Journal of Alzheimer's Disease - Volume 88, issue 4

Authors: Agüera-Ortiz, Luis | Babulal, Ganesh M. | Bruneau, Marie-Andrée | Creese, Byron | D’Antonio, Fabrizia | Fischer, Corinne E. | Gatchel, Jennifer R. | Ismail, Zahinoor | Kumar, Sanjeev | McGeown, William J. | Mortby, Moyra E. | Nuñez, Nicolas A. | de Oliveira, Fabricio F. | Pereiro, Arturo X. | Ravona-Springer, Ramit | Rouse, Hillary J. | Wang, Huali | Lanctôt, Krista L.

Article Type: Review Article

Abstract: Psychotic phenomena are among the most severe and disruptive symptoms of dementias and appear in 30% to 50% of patients. They are associated with a worse evolution and great suffering to patients and caregivers. Their current treatments obtain limited results and are not free of adverse effects, which are sometimes serious. It is therefore crucial to develop new treatments that can improve this situation. We review available data that could enlighten the future design of clinical trials with psychosis in dementia as main target. Along with an explanation of its prevalence in the common diseases that cause dementia, we present …proposals aimed at improving the definition of symptoms and what should be included and excluded in clinical trials. A review of the available information regarding the neurobiological basis of symptoms, in terms of pathology, neuroimaging, and genomics, is provided as a guide towards new therapeutic targets. The correct evaluation of symptoms is transcendental in any therapeutic trial and these aspects are extensively addressed. Finally, a critical overview of existing pharmacological and non-pharmacological treatments is made, revealing the unmet needs, in terms of efficacy and safety. Our work emphasizes the need for better definition and measurement of psychotic symptoms in dementias in order to highlight their differences with symptoms that appear in non-dementing diseases such as schizophrenia. Advances in neurobiology should illuminate the development of new, more effective and safer molecules for which this review can serve as a roadmap in the design of future clinical trials. Show more

Keywords: Clinical trials, dementia, delusions, hallucinations, investigational therapies, psychotic disorders

DOI: 10.3233/JAD-215483

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1203-1228, 2022

Authors: Turnbull, Adam | Kaplan, Robert M. | Adeli, Ehsan | Lin, Feng V.

Article Type: Review Article

Abstract: Brain aging leads to difficulties in functional independence. Mitigating these difficulties can benefit from technology that predicts, monitors, and modifies brain aging. Translational research prioritizes solutions that can be causally linked to specific pathophysiologies at the same time as demonstrating improvements in impactful real-world outcome measures. This poses a challenge for brain aging technology that needs to address the tension between mechanism-driven precision and clinical relevance. In the current opinion, by synthesizing emerging mechanistic, translational, and clinical research-related frameworks, and our own development of technology-driven brain aging research, we suggest incorporating the appreciation of four desiderata (causality, informativeness, transferability, and …fairness) of explainability into early-stage research that designs and tests brain aging technology. We apply a series of work on electrocardiography-based “peripheral” neuroplasticity markers from our work as an illustration of our proposed approach. We believe this novel approach will promote the development and adoption of brain aging technology that links and addresses brain pathophysiology and functional independence in the field of translational research. Show more

Keywords: Artificial intelligence, brain aging, explainability, technology, translational research

DOI: 10.3233/JAD-220441

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1229-1239, 2022

Authors: Plantone, Domenico | Pardini, Matteo | Locci, Sara | Nobili, Flavio | De Stefano, Nicola

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) represents the most common type of neurodegenerative dementia and is characterized by extracellular amyloid-β (Aβ) deposition, pathologic intracellular tau protein tangles, and neuronal loss. Increasing evidence has been accumulating over the past years, supporting a pivotal role of inflammation in the pathogenesis of AD. Microglia, monocytes, astrocytes, and neurons have been shown to play a major role in AD-associated inflammation. However recent studies showed that the role of both T and B lymphocytes may be important. In particular, B lymphocytes are the cornerstone of humoral immunity, they constitute a heterogenous population of immune cells, being their mature …subsets significantly impacted by the inflammatory milieu. The role of B lymphocytes on AD pathogenesis is gaining interest for several reasons. Indeed, the majority of elderly people develop the process of “inflammaging”, which is characterized by increased blood levels of proinflammatory molecules associated with an elevated susceptibility to chronic diseases. Epitope-specific alteration pattern of naturally occurring antibodies targeting the amino-terminus and the mid-domain of Aβ in both plasma and cerebrospinal fluid has been described in AD patients. Moreover, a possible therapeutic role of B lymphocytes depletion was recently demonstrated in murine AD models. Interestingly, active immunization against Aβ and tau, one of the main therapeutic strategies under investigation, depend on B lymphocytes. Finally. several molecules being tested in AD clinical trials can modify the homeostasis of B cells. This review summarizes the evidence supporting the role of B lymphocytes in AD from the pathogenesis to the possible therapeutic implications. Show more

