Journal of Alzheimer's Disease - Volume 73, issue 2

Authors: Zuelsdorff, Megan | Okonkwo, Ozioma C. | Norton, Derek | Barnes, Lisa L. | Graham, Karen L. | Clark, Lindsay R. | Wyman, Mary F. | Benton, Susan F. | Gee, Alexander | Lambrou, Nickolas | Johnson, Sterling C. | Gleason, Carey E.

Article Type: Research Article

Abstract: Background: It is well-documented that African Americans have elevated risk for cognitive impairment and dementia in late life, but reasons for the racial disparities remain unknown. Stress processes have been linked to premature age-related morbidity, including Alzheimer’s and related dementias (ADRD), and plausibly contribute to social disparities in cognitive aging. Objective: We examined the relationship between stressful life events and cognitive decline among African American and White participants enrolled in the Wisconsin Registry for Alzheimer’s Prevention (WRAP). Methods: Linear mixed models including demographic, literacy, and health-related covariates were used to estimate (1) relationships between a life …event index score and decline in cognitive test performance in two domains of executive function (Speed & Flexibility, Working Memory) and one domain of episodic memory (Verbal Learning & Memory) among 1,241 WRAP enrollees, stratified by race, and (2) contributions of stressful life events to racial differences in cognition within the full sample. Results: African Americans (N = 50) reported more stressful life events than Whites (N = 1,191). Higher stress scores associated with poorer Speed & Flexibility performance in both groups, though not with declines across time, and partially explained racial differentials in this domain. Among African Americans only, stressor exposure also associated with age-related decline in Verbal Learning & Memory. Stressor-cognition relationships were independent of literacy and health-related variables. Conclusions: Greater lifetime stress predicted poorer later-life cognition, and, in a small sample of African Americans, faster declines in a key domain of episodic memory. These preliminary findings suggest that future work in large minority aging cohorts should explore stress as an important source of modifiable, socially-rooted risk for impairment and ADRD in African Americans, who are disproportionately exposed to adverse experiences across the life course. Show more

Keywords: African Americans, Alzheimer’s disease, life course, stress

DOI: 10.3233/JAD-190439

Citation: Journal of Alzheimer's Disease, vol. 73, no. 2, pp. 671-682, 2020

Authors: van Havre, Zoe | Maruff, Paul | Villemagne, Victor L. | Mengersen, Kerrie | Rousseau, Judith | White, Nicole | Doecke, James D.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) has a long pathological process, with an approximate lead-time of 20 years. During the early stages of the disease process, little evidence of the building pathology is identifiable without cerebrospinal fluid and/or imaging analyses. Clinical manifestations of AD do not present until irreversible pathological changes have occurred. Given an opportunity to provide treatment prior to irreversible pathological change, this study aims to identify a subgroup of cognitively normal (CN) participants from the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL), where subtle changes in cognition are indicative of early AD-related pathology. Using a Bayesian method …for unsupervised clustering via mixture models, we define an aggregate measure of posterior probabilities (AMPP score) establishing the likelihood of pre-clinical AD. From Baseline through to 54 months, visuo-spatial function had the greatest contribution to the AMPP score, followed by attention and processing speed and visual memory. Participants with the highest AMPP scores had both increasing neo-cortical amyloid burden and decreasing hippocampus volume over 54 months, compared to those in the lowest category with stable amyloid burden and hippocampus volume. The identification of a possible pre-clinical stage in CN participants via this method, without the aid of disease specific biomarkers, represents an important step in utilizing the strength of cognitive composite scores for the early detection of AD pathology. Show more

Keywords: Alzheimer’s disease, Bayesian, mixture models, model averaging, neuropsychological composite score, overfitting, posterior probability, unsupervised clustering

