Journal of Alzheimer's Disease - Volume 77, issue 4

Authors: Vila-Castelar, Clara | Guzmán-Vélez, Edmarie | Pardilla-Delgado, Enmanuelle | Buckley, Rachel F. | Bocanegra, Yamile | Baena, Ana | Fox-Fuller, Joshua T. | Tirado, Victoria | Muñoz, Claudia | Giraldo, Margarita | Acosta-Baena, Natalia | Rios-Romenets, Silvia | Langbaum, Jessica B. | Tariot, Pierre N. | Lopera, Francisco | Reiman, Eric M. | Quiroz, Yakeel T.

Article Type: Research Article

Abstract: Background: Growing evidence suggests that there may be a sex-specific biological risk for Alzheimer’s disease (AD). Individuals with autosomal dominant AD due to a mutation (E280A) in Presenilin-1 (PSEN1 ) are genetically determined to develop early-onset dementia and thus, have few age-related risk factors for AD that are known to vary by sex (i.e., cardiovascular disease, menopause, life expectancy). Objective: Investigate sex differences in markers of cognition and neurodegeneration in autosomal dominant AD. Methods: We conducted a retrospective study in 19 cognitively-unimpaired PSEN1 mutation carriers (age range 20–44; 11 females), 11 symptomatic carriers (age range …42–56; 8 females), and 23 matched non-carriers family members (age range 20–50; 13 females). We examined hippocampal volume ratio, CERAD Total Score, and CERAD Word List (i.e., Learning, Delayed Recall, and Recognition). Mann-Whitney U tests, Spearman correlations and regression models were conducted. Results: There were no differential associations between age, CERAD Total Score, CERAD Word List–Learning, Delayed Recall, Recognition, and hippocampal volume ratio in male and female carriers and non-carriers. Cognitively-unimpaired female carriers showed better CERAD Total scores and CERAD Word List-Learning than cognitively-unimpaired male carriers, despite having similar hippocampal volume ratios. The interaction of sex and hippocampal volume ratio did not predict cognitive performance across groups. Conclusion: Our preliminary findings suggest that cognitively-unimpaired female carriers showed a verbal memory reserve, and as disease progresses, female carriers did not exhibit a cognitive susceptibility to AD-related neurodegeneration. Future studies with larger samples of autosomal dominant AD are warranted to further understand sex differences in AD-related clinical and pathological markers. Show more

Keywords: Alzheimer’s disease, atrophy, cognition, familial Alzheimer’s disease, memory, sex

DOI: 10.3233/JAD-200723

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1743-1753, 2020

Authors: Pisano, Francesca | Caltagirone, Carlo | Satriano, Federica | Perri, Roberta | Fadda, Lucia | Marangolo, Paola

Article Type: Research Article

Abstract: Background: Recently, a growing body of evidence has shown that, from the early stage of impairment, Alzheimer’s patients (AD) present difficulties on a variety of tasks mostly relying on executive functions. These strongly impact their daily life activities causing a severe loss of independency and autonomy. Objective: To evaluate the efficacy of transpinal direct current stimulation (tsDCS) combined with cognitive trainings for improving attentional and executive function abilities in a group of AD patients. Methods: In a randomized-double blind design, sixteen AD patients underwent different cognitive trainings combined with tsDCS. During the treatment, each subject received …tsDCS (20 min, 2 mA) over the thoracic vertebrae (IX-X vertebrae) in two different conditions: 1) anodal, and 2) sham while performing three computerized tasks: alertness, selective attention, and executive functions. Each experimental condition was run in ten consecutive daily sessions over two weeks. Results: After anodal tsDCS, a greater improvement in executive functions compared to sham condition was found. More importantly, the follow-up testing revealed that these effects lasted over 1 month after the intervention and generalized to the different neuropsychological tests administered before, after the treatment and at one month after the end of the intervention. This generalization was present also in the attentional domain. Conclusion: This evidence emphasizes, for the first time, that tsDCS combined with cognitive training results efficacious for AD patients. We hypothesize that enhancing activity into the spinal sensorimotor pathways through stimulation improved cognitive abilities which rely on premotor activity, such as attention and executive functions. Show more

Keywords: Alzheimer’s disease, cognitive training, neuromodulation, transpinal stimulation, tsDCS

DOI: 10.3233/JAD-200695

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1755-1764, 2020

Authors: Holloway, Olivia G. | King, Anna E. | Ziebell, Jenna M.

