Journal of Alzheimer's Disease - Volume 84, issue 3

Authors: Aranđelović, Jovana | Santrač, Anja | Batinić, Bojan | Todorović, Lidija | Ahmed Khan, Md Zubair | Rashid, Farjana | Poe, Michael M. | Obradović, Aleksandar | Cook, James M. | Savić, Miroslav M.

Article Type: Research Article

Abstract: Background: Positive and negative allosteric modulators of α5 GABAA receptors (PAM and NAM, respectively) are worthy of investigation as putative treatments of Alzheimer’s disease (AD). However, their potential to modify a dynamic range of behaviors in AD models needs to be systematically examined. Objective: The study aimed to assess effects of MP-III-022 as PAM and PWZ-029 as NAM on emotional reactivity, motivation, and motor function, as well as on gene expression of GABRA2, GABRA3 and GABRA5 subunit of GABAA receptors in prefrontal cortex (PFC) and hippocampus (HC) in 5xFAD mice, as an early-onset transgenic AD model. …Methods: The 6-month-old 5xFAD transgenic and non-transgenic mice of both genders underwent a battery of reflexes and behavioral tests (sensorimotor tests, elevated plus maze, and open field) after 10-day intraperitoneal treatment with MP-III-022, PWZ-029, or solvent. The behavioral battery was followed by qPCR analysis of gene expression. Results: MP-III-022 induced a decline in motor function, while PWZ-029 further decreased emotionality of transgenic males, as compared to the transgenic control. No interfering effects on non-cognitive behavior were observed in female mice. In HC, both treatments reversed reciprocal GABRA2 and GABRA3 changes in transgenic females. In PFC, MP-III-022 decreased GABRA5 in both genders, while PWZ-029 increased GABRA2 in male transgenic animals. Conclusion: Gender-dependent protracted effects of PAMs and NAMs in AD model, with detrimental impact on motor capabilities of PAM, and attenuation of emotionality elicited by NAM in transgenic males, were revealed. This favors future research of α5 GABAA receptor modulation in females as more promising. Show more

Keywords: 5xFAD, α5 GABAA receptors, Alzheimer’s disease, emotionality, motor function, motivation, negative allosteric modulation, positive allosteric modulation

DOI: 10.3233/JAD-215079

Citation: Journal of Alzheimer's Disease, vol. 84, no. 3, pp. 1291-1302, 2021

Authors: Imahori, Yume | Vetrano, Davide L. | Ljungman, Petter | Qiu, Chengxuan

Article Type: Research Article

Abstract: Background: Markers of altered cardiac function might predict cognitive decline and dementia. Objective: This systematic review aims to review the literature that examines the associations of various electrocardiogram (ECG) markers with cognitive decline and dementia in middle-aged and elderly populations. Methods: We searched PubMed, Embase, and Web of Science through 1 July 2020 for literature and conducted a systematic literature review. We included studies examining the associations of ECG markers (e.g., left ventricular hypertrophy [LVH], spatial QRS-T angle, and QT prolongation) with cognitive function and dementia in adult populations regardless of study setting and design, but …excluded studies examining atrial fibrillation and heart rate variability. Results: Fourteen community-based cross-sectional and longitudinal studies were identified. ECG markers were investigated in association with dementia in four prospective studies, and with cognitive decline in ten prospective studies. ECG-assessed LVH was associated with dementia in one study while five heterogeneous prospective studies yielded inconsistent associations with cognitive decline. Regarding ventricular repolarization markers, spatial QRS-T angle was associated with cognitive decline in one study while another study found no association between QT prolongation and cognitive decline. High resting heart rate was associated with both dementia and cognitive decline in one study but not associated with dementia in another study. P-wave abnormality was significantly associated with incident dementia and cognitive decline in one prospective study. Conclusion: Some ECG markers were associated with incident dementia and cognitive decline. However, limited number of heterogeneous studies did not allow us to make firm conclusions. Further studies are needed. Show more

Keywords: Cognitive decline, dementia, electrocardiogram, epidemiology, systematic literature review