DOI: 10.3233/JAD-191095

Citation: Journal of Alzheimer's Disease, vol. 73, no. 2, pp. 683-693, 2020

Authors: Kumar, Rajnish | Pavlov, Pavel F. | Winblad, Bengt

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) represents a major public health threat and, unfortunately, available therapeutics provide only temporary symptomatic relief. AD is a complex multifactorial disease and failure of single target therapeutics targeting amyloid-β (Aβ) in recent clinical trials suggests that future AD drug development should be focused on simultaneous targeting of several pathological hallmarks of the disease. Recently, we have shown that GMP-1, a 2-(methoxymethyl)pyrimido [1, 2-a ] benzimidazol-4-ol, protects mitochondrial function in drosophila and mice models of AD, and improved memory and behavior indicating neuroprotective effect of GMP-1 treatment. Here, we have found that GMP-1 specifically binds to copper and zinc, …metals that are dysregulated in AD brain. Addition of GMP-1 does not inhibit metal-dependent enzymatic reactions. Also, binding of Zn(II) and Cu(II) by GMP-1 is weaker than the 8-hydroxyquinoline scaffold compound clioquinol previously tested in AD clinical trials. However, GMP-1 affects Cu(II)-dependent Aβ fibrillization as well as oxidative damage and viability of SH-SY5Y cells upon addition of Cu(II) and Aβ. Our data provide new insight on GMP-1 as a Zn(II) and Cu(II) specific metal chelator of moderate affinity that can be responsible for some of its neuroprotective effects observed in AD animal models. Show more

Keywords: Alzheimer’s disease, metal chelation, multi-target-directed ligands, treatment strategies

DOI: 10.3233/JAD-190695

Citation: Journal of Alzheimer's Disease, vol. 73, no. 2, pp. 695-705, 2020

Authors: Fani, Lana | Hilal, Saima | Sedaghat, Sanaz | Broer, Linda | Licher, Silvan | Arp, Pascal P. | van Meurs, Joyce B.J. | Ikram, M. Kamran | Ikram, M. Arfan

Article Type: Research Article

Abstract: There is a wide interest in biomarkers that capture the burden of detrimental factors as these accumulate with the passage of time, i.e., increasing age. Telomere length has received considerable attention as such a marker, because it is easily quantified and it may aid in disentangling the etiology of dementia or serve as predictive marker. We determined the association of telomere length with risk of Alzheimer’s disease and all-cause dementia in a population-based setting. Within the Rotterdam Study, we performed quantitative PCR to measure mean leukocyte telomere length in blood. We determined the association of telomere length with risk of …Alzheimer’s disease until 2016, using Cox regression models. Of 1,961 participants (mean age 71.4±9.3 years, 57.1% women) with a median follow-up of 8.3 years, 237 individuals were diagnosed with Alzheimer’s disease. We found a U-shaped association between telomere length and risk of Alzheimer’s disease: compared to the middle tertile the adjusted hazard ratio was 1.59 (95% confidence interval (CI), 1.13–2.23) for the lowest tertile and 1.47 (1.03–2.10) for the highest tertile. Results were similarly U-shaped but slightly attenuated for all-cause dementia. In conclusion, shorter and longer telomere length are both associated with an increased risk of Alzheimer’s disease in the general population. Show more

Keywords: Alzheimer’s disease, dementia, population-based, prospective cohort study, telomere

DOI: 10.3233/JAD-190759

Citation: Journal of Alzheimer's Disease, vol. 73, no. 2, pp. 707-714, 2020

Authors: Canevelli, Marco | Zaccaria, Valerio | Lacorte, Eleonora | Cova, Ilaria | Remoli, Giulia | Bacigalupo, Ilaria | Cascini, Silvia | Bargagli, Anna Maria | Pomati, Simone | Pantoni, Leonardo | Vanacore, Nicola