Article Type: Research Article

Abstract: Background: Microglia are traditionally described as the immune cells of the brain and have an inflammatory role in Alzheimer’s disease (AD). Microglial morphological and phenotypic shifts in AD have not been fully characterized; however, microglia are often described as either pro- or anti-inflammatory. Objective: To determine microglial if microglial morphology and phenotype changes with disease status. Methods: This study observed morphology through Iba1 immunohistochemistry on tissue sections encompassing the primary motor cortex and somatosensory barrel fields. Immunohistochemistry for pro-inflammatory markers: CD14 and CD40; and anti-inflammatory markers: CD16 and TREM2, was performed at 3, 6, and 12 …months of age which correlated with pre-plaque, onset, and significant plaque load in APP/PS1 brains (n  = 6) and compared to age-matched littermate controls (n  = 6). Results: Microglia demonstrated a defined morphological shift with time. Deramified morphologies increased in the APP/PS1, at both 6 months (p  < 0.0001) and 12 months (p  < 0.0001). At 12 months, there were significantly lower numbers of ramified microglia (p  < 0.001). Results indicated that microglia have a heterogenic marker immunoreactivity as CD16, TREM2, and CD40 were associated with an activated morphology at the same time points. All inflammatory markers were significantly upregulated at 12 months in the APP/PS1 mice (TREM2 (F (2,30)   = 10.75, p  = 0.0003), CD40 (F (2,30)   = 15.86, p  < 0.0001), CD14 (F (2,30)   = 6.84, p  = 0.0036), and CD16 (F (2,30)   = 3.026, p  = 0.0635)). Conclusion: Our data indicate that pro- and anti-inflammatory factors of microglia occur in APP/PS1 mice. Show more

Keywords: Alzheimer’s disease, anti-inflammatory, microglia, morphology, phenotype, pro-inflammatory

DOI: 10.3233/JAD-200098

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1765-1781, 2020

Authors: Hulme, Bethany | Didikoglu, Altug | Bradburn, Steven | Robinson, Andrew | Canal, Maria | Payton, Antony | Pendleton, Neil | Murgatroyd, Chris

Article Type: Research Article

Abstract: Background: An early symptom of Alzheimer’s disease (AD) is a disturbance of the circadian rhythm that is associated with disrupted sleep/wake cycles. Objective: To investigate if BMAL1 , a key gene that drives the circadian cycle, is epigenetically regulated in brains in relation to longitudinal changes in cognition, sleep quality, and AD neuropathology. Methods: Frontal cortex tissues were acquired from the Manchester Brain Bank (N  = 96). DNA methylation at six CpG sites at the promoter of BMAL1 , determined using bisulfite pyrosequencing, was tested for associations with Braak stage, CERAD score and Thal phase, longitudinal changes …in cognition, sleep measurements and cross-section measures of depressive symptoms (BDI score). Results: Methylation across all the CpGs strongly correlated with each other. We found increased CpG2 methylation with higher Braak (t(92), p  = 0.015) and CERAD (t(94), p  = 0.044) stages. No significance was found between longitudinal fluid intelligence, processing speed and memory tests, but methylation at CpG1 (r  = 0.20, p  = 0.05) and CpG4 (r  = 0.20, p  = 0.05) positively correlated with vocabulary. CpG2 positively correlated with cross-sectional fluid intelligence (r  = 0.20 p  = 0.05) and vocabulary (r  = 0.22 p  = 0.03). Though longitudinal analysis revealed no significance between sleep duration, midsleep and efficiency for any of the CpG sites, CpG3 (B  = 0.03, 95% CI, p  = 0.03) and CpG5 (B  = 0.04, 95% CI, p  = 0.01) significantly correlated with night wake. CpG4 correlated with depressive symptoms (B  = –0.27, 95% CI, p  = 0.02). Conclusion: Methylation of BMAL1 associated with tau pathology, changes in cognitive measures, a measure of sleep and depressive symptoms, suggesting an involvement of the circadian cycle. Show more

Keywords: Alzheimer’s disease, BMAL1, circadian cycle, cognition, depressive symptoms, sleep quality

DOI: 10.3233/JAD-200634

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1783-1792, 2020

Authors: Smith, Patrick J. | Mabe, Stephanie M. | Sherwood, Andrew | Doraiswamy, P. Murali | Welsh-Bohmer, Kathleen A. | Burke, James R. | Kraus, William E. | Lin, Pao-Hwa | Browndyke, Jeffrey N. | Babyak, Michael A. | Hinderliter, Alan L. | Blumenthal, James A.