Keywords: Aging, Alzheimer’s disease, amyloid beta-peptides, B-lymphocytes, vaccination

DOI: 10.3233/JAD-220261

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1241-1262, 2022

Authors: Li, Hui | Su, Wenlong | Dang, Hui | Han, Kaiyue | Lu, Haitao | Yue, Shouwei | Zhang, Hao

Article Type: Systematic Review

Abstract: Background: The prevalence of mild cognitive impairment (MCI) continues to increase due to population aging. Exercise has been a supporting health strategy that may elicit beneficial effects on cognitive function and prevent dementia. Objective: This study aimed to examine the effects of aerobic, resistance, and multimodal exercise training on cognition in adults aged > 60 years with MCI. Methods: We searched the Cochrane Library, PubMed, and Embase databases and ClinicalTrials.gov (https://clinicaltrials.gov ) up to November 2021, with no language restrictions. We included all published randomized controlled trials (RCTs) comparing the effect of exercise programs on cognitive function …with any other active intervention or no intervention in participants with MCI aged > 60 years. Results: Twelve RCTs were included in this review. Meta-analysis results revealed significant improvements in resistance training on measures of executive function (p  < 0.05) and attention (p  < 0.05); no significant differences were observed between aerobic exercise and controls on any of the cognitive comparisons. Conclusion: Exercise training had a small beneficial effect on executive function and attention in older adults with MCI. Larger studies are required to examine the effects of exercise and the possible moderators. Show more

Keywords: Aged, exercise, meta-analysis, mild cognitive impairment, systematic review

DOI: 10.3233/JAD-220243

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1263-1278, 2022

Authors: Krance, Saffire H. | Wu, Che-Yuan | Chan, Alison C.Y. | Kwong, Stephanie | Song, Bing Xin | Xiong, Lisa Y. | Ouk, Michael | Chen, Ming Hui | Zhang, Jane | Yung, Adrian | Stanley, Meagan | Herrmann, Nathan | Lanctôt, Krista L. | Swardfager, Walter

Article Type: Systematic Review

Abstract: Background: The endosomal-lysosomal and autophagy (ELA) pathway may be implicated in the progression of Alzheimer’s disease (AD); however, findings thus far have been inconsistent. Objective: To systematically summarize differences in endosomal-lysosomal and autophagy proteins in the cerebrospinal fluid (CSF) of people with AD and healthy controls (HC). Methods: Studies measuring CSF concentrations of relevant proteins in the ELA pathway in AD and healthy controls were included. Standardized mean differences (SMD) with 95% confidence intervals (CI) between AD and healthy controls in CSF concentrations of relevant proteins were meta-analyzed using random-effects models. Results: Of 2,471 …unique studies, 43 studies were included in the systematic review and meta-analysis. Differences in ELA protein levels in the CSF between AD and healthy controls were observed, particularly in lysosomal membrane (LAMP-1: NAD /NHC  = 348/381, SMD [95% CI] = 0.599 [0.268, 0.930], I2  = 72.8%; LAMP-2: NAD /NHC  = 401/510, SMD [95% CI] = 0.480 [0.134, 0.826], I2  = 78.7%) and intra-lysosomal proteins (GM2A: NAD /NHC  = 390/420, SMD [95% CI] = 0.496 [0.039, 0.954], I2  = 87.7%; CTSB: NAD /NHC  = 485/443, SMD [95% CI] = 0.201 [0.029, 0.374], I2  = 28.5%; CTSZ: NAD /NHC  = 535/820, SMD [95% CI] = –0.160 [–0.305, –0.015], I2  = 24.0%) and in proteins involved in endocytosis (AP2B1:NAD /NHC  = 171/205, SMD [95% CI] = 0.513 [0.259, 0.768], I2  = 27.4%; FLOT1: NAD /NHC  = 41/45, SMD [95% CI] = –0.489 [–0.919, –0.058], I2 <0.01). LC3B, an autophagy marker, also showed a difference (NAD /NHC  = 70/59, SMD [95% CI] = 0.648 [0.180, 1.116], I2  = 38.3%)), but overall there was limited evidence suggesting differences in proteins involved in endosomal function and autophagy. Conclusion: Dysregulation of proteins in the ELA pathway may play an important role in AD pathogenesis. Some proteins within this pathway may be potential biomarkers for AD. Show more