Article Type: Research Article

Abstract: Background: The construct of mild cognitive impairment (MCI) is triggering growing clinical and research interest. The detection of MCI may be affected by diverse ethno-cultural determinants possibly influencing the personal and social perception of the individual cognitive functioning as well as the reliability of objective cognitive assessment. These challenges may acquire special relevance in subjects with a migration background and composing ethnic minority groups. Objective: The present study is aimed at providing an estimate of the number of MCI cases occurring in the migrant population living in the extended European Union (EU) in 2018. Methods: The …number of MCI cases in older migrants living in Europe and in each of the 32 considered countries was estimated by multiplying the number of migrants, provided by Eurostat, with the age-specific prevalence rates, derived by the harmonized data produced by the COSMIC collaboration and based on different operational definitions of MCI. Results: Nearly 686,000 cases of MCI were estimated in the extended EU by applying age-specific prevalence rates based on the International Working Group criteria. Higher figures were obtained when the Clinical Dementia Rating- and the Mini Mental State Examination-based criteria were applied. The proportion of MCI cases in migrant subjects ranged from 1.1% (Romania) to 54.1% (Liechtenstein) (median: 8.4%; IQR: 4.7%–14.2%). Conclusions: MCI represents and will increasingly constitute a relevant issue in the migrant population living in Europe. The present data reinforce the need of developing approaches and models of care that may be diversity-sensitive and inclusive for a culturally variegated population. Show more

Keywords: Cognitive disorders, health disparities, migration, mild cognitive impairment, neuroepidemiology

DOI: 10.3233/JAD-191012

Citation: Journal of Alzheimer's Disease, vol. 73, no. 2, pp. 715-721, 2020

Authors: Wilson, Edward N. | Do Carmo, Sonia | Welikovitch, Lindsay A. | Hall, Hélène | Aguilar, Lisi Flores | Foret, Morgan K. | Iulita, M. Florencia | Jia, Dan Tong | Marks, Adam R. | Allard, Simon | Emmerson, Joshua T. | Ducatenzeiler, Adriana | Cuello, A. Claudio

Article Type: Research Article

Abstract: Epidemiological, preclinical, and clinical studies have suggested a role for microdose lithium in reducing Alzheimer’s disease (AD) risk by modulating key mechanisms associated with AD pathology. The novel microdose lithium formulation, NP03, has disease-modifying effects in the McGill-R-Thy1-APP transgenic rat model of AD-like amyloidosis at pre-plaque stages, before frank amyloid-β (Aβ) plaque deposition, during which Aβ is primarily intraneuronal. Here, we are interested in determining whether the positive effects of microdose lithium extend into early Aβ post-plaque stages. We administered NP03 (40μ g Li/kg; 1 ml/kg body weight) to McGill-R-Thy1-APP transgenic rats for 12 weeks spanning the transition phase from …plaque-free to plaque-bearing. The effect of NP03 on remote working memory was assessed using the novel object recognition task. Levels of human Aβ38 , Aβ40 , and Aβ42 as well as levels of pro-inflammatory mediators were measured in brain-extracts and plasma using electrochemiluminescent assays. Mature Aβ plaques were visualized with a thioflavin-S staining. Vesicular acetylcholine transporter (VAChT) bouton density and levels of chemokine (C-X-C motif) ligand 1 (CXCL1), interleukin-6 (IL-6), and 4-hydroxynonenal (4-HNE) were probed using quantitative immunohistochemistry. During the early Aβ post-plaque stage, we find that NP03 rescues functional deficits in object recognition, reduces loss of cholinergic boutons in the hippocampus, reduces levels of soluble and insoluble cortical Aβ42 and reduces hippocampal Aβ plaque number. In addition, NP03 reduces markers of neuroinflammation and cellular oxidative stress. Together these results indicate that microdose lithium NP03 is effective at later stages of amyloid pathology, after appearance of Aβ plaques. Show more

Keywords: Aβ pathology, Alzheimer’s disease, brain repair, cholinergic boutons, cognition, lithium microdose, neuroinflammation, oxidative stress, transgenic rat model

DOI: 10.3233/JAD-190862

Citation: Journal of Alzheimer's Disease, vol. 73, no. 2, pp. 723-739, 2020

Authors: Crespo-Cuevas, Ane Miren | López-Cancio, Elena | Cáceres, Cynthia | González, Anna | Ispierto, Lourdes | Hernández-Pérez, María | Mataró, María | Planas, Anna | Canento, Tamara | Martín, Lorena | Arenillas, Juan Francisco | Alvarez, Ramiro | Vilas, Dolores

