Journal of Alzheimer's Disease - Volume 95, issue 3

Authors: Cody, Shameka L. | Miller, Gabe H. | Fazeli, Pariya L. | Wang, Ge | Li, Wei | Goodin, Burel R. | Vance, David E.

Article Type: Review Article

Abstract: Mild to moderate forms of neurocognitive impairment persist among people living with HIV (PLWH), despite being virally suppressed on antiretroviral therapy. PLWH are disproportionally impacted by physiological and psychosocial comorbidities compared to those without HIV. As adults live longer with HIV, the neurocognitive burden of physiological and psychosocial stressors can impair everyday functioning and may contribute to the development of neurodegenerative diseases such as Alzheimer’s disease. This article outlines neurocognitive consequences of everyday stressors in PLWH. While some lifestyle factors can exacerbate inflammatory processes and promote negative neurocognitive health, novel interventions including the use of cannabinoids may be neuroprotective for …aging PLWH who are at risk for elevated levels of inflammation from comorbidities. Studies of integrated neurocognitive rehabilitation strategies targeting lifestyle factors are promising for improving neurocognitive health, and may over time, reduce the risk of Alzheimer’s disease in PLWH. Show more

Keywords: Aging, Alzheimer’s disease, HIV, neurocognitive impairment, neuroinflammation

DOI: 10.3233/JAD-230203

Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 753-768, 2023

Authors: Sharma, Sneha R. | Chen, Yu

Article Type: Review Article

Abstract: Rheumatoid arthritis (RA) is hypothesized to be associated with cognitive impairment and dementia, including Alzheimer’s disease, through shared biological processes related to inflammation. It is important to elucidate this potential relationship as both conditions confer increased morbidity and even mortality among older adults. This narrative review provides a survey of recent epidemiologic studies, examining the association between rheumatoid arthritis and either dementia or cognitive impairment. Sixteen studies were included after searching in PubMed and EMBASE. All were published between 2012 and 2022 and were characterized as epidemiologic studies (either cohort, cross-sectional, or case-control). Studies varied in location, design, measures of …exposure and outcome, and covariates considered. Of the 16 studies included, only five found statistically significant positive associations between RA and dementia or cognitive impairment. One study found an inverse relationship, while five studies found no associations at all. The remaining five studies found variable statistically significant associations between demographic or RA disease characteristics and cognitive measures. Given these mixed findings, further studies at both the mechanistic and population level are needed to clarify the possible shared biological underpinnings of these two conditions. Show more

Keywords: Aging, Alzheimer’s disease, cognition, dementia, rheumatoid arthritis

DOI: 10.3233/JAD-230234

Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 769-783, 2023

Authors: Wu, Yingying | Eisel, Ulrich L.M.

Article Type: Review Article

Abstract: Microglia and astrocytes are regarded as active participants in the central nervous system under various neuropathological conditions, including Alzheimer’s disease (AD). Both microglia and astrocyte activation have been reported to occur with a spatially and temporarily distinct pattern. Acting as a double-edged sword, glia-mediated neuroinflammation may be both detrimental and beneficial to the brain. In a variety of neuropathologies, microglia are activated before astrocytes, which facilitates astrocyte activation. Yet reactive astrocytes can also prevent the activation of adjacent microglia in addition to helping them become activated. Studies describe changes in the genetic profile as well as cellular and molecular responses …of these two types of glial cells that contribute to dysfunctional immune crosstalk in AD. In this paper, we construct current knowledge of microglia-astrocyte communication, highlighting the multifaceted functions of microglia and astrocytes and their role in AD. A thorough comprehension of microglia-astrocyte communication could hasten the creation of novel AD treatment approaches. Show more

Keywords: Alzheimer’s disease, astrocyte, cellular crosstalk, microglia, neuroinflammation

DOI: 10.3233/JAD-230199

Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 785-803, 2023

Authors: Sattarov, Roman | Toresson, Håkan | Orbjörn, Camilla | Mattsson-Carlgren, Niklas