Article Type: Research Article

Abstract: Background: Previous studies have demonstrated that aerobic exercise (AE) and the Dietary Approaches to Stop Hypertension (DASH) diet can improve neurocognition. However, the mechanisms by which lifestyle improves neurocognition have not been widely studied. We examined the associations between changes in metabolic, neurotrophic, and inflammatory biomarkers with executive functioning among participants from the Exercise and Nutritional Interventions for Neurocognitive Health Enhancement (ENLIGHTEN) trial. Objective: To examine the association between changes in metabolic function and neurocognition among older adults with cognitive impairment, but without dementia (CIND) participating in a comprehensive lifestyle intervention. Methods: ENLIGHTEN participants were randomized …using a 2×2 factorial design to receive AE, DASH, both AE+DASH, or a health education control condition (HE) for six months. Metabolic biomarkers included insulin resistance (homeostatic model assessment [HOMA-IR]), leptin, and insulin-like growth factor (IGF-1); neurotrophic biomarkers included brain derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF); and inflammatory biomarkers included interleukin-6 (IL-6) and C-Reactive Protein (CRP). Results: Participants included 132 sedentary older adults (mean age = 65 [SD = 7]) with CIND. Results demonstrated that both AE (d  = 0.48, p  = 0.015) and DASH improved metabolic function (d  = 0.37, p  = 0.039), without comparable improvements in neurotrophic or inflammatory biomarkers. Greater improvements in metabolic function, including reduced HOMA-IR (B = –2.3 [–4.3, –0.2], p  = 0.033) and increased IGF-1 (B = 3.4 [1.2, 5.7 ], p  = 0.004), associated with increases in Executive Function. Conclusion: Changes in neurocognition after lifestyle modification are associated with improved metabolic function. Show more

Keywords: Aerobic exercise, CIND, DASH diet, executive function, lifestyle modification, metabolic function, vascular risk factors

DOI: 10.3233/JAD-200374

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1793-1803, 2020

Authors: Abdelnour, Carla | Esteban de Antonio, Ester | Pérez-Cordón, Alba | Lafuente, Asunción | Buendía, Mar | Pancho, Ana | Jofresa, Sara | Aguilera, Nuria | Ibarria, Marta | Cuevas, Rosario | Cañada, Laia | Calvet, Anna | Diego, Susana | González-Pérez, Antonio | Orellana, Adela | Montrreal, Laura | de Jorge, Laura | Marquié, Marta | Benaque, Alba | Gurruchaga, Miren | Tárraga, Lluís | Ruiz, Agustín | Boada, Mercè | For the Research Center and Memory Clinic, Fundació ACE

Collaborators: Isabel, Hernández | Montserrat, Alegret | Pilar, Cañabate | Isabel, Rodríguez | Maitee, Rosende-Roca | Juan Pablo, Tartari | Rogelio, López | Silvia, Gil | Liliana, Vargas | Ana, Mauleón | Ana, Espinosa | Gemma, Ortega | Angela, Sanabria | Emilio, Alarcón | Mariola, Moreno | Silvia, Preckler | Natalia, Roberto | Sergi, Valero | Itziar, de Rojas | Sonia, Moreno-Grau | Elvira, Martín

Article Type: Research Article

Abstract: Background: The COVID-19 pandemic has brought great disruption to health systems worldwide. This affected ongoing clinical research, particularly among those most vulnerable to the pandemic, like dementia patients. Fundació ACE is a research center and memory clinic based in Barcelona, Spain, one of the hardest-hit countries. Objective: To describe the ad-hoc strategic plan developed to cope with this crisis and to share its outcomes. Methods: We describe participants’ clinical and demographic features. Additionally, we explain our strategic plan aimed at minimizing the impact on clinical trial research activities, which included SARS-CoV-2 RT-PCR and IgG serological tests …to all participants and personnel. The outcomes of the plan are described in terms of observed safety events and drop-outs during the study period. Results: A total of 130 patients were participating in 16 active clinical trials in Fundació ACE when the lockdown was established. During the confinement, we performed 1018 calls to the participants, which led to identify adverse events in 26 and COVID-19 symptoms in 6. A total of 83 patients (64%) could restart on-site visits as early as May 11, 2020. All SARS-CoV-2 RT-PCR diagnostic tests performed before on-site visits were negative and only three IgG serological tests were positive. Throughout the study period, we only observed one drop-out, due to an adverse event unrelated to COVID-19. Discussion: The plan implemented by Fundació ACE was able to preserve safety and integrity of ongoing clinical trials. We must use the lessons learned from the pandemic and design crisis-proof protocols for clinical trials. Show more

Keywords: Alzheimer’s disease, clinical trials, coronavirus, pandemics, telemedicine

DOI: 10.3233/JAD-200750

Citation: Journal of Alzheimer's Disease, vol. 77, no. 4, pp. 1805-1813, 2020