Article Type: Research Article

Abstract: Background: Non-invasive biomarkers of cognitive impairment are needed. We aim to evaluate transcranial sonographic markers as predictors of cognitive impairment in a prospective cohort. Objective: To study the changes in the third ventricle diameter and the SN echogenicity between the baseline and the control visit, as well as its association with cognitive performance and the diagnosis of cognitive impairment in a prospective cohort. Methods: From the longitudinal population-based Asymptomatic Intracranial Atherosclerosis Study, we selected those subjects that received a complete transcranial sonography (TCS) and extensive cognitive testing, both at baseline and follow-up. We evaluated third ventricle …(IIIv) width, echogenicity of substantia nigra (SN), and temporal changes of these parameters. Results: We included 289 participants with a median follow-up time of 7.16 years. Those subjects who developed cognitive decline (n  = 23, 7.96%) had a larger IIIv at baseline than those who did not (0.54±0.14 cm versus 0.41±0.15 cm; p  = 0.001). A cut-off point of 0.465 cm for the IIIv width was identified as an independent predictor of long-term cognitive impairment after adjustment for age, gender, educational level, and vascular risk score. Change in IIIv diameter after follow-up was not associated with diagnosis of cognitive impairment. The area of SN and the presence of hyperechogenicity of the SN remained stable over time and was not associated with the diagnosis of cognitive impairment. Conclusion: IIIv width assessed by TCS emerged as an independent predictor of long-term cognitive impairment. Show more

Keywords: Cognitive decline, dementia, sonography, third ventricle, transcranial

DOI: 10.3233/JAD-190949

Citation: Journal of Alzheimer's Disease, vol. 73, no. 2, pp. 741-749, 2020

Authors: Wu, Wanqing | Ding, Ding | Zhao, Qianhua | Wang, Ruru | Liang, Xiaoniu | Xiao, Zhenxu | Luo, Jianfeng | Guo, Qihao | Hong, Zhen

Article Type: Research Article

Abstract: Background: There is significant evidence that physical activity has profound effects on the neurochemistry and plasticity of the brain and may prevent cognitive decline. Objective: This study aimed to determine the association between physical activity and incident dementia among older Chinese adults. Methods: In the prospective phase of the Shanghai Aging Study, 1,648 community-dwellers aged 60 years or older were followed for an average of 5 years. Their physical activity was assessed based on questionnaires. The physical activities were further transformed into metabolic equivalent values. A consensus diagnosis of incident dementia was ascertained based on medical, …neurological, and neuropsychological data and the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Results: We identified 166 incident dementia cases; the incidence rate was 19.4 per 1000 person-years. A multivariate Cox regression model indicated that compared to low levels of physical activity, medium-to-high levels of physical activity were associated with a reduced risk of dementia (hazard ratio, 95% confidence interval = 0.62, 0.44–0.89) after adjusting for age, sex, years of education, apolipoprotein E ɛ 4, and other confounders. Conclusion: Our findings demonstrate that medium-to-high level of physical activity is protective against dementia in older adults. Show more

Keywords: Chinese, cognition, cohort studies, dementia, incidence, physical activity