Article Type: Systematic Review

Abstract: Background: Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder without a cure. Innovative disease models, such as induced neurons (iNs), could enhance our understanding of AD mechanisms and accelerate treatment development. However, a review of AD human iN studies is necessary to consolidate knowledge. Objective: The objective of this review is to examine the current body of literature on AD human iN cells and provide an overview of the findings to date. Methods: We searched two databases for relevant studies published between 2010 and 2023, identifying nine studies meeting our criteria. Results: Reviewed studies …indicate the feasibility of generating iNs directly from AD patients’ fibroblasts using chemical induction or viral vectors. These cells express mature neuronal markers, including MAP-2, NeuN, synapsin, and tau. However, most studies were limited in sample size and primarily focused on autosomal dominant familial AD (FAD) rather than the more common sporadic forms of AD. Several studies indicated that iNs derived from FAD fibroblasts exhibited abnormal amyloid-β metabolism, a characteristic feature of AD in humans. Additionally, elevated levels of hyperphosphorylated tau, another hallmark of AD, were reported in some studies. Conclusion: Although only a limited number of small-scale studies are currently available, AD patient-derived iNs hold promise as a valuable model for investigating AD pathogenesis. Future research should aim to conduct larger studies, particularly focusing on sporadic AD cases, to enhance the clinical relevance of the findings for the broader AD patient population. Moreover, these cells can be utilized in screening potential novel treatments for AD. Show more

Keywords: Adult human dermal fibroblasts, Alzheimer’s disease, amyloid-β , APOE , APP , familial Alzheimer’s disease, human induced-neurons, sporadic Alzheimer’s disease, tau

DOI: 10.3233/JAD-230119

Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 805-828, 2023

Authors: Pozzi, Federico Emanuele | Appollonio, Ildebrando | Ferrarese, Carlo | Tremolizzo, Lucio

Article Type: Systematic Review

Abstract: Background: Traditional board games can entail significant skills encompassing several cognitive functions across different domains. Therefore, they may potentially represent effective cognitive interventions in the aging population with or without Alzheimer’s disease or other types of dementia. Objective: We aimed at verifying the hypothesis that traditional board games can prevent or slow down cognitive decline, through a systematic review on traditional board games and dementia. Methods: We searched five databases with tailored search strings. We included studies assessing the impact of board games on elderly subjects at risk of or suffering from cognitive …impairment, or subjects with cognitive impairment irrespective of age. Studies where the effect of board games was not separated by cards or other games were excluded. A meta-analysis was performed for specific cognitive and non-cognitive outcomes. Results: Board games improved mental function, as measured by Montreal Cognitive Assessment (p  = 0.003) and Mini-Mental State Examination (p  = 0.02). Ska and Go improved Trail Making Test –A, while Mahjong improved executive functions. There was no consistent effect across different games on Digit Span or Categorical Fluency. Chess improved quality of life measured with the WHO-QoL-OLD scale (p  < 0.00001). Mahjong temporarily improved depressive symptoms. Go increased BDNF levels and left middle temporal gyrus and bilateral putamen metabolism. Conclusions: Traditional board games may slow global cognitive decline and improve the quality of life in elderly subjects. Different games have varying impacts on specific cognitive domains, possibly mediated by functional and biological factors. Show more

Keywords: Alzheimer’s disease, cognition, dementia, primary prevention, recreational games, secondary prevention, systematic review, tertiary prevention

DOI: 10.3233/JAD-230473

Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 829-845, 2023

Authors: Alam, Rifat B. | Rahman, Abir | Aguiñaga, Susan | Schwingel, Andiara

Article Type: Short Communication

Abstract: This study examined ethnic/racial influences on the relationship of cognitive performance and functional abilities of 2,713 older individuals from the National Health and Nutrition Examination Survey (NHANES). Functional domains included activities of daily living (ADL), instrumental ADL, and leisure and social activities. In adjusted logistic regression models, low cognitive performance as assessed by the Digit Symbol Substitution Test was found significantly associated with functional limitation in each domain. However, moderation analysis revealed that being Hispanic and non-Hispanic Black may weaken this association demonstrating protective effects of underrepresented ethnic/racial status. Future studies should investigate perceived discrimination and resilience.