DOI: 10.3233/JAD-210606

Citation: Journal of Alzheimer's Disease, vol. 84, no. 3, pp. 1303-1322, 2021

Authors: Liu, Hongliang | Lutz, Michael | Luo, Sheng | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI) is a heterogeneous condition and MCI patients are at increased risk of progression to dementia due to Alzheimer’s disease (AD). Objective: In this study, we aim to evaluate the associations between polygenic risk scores (PRSs) and 1) time to AD progression from MCI, 2) changes in longitudinal cognitive impairment, and 3) biomarkers from cerebrospinal fluid and imaging. Methods: We constructed PRS by using 40 independent non-APOE SNPs from well-replicated AD GWASs and tested its association with the progression time from MCI to AD by using 767 MCI patients from the …ADNI study and 1373 patients from the NACC study. PRSs calculated with other methods were also computed. Results: We found that the PRS constructed with SNPs that reached genome-wide significance predicted the progression from MCI to AD (beta = 0.182, SE = 0.061, p  = 0.003) after adjusting for the demographic and clinical variables. This association was replicated in the NACC dataset (beta = 0.094, SE = 0.037, p  = 0.009). Further analyses revealed that PRS was associated with the increased ADAS-Cog11/ADAS-Cog13/ADASQ4 scores, tau/ptau levels, and cortical amyloid burdens (PiB-PET and AV45-PET), but decreased hippocampus and entorhinal cortex volumes (p  < 0.05). Mediation analysis showed that the effect of PRS on the increased risk of AD may be mediated by Aβ42 (beta = 0.056, SE = 0.026, p  = 0.036). Conclusion: Our findings suggest that PRS can be useful for the prediction of time to AD and other clinical changes after the diagnosis of MCI. Show more

Keywords: Alzheimer’s disease, longitudinal analysis, mild cognitive impairment, neuroimaging, polygenic risk score, survival analysis

DOI: 10.3233/JAD-210700

Citation: Journal of Alzheimer's Disease, vol. 84, no. 3, pp. 1323-1335, 2021

Authors: Jung, Youjin | Viviano, Raymond P. | van Rooden, Sanneke | van der Grond, Jeroen | Rombouts, Serge A.R.B. | Damoiseaux, Jessica S.

Article Type: Research Article

Abstract: Background: White matter hyperintensities (WMH) show a robust relationship with arterial pressure as well as objective and subjective cognitive functioning. In addition, APO E ɛ4 carriership may influence how arterial pressure affects cognitive functioning. Objective: To determine the role of region-specific WMH burden and APOE ɛ4 carriership on the relationship between mean arterial pressure (MAP) and cognitive function as well as subjective cognitive decline (SCD). Methods: The sample consisted of 87 cognitively unimpaired middle-aged to older adults aged 50–85. We measured WMH volume for the whole brain, anterior thalamic radiation (ATR), forceps minor, and superior …longitudinal fasciculus (SLF). We examined whether WMH burden mediated the relationship between MAP and cognition (i.e., TMT-A score for processing speed; Stroop performance for executive function) as well as SCD (i.e., Frequency of Forgetting (FoF)), and whether APOE ɛ4 carriership moderated that mediation. Results: WMH burden within SLF mediated the effect of MAP on Stroop performance. Both whole brain and ATR WMH burden mediated the effect of MAP on FoF score. In the MAP–WMH–Stroop relationship, the mediation effect of SLF WMH and the effect of MAP on SLF WMH were significant only in APOE ɛ4 carriers. In the MAP–WMH–FoF relationship, the effect of MAP on whole brain WMH burden was significant only in ɛ4 carriers. Conclusion: WMH burden and APOE genotype explain the link between blood pressure and cognitive function and may enable a more accurate assessment of the effect of high blood pressure on cognitive decline and risk for dementia. Show more

Keywords: Aging, Alzheimer’s disease, apolipoprotein E4, blood pressure, dementia, executive function, subjective cognitive decline, white matter hyperintensities

DOI: 10.3233/JAD-210695

Citation: Journal of Alzheimer's Disease, vol. 84, no. 3, pp. 1337-1350, 2021

Authors: Hu, Di | Liu, Chuning | Xia, Kai | Abramowitz, Amy | Wu, Guorong | and Alzheimer’s Disease Neuroimaging Initiative (ADNI)