DOI: 10.3233/JAD-190937

Citation: Journal of Alzheimer's Disease, vol. 73, no. 2, pp. 751-758, 2020

Authors: Wang, Yan-Li | Chen, Wei | Cai, Wen-Jie | Hu, Hao | Xu, Wei | Wang, Zuo-Teng | Cao, Xi-Peng | Tan, Lan | Yu, Jin-Tai | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: White matter hyperintensities (WMHs), mainly caused by cerebrovascular injury, may lead to cognitive impairment. In order to identify whether the volume of WMHs is associated with cognitive decline over years, this longitudinal study involved 818 individuals from the ADNI-2 dataset from August 2010 to May 2017. Cross-sectional and longitudinal associations of WMHs with 8 cognitive domains were explored, using Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Clinical Dementia Rating Sum of Boxes (CDRSB), Alzheimer Disease Assessment Scale-Cognitive (ADAS-Cog13), Rey Auditory Verbal Learning Test (RAVLT), Functional Assessment Questionnaire (FAQ), executive function (ADNI-EF), and memory function (ADNI-Mem). The association analyses were …performed using multiple linear regression models, linear mixed models, Spearman rank correlation, and Kaplan-Meier survival curves. The volumes of WMHs were greater in patients with Alzheimer’s disease (AD) dementia compared with controls (p  < 0.001) and mild cognitive impairment (p  = 0.006) patients at baseline. The bigger volumes of WMHs correlated with worse performances on ADAS-Cog13 and ADNI-EF (p  = 0.029; p  = 0.003) at baseline and MMSE, MoCA, CDRSB, ADAS-Cog13, FAQ, and ADNI-Mem (overall p  < 0.05) longitudinally, after adjusting for age, sex, educational level, apolipoprotein E ɛ 4 genotype, hypertension, hyperlipidemia, diabetes, smoking, infarction, and diagnosis. Additionally, the correlations between the change rate of WMHs and change rates of MMSE, MoCA, CDRSB, FAQ, ADNI-EF, and ADNI-Mem were statistically significant. Furthermore, patients with high WMH volumes showed an increased likelihood of dementia. The results of the study suggest that WMH volume is associated with cognitive decline, and it contributes to the conversion to AD. Show more

Keywords: Alzheimer’s disease, Alzheimer’s Disease Neuroimaging Initiative, cognition, white matter hyperintensities

DOI: 10.3233/JAD-191005

Citation: Journal of Alzheimer's Disease, vol. 73, no. 2, pp. 759-768, 2020

Authors: Bisbe, Marta | Fuente-Vidal, Andrea | López, Elisabet | Moreno, Marta | Naya, Marian | de Benetti, Claudio | Milà, Raimon | Bruna, Olga | Boada, Mercè | Alegret, Montserrat

Article Type: Research Article

Abstract: Background: Recent research on mild cognitive impairment (MCI) has primarily focused on searching for measures to prevent or delay the progression of MCI to dementia. Physical exercise has shown to be effective in the prevention of age-related cognitive decline in elderly adults with MCI. However, the most effective type and dose of exercise for the improvement of cognition are yet to be determined. Objective: To compare the cognitive effects of choreographed exercise (Choreography group) with a multimodal physical therapy program (Physical Therapy group) in elderly adults with amnestic MCI, a population with an increased risk of developing dementia. …Methods: We conducted a randomized clinical trial with two parallel groups under allocation concealment and assessor blinding. Participants were allocated into Choreography or Physical Therapy group and performed exercises twice per week in 60-minute sessions during 12 weeks. Results: Thirty-six participants with amnestic MCI, ages 65 to 85, were assessed at baseline and after 12 weeks of intervention, by comprehensive validated neuropsychological and physical assessments. A Repeated measures General Lineal Model showed statistically significant differences in cognitive and physical outcomes. Both groups significantly improved in visual delayed recall. The Choreography group exhibited significantly more benefits on verbal recognition memory than the Physical Therapy group. Conclusion: Greater cognitive benefits were achieved in the choreographic intervention than in the multimodal physical therapy, mainly in those functions more related to the risk of conversion to dementia. Additional studies are needed to confirm whether the observed effects are related to delayed onset of Alzheimer’s disease in elderly adults with amnestic MCI. Show more

Keywords: Aging, Alzheimer’s disease, cognitive decline, dancing, mild cognitive impairment, motor skills, neuropsychology, physical exercise, physical therapy, physical activity

DOI: 10.3233/JAD-190552

Citation: Journal of Alzheimer's Disease, vol. 73, no. 2, pp. 769-783, 2020