Keywords: Alzheimer’s disease, autophagy, biomarkers, dementia, endosomes, lysosomes, meta-analysis, proteins, systematic review

DOI: 10.3233/JAD-220360

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1279-1292, 2022

Authors: Mohamad Asfia, Siti Khadijah Binti | Bucholc, Jessica | McCaffrey, Nikki | Mihalopoulos, Cathrine | Muldowney, Anne | Engel, Lidia

Article Type: Systematic Review

Abstract: Background: There is currently a lack of a comprehensive review identifying the broad scope of factors that impact quality of life (QoL) of informal carers of people with dementia in order to validate existing measures and inform the provision of support services for carers of people with dementia that impact QoL domains important to them. Objective: To explore and identify QoL impacts on informal carers from providing care to people with dementia. Methods: A systematic review was conducted across four databases: EMBASE, CINAHL, PsychINFO, and Medline. Eligible studies consisted of published, peer-reviewed, qualitative studies focusing on …lived experiences of informal carers of people with dementia. Non-English studies and quantitative studies were excluded. Screening of included studies was conducted independently by three reviewers. A “best-fit” framework synthesis was used to combine the qualitative data, applying deductive and inductive analysis techniques. Quality assessment was conducted using the Critical Appraisal Skills Programme. Results: Of the 4,251 articles identified, 59 articles were included. Five main themes pertaining to QoL aspects were identified that included coping (emotion-coping and problem-coping), relationship with the person with dementia (sense of loss and change in relationship), support (formal support and informal support), interference with life (control over caring situation, and freedom and independence), and health (physical health, emotional and mental health, and social health). Conclusion: This study identified domains of QoL that are impacted by providing informal care to people living with dementia, offering a conceptual framework for instrument validation and development as well as guidance for service provision. Show more

Keywords: Caregivers, dementia, qualitative research, quality of life, review

DOI: 10.3233/JAD-220219

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1293-1309, 2022

Authors: Luo, Anling | Ning, Pingping | Lu, Haitao | Huang, Hongyan | Shen, Qiuyan | Zhang, Dan | Xu, Fang | Yang, Li | Xu, Yanming

Article Type: Systematic Review

Abstract: Background: As one of the widely used drugs for the management of type 2 diabetes mellites (T2DM), metformin is increasingly believed to delay cognitive deterioration and therapeutically for Alzheimer’s disease (AD) patients especially those with T2DM. However, studies of the potential neuroprotective effects of metformin in AD patients have reported contradictory results. Objective: This study aimed to evaluate the association between metformin and the risk of developing AD. Methods: We systematically searched the PubMed, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases to identify clinical observational studies on the relationship between …AD risk and metformin use published before December 20, 2021. Two investigators independently screened records, extracted data, and assessed the quality of the studies. Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated using random-effect models. Results: After screening a total of 1,670 records, we included 10 studies involving 229,110 participants. The meta-analysis showed no significant association between AD incidence and metformin exposure (OR 1.17, 95% CI 0.88–1.56, p  = 0.291). However, subgroup analysis showed that among Asians, the risk of AD was significantly higher among metformin users than those who did not (OR 1.71, 95% CI 1.24–2.37, p  = 0.001). Conclusion: The available evidence does not support the idea that metformin reduces risk of AD, and it may, in fact, increase the risk in Asians. Further well-designed randomized controlled trials are required to understand the role played by metformin and other antidiabetic drugs in the prevention of AD and other neurodegenerative diseases. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, meta-analysis, metformin

DOI: 10.3233/JAD-220180

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1311-1323, 2022

Authors: Almulla, Abbas F. | Supasitthumrong, Thitiporn | Amrapala, Arisara | Tunvirachaisakul, Chavit | Jaleel, Al-Karrar Kais Abdul | Oxenkrug, Gregory | Al-Hakeim, Hussein K. | Maes, Michael

