, inflammation

DOI: 10.3233/JAD-220494

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 381-387, 2022

Authors: Ceresetti, Romain | Rouch, Isabelle | Laurent, Bernard | Getenet, Jean-Claude | Pommier, Morgane | de Chalvron, Stéphanie | Chainay, Hanna | Borg, Céline

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative pathology that disrupts processing of facial expressions of emotion. The impairment was demonstrated for negative emotions in tasks of matching, discriminating, and labeling facial expressions but no study has included the expression of pain in its protocol. Objective: The objective was to study the processing of emotional facial expressions in AD with a particular interest in pain expression. Methods: Twenty-seven controls, 15 mild AD patients, and 15 moderate AD patients had to perform four emotional tasks: identification of facial expressions, matching pain expressions, discriminating the intensity of pain expressions, …and judging pain intensity. Results: Some emotions were less efficiently recognized by AD patients compared to controls (p  < 0.001), specifically fear from the mild stage (p  < 0.05), pain and disgust from the moderate stage (p  < 0.05 and p  < 0.001 respectively). The Exploratory Factor Analysis showed that recognition of pain and recognition of other discreet emotions were underpinned by two different latent factors. Performances on pain expression matching task and pain intensity discrimination task did not differ by group. (p  = 0.334 and p  = 0.787 respectively). Finally, moderate AD patients judged the pain less intensively than the Control group for both, moderate, and severe pain intensity (p  < 0.001). Conclusion: Our data suggest that AD disrupts the recognition of pain expression along with recognition of fear and disgust. Additionally, AD patients seem to underestimate pain intensity compared to controls. The self-rated pain scales should be adapted to the pain processing deficit of AD patients. Show more

Keywords: Alzheimer’s disease, facial expression, identification of pain, pain intensity, painful faces

DOI: 10.3233/JAD-220236

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 389-398, 2022