Keywords: Alzheimer’s disease, cognitive performance, dementia, functional limitation, racial disparities, resilience

DOI: 10.3233/JAD-220814

Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 847-854, 2023

Authors: Heidarzadeh, Neda | Ratté, Sylvie

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disease that results in cognitive decline, dementia, and eventually death. Diagnosing early signs of AD can help clinicians to improve the quality of life. Objective: We developed a non-invasive approach to help neurologists and clinicians to distinguish probable AD patients and healthy controls (HC). Methods: The patients’ gaze points were followed based on the words they used to describe the Cookie Theft (CT) picture description task. We hypothesized that the timing of words enunciation aligns with the participant’s eye movements. The moments that each word was spoken were …then aligned with specific regions of the image. We then applied machine learning algorithms to classify probable AD and HC. We randomly selected 60 participants (30 AD and 30 HC) from the Dementia Bank (Pitt Corpus). Results: Five main classifiers were applied to different features extracted from the recorded audio and participants’ transcripts (AD and HC). Support vector machine and logistic regression had the highest accuracy (up to 80% and 78.33%, respectively) in three different experiments. Conclusions: In conclusion, point-of-gaze can be applied as a non-invasive and less expensive approach compared to other available methods (e.g., eye tracker devices) for early-stage AD diagnosis. Show more

Keywords: Alzheimer’s disease, classification, cookie theft picture description task, eye movement, machine learning, non-invasive, point-of-gaze

DOI: 10.3233/JAD-220711

Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 855-868, 2023

Authors: Bei, Jiani | Miranda-Morales, Ernesto G. | Gan, Qini | Qiu, Yuan | Husseinzadeh, Sorosh | Liew, Jia Yi | Chang, Qing | Krishnan, Balaji | Gaitas, Angelo | Yuan, Subo | Felicella, Michelle | Qiu, Wei Qiao | Fang, Xiang | Gong, Bin

Article Type: Research Article

Abstract: Background: Blood-brain barrier (BBB) breakdown is a crucial aspect of Alzheimer’s disease (AD) progression. Dysfunction in BBB is primarily caused by impaired tight junction and adherens junction proteins in brain microvascular endothelial cells (BMECs). The role of adherens junctions in AD-related BBB dysfunction remains unclear. Exosomes from senescent cells have unique characteristics and contribute to modulating the phenotype of recipient cells. However, it remains unknown if and how these exosomes cause BMEC dysfunction in AD. Objective: This study aimed to investigate the impact of AD circulating exosomes on brain endothelial dysfunction. Methods: Exosomes were isolated from …sera of AD patients and age- and sex-matched cognitively normal controls using size-exclusion chromatography. The study measured the biomechanical nature of BMECs’ endothelial barrier, the lateral binding forces between live BMECs. Paracellular expressions of the key adherens junction protein vascular endothelial (VE)-cadherin were visualized in BMEC cultures and a 3D BBB model using human BMECs and pericytes. VE-cadherin signals were also examined in brain tissues from AD patients and normal controls. Results: Circulating exosomes from AD patients reduced VE-cadherin expression levels and impaired barrier function in recipient BMECs. Immunostaining analysis demonstrated that AD exosomes damaged VE-cadherin integrity in a 3D microvascular tubule formation model. The study found that AD exosomes weakened BBB integrity depending on their RNA content. Additionally, diminished microvascular VE-cadherin expression was observed in AD brains compared to controls. Conclusion: These findings highlight the significant role of circulating exosomes from AD patients in damaging adherens junctions of recipient BMECs, dependent on exosomal RNA. Show more

Keywords: Alzheimer’s disease, blood-brain barrier, 3D microvascular model, exosome, endothelial barrier dysfunction, fluidic AFM, VE-cadherin

DOI: 10.3233/JAD-230347

Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 869-885, 2023

Authors: Rognoni, Teresa | Fernández-Matarrubia, Marta | Martinez-González, Miguel Ángel | Salas-Salvadó, Jordi | Corella, Dolores | Castañer, Olga | Martínez, J. Alfredo | Alonso-Gómez, Ángel M. | Gómez-Gracia, Enrique | Vioque, Jesús | Romaguera, Dora | López-Miranda, José | Estruch, Ramón | Tinahones, Francisco J. | Santos-Lozano, José Manuel | Serra-Majem, Lluis | Cano Ibañez, Naomi | Tur, Josep A. | Micó Pérez, Rafael | Pintó, Xavier | Delgado-Rodríguez, Miguel | Ortiz Ramos, María | Vidal, Josep | Vázquez, Clotilde | Daimiel, Lidia | Ros, Emilio | Goñi-Ruiz, Nuria | Babio, Nancy | Sorlí, José V. | Schröder, Helmut | García-Rios, Antonio | Compañ-Gabucio, Laura | Warnberg, Julia | Zulet, M. Ángeles | Chaplin, Alice | Sacanella, Emilio | Bouzalmate-Hajjaj, Amira | Tojal-Sierra, Lucas | Damas-Fuentes, Miguel | Vázquez, Zenaida | Gómez-Martínez, Carlos | Saiz, Carmen | Malcampo, Mireia | Ortiz-Morales, Ana M. | Martínez-Avilés, Vanessa | García-Gavilan, Jesús | Abete, Itziar | Fitó, Montserrat | Toledo, Estefanía