Article Type: Systematic Review

Abstract: Background: Alzheimer’s disease (AD), which is characterized by progressive brain dysfunction and memory loss, is one of the most significant global health concerns for older adults. Neuroinflammation and increased oxidative stress contribute to the pathophysiology of AD, thereby presumably inducing tryptophan (TRP) degradation through the TRP catabolite (TRYCAT) pathway. Objective: To delineate the activity of the TRYCAT pathway along with levels of TRP and tryptophan catabolites (TRYCATs) in AD patients. Methods: We used PubMed, Google Scholar, Web of Science, and SciFinder during the month of January 2022 to gather the pertinent publications. We found 19 eligible …articles which involved 738 patients and 665 healthy controls. Results: Our results revealed a significant difference (p  = 0.008) in the kynurenine (KYN)/TRP ratio (standardized mean difference, SMD = 0.216, 95% confidence interval, CI: 0.057; 0.376), and a significant decrease in TRP in AD patients (SMD = –0.520, 95% CI: –0.738; –0.302, p  < 0.0001). Moreover, we also found a significant increase in the central nervous system (CNS), brain, and cerebrospinal fluid kynurenic acid (KA)/KYN ratio but not in peripheral blood, as well as a significant decrease in plasma KA and xanthurenic acid in the CNS and blood. Conclusion: AD is characterized by TRP depletion but not by an overactivity of the TRYCAT pathway. IDO-induced production of neurotoxic TRYCATs is not a key factor in the pathophysiology of AD. Show more

Keywords: Biomarkers, inflammation, kynurenine, neuro-immune, oxidative stress, psychiatry

DOI: 10.3233/JAD-220295

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1325-1339, 2022

Authors: Papaioannou, Themis | Voinescu, Alexandra | Petrini, Karin | Stanton Fraser, Danaë

Article Type: Systematic Review

Abstract: Background: Mild cognitive impairment (MCI) and dementia result in cognitive decline which can negatively impact everyday functional abilities and quality of life. Virtual reality (VR) interventions could benefit the cognitive abilities of people with MCI and dementia, but evidence is inconclusive. Objective: To investigate the efficacy of VR training on global and domain-specific cognition, activities of daily living and quality of life. To explore the influence of priori moderators (e.g., immersion type, training type) on the effects of VR training. Adverse effects of VR training were also considered. Methods: A systematic literature search was conducted on …all major databases for randomized control trial studies. Two separate meta-analyses were performed on studies with people with MCI and dementia. Results: Sixteen studies with people with MCI and four studies with people with dementia were included in each meta-analysis. Results showed moderate to large effects of VR training on global cognition, attention, memory, and construction and motor performance in people with MCI. Immersion and training type were found to be significant moderators of the effect of VR training on global cognition. For people with dementia, results showed moderate to large improvements after VR training on global cognition, memory, and executive function, but a subgroup analysis was not possible. Conclusion: Our findings suggest that VR training is an effective treatment for both people with MCI and dementia. These results contribute to the establishment of practical guidelines for VR interventions for patients with cognitive decline. Show more

Keywords: Cognition, cognitive rehabilitation, cognitive training, dementia, mild cognitive impairment, virtual reality

DOI: 10.3233/JAD-210672

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1341-1370, 2022

Authors: Han, Sang-Won | Park, Young Ho | Jang, Eun Sun | Nho, Kwangsik | Kim, SangYun

Article Type: Short Communication

Abstract: To investigate an association of serum liver enzymes with Alzheimer’s disease (AD) diagnosis and cognitive performance, we performed logistic and linear regression analyses in 781 patients with AD and 405 cognitively normal subjects. We found that alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels had significant positive associations with cognitive performance and were significantly decreased in AD patients. The alkaline phosphatase level and AST to ALT ratio were significantly negatively associated with cognitive performance and were significantly increased in AD patients. This suggests that these liver enzymes might be implicated in the pathogenesis of AD.

Keywords: Alzheimer’s disease, cognition, liver enzymes, neuropsychological assessment

DOI: 10.3233/JAD-220343

Citation: Journal of Alzheimer's Disease, vol. 88, no. 4, pp. 1371-1376, 2022