Article Type: Research Article

Abstract: Background: It has been proposed that physical activity (PA) could prevent cognitive decline. Objective: To evaluate the association between changes in PA and changes in cognitive function in a cohort of adults with metabolic syndrome. Methods: Longitudinal observational study including 5,500 adults (mean age 65 years, SD = 5; women = 49.3% ) with metabolic syndrome. Participants underwent physical activity measurements and cognitive evaluation at baseline and at two-years of follow-up. PA was quantified using the Minnesota questionnaire-shortened version. Cognitive function was evaluated using a battery of tests: Mini-Mental Test Examination, Clock Drawing Test, Trail Making Test A and B, …Verbal Fluency Test, and Digit Span. The primary outcome was two-year change in cognition, measured through the Global Composite Score (GCS) of all neuropsychological tests. Multivariable-adjusted linear regression models were fitted with baseline PA and their changes as the main exposures and changes in cognitive function as the outcome. Results: No significant association was found between PA levels (or their changes) in the GCS of cognitive function. A greater increase in PA levels was associated with a more favorable two-year change in the Trail Making Test A (Q4 versus Q1: b  = – 2.24s, 95% CI –4.36 to –0.12s; p- trend = 0.020). No significant association was found for other neuropsychological test. Conclusion: Our results do not support an association between increases in PA and the evolution of the global cognitive function at two-year in an intervention trial which included PA promotion in one of its two randomized arms, but they suggested a possible beneficial effect of PA on attentional function in older adults. Show more

Keywords: Alzheimer’s disease, cognitive function, dementia, metabolic syndrome, physical activity, prevention

DOI: 10.3233/JAD-230105

Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 887-899, 2023

Authors: Wang, Rumi | Kuang, Chen | Guo, Chengyu | Chen, Yong | Li, Canyang | Matsumura, Yoshihiro | Ishimaru, Masashi | Van Pelt, Alice J. | Chen, Fei

Article Type: Research Article

Abstract: Background: To date, the reliable detection of mild cognitive impairment (MCI) remains a significant challenge for clinicians. Very few studies investigated the sensitivity of acoustic features in detecting Mandarin-speaking elders at risk for MCI, defined as “putative MCI” (pMCI). Objective: This study sought to investigate the possibility of using automatically extracted speech acoustic features to detect elderly people with pMCI and reveal the potential acoustic markers of cognitive decline at an early stage. Methods: Forty-one older adults with pMCI and 41 healthy elderly controls completed four reading tasks (syllable utterance, tongue twister, diadochokinesis, and short sentence …reading), from which acoustic features were extracted automatically to train machine learning classifiers. Correlation analysis was employed to evaluate the relationship between classifier predictions and participants’ cognitive ability measured by Mini-Mental State Examination 2. Results: Classification results revealed that some temporal features (e.g., speech rate, utterance duration, and the number of silent pauses), spectral features (e.g., variability of F1 and F2), and energy features (e.g., SD of peak intensity and SD of intensity range) were effective predictors of pMCI. The best classification result was achieved in the Random Forest classifier (accuracy = 0.81, AUC = 0.81). Correlation analysis uncovered a strong negative correlation between participants’ cognitive test scores and the probability estimates of pMCI in the Random Forest classifier, and a modest negative correlation in the Support Vector Machine classifier. Conclusions: The automatic acoustic analysis of speech could provide a promising non-invasive way to assess and monitor the early cognitive decline in Mandarin-speaking elders. Show more

Keywords: Alzheimer’s disease, machine learning, Mandarin, mild cognitive impairment, speech

DOI: 10.3233/JAD-230373

Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 901-914, 2023