Article Type: Research Article

Abstract: Background: With the rapid development of neurobiology and neuroimaging technologies, mounting evidence shows that Alzheimer’s disease (AD) is caused by the build-up of two abnormal proteins, amyloid-β plaques (A) and neurofibrillary tangles (T). Over time, these AD-related neuropathological burdens begin to spread throughout the brain, which results in the characteristic progression of symptoms in AD. Objective: Although tremendous efforts have been made to link biological indicators to the progression of AD, limited attention has been paid to investigate the multi-factorial role of socioeconomic status (SES) in the prevalence or incidence of AD. There is high demand to explore …the synergetic effect of sex and SES factors in moderating the neurodegeneration process caused by the accumulation of A and T biomarkers. Methods: We carry out a meta-data analysis on the longitudinal neuroimaging data, clinical outcomes, genotypes, and demographic data in Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu ). Results: Our major findings include 1) education and occupation show resilience effects at the angular gyrus, superior parietal lobule, lateral occipital-temporal sulcus, and posterior transverse collateral sulcus where we found significant slowdown of neurodegeneration due to higher education level or more advanced occupation rank; 2) A and T biomarkers manifest different spatial patterns of brain resilience; 3) BDNF (brain-derived neurotrophic factor) single nucleotide polymorphism (SNP) rs10835211 shows strong association to the identified resilience effect; 4) the identified resilience effect is associated with the clinical manifestation in memory, learning, and organization performance. Conclusion: Several brain regions manifest resilience from SES to A and T biomarkers. BDNF SNPs have a potential association with the resilience effect from SES. In addition, cognitive measures of learning and memory demonstrate the resilience effect. Show more

Keywords: Alzheimer’s disease, cognitive reserve, computational proxy, neurodegeneration

DOI: 10.3233/JAD-215160

Citation: Journal of Alzheimer's Disease, vol. 84, no. 3, pp. 1351-1362, 2021

Authors: Lindgren, Emma | Sörenson, Josephine | Wattmo, Carina | Kåreholt, Ingemar | Nägga, Katarina

Article Type: Research Article

Abstract: Background: With a growing elderly population worldwide, the prevalence of dementia is rapidly increasing. Studies from high income countries have shown that belonging to a minority ethnic group increases the risk of health disadvantages. Objective: The aim of the present registry-based study was to identify potential differences in diagnostics, treatment, and care of individuals with dementia focusing on foreign-born in Sweden and the impact of country level socioeconomic position (SEP). Methods: The study was based on a large dataset from the Swedish Dementia Registry (SveDem) and the Swedish Tax Agency’s population registry. Data on demographic variables, …cognitive tests, clinical assessments, medication, diagnosis, and interventions initiated at diagnosis were collected. Country level SEP was determined by country of birth as classified by World Bank Country and Lending groups. Results: Of 57,982 patients with dementia registered in SveDem, 7,171 (12.4%) were foreign-born. The foreign-born were significantly younger at diagnosis (p  < 0.001), had a lower MMSE score (p  < 0.001), lower odds of receiving a specific dementia diagnosis (p  < 0.001), lower use of acetylcholinesterase inhibitors (p  < 0.001), and overall a higher use of neuroleptics compared with the Swedish-born group. The lower SEP, the greater differences to Swedish-born were seen in many of the examined variables. Conclusion: There were significant differences in dementia diagnostics, treatment, and care between foreign-born and Swedish-born, a lower SEP indicating greater differences. Further research should focus on various socioeconomic aspects and health care outcomes for a more profound analysis of equity in dementia care. Show more

Keywords: Dementia care, differences, immigrant, minority ethnic group, qualitative registry, socioeconomic position

DOI: 10.3233/JAD-210734

Citation: Journal of Alzheimer's Disease, vol. 84, no. 3, pp. 1363-1371, 2021

Authors: Newby, Danielle | Winchester, Laura | Sproviero, William | Fernandes, Marco | Wang, Dai | Kormilitzin, Andrey | Launer, Lenore J. | Nevado-Holgado, Alejo J.

Article Type: Research Article

Abstract: Background: Mid-life hypertension is an established risk factor for cognitive impairment and dementia and related to greater brain atrophy and poorer cognitive performance. Previous studies often have small sample sizes from older populations that lack utilizing multiple measures to define hypertension such as blood pressure, self-report information, and medication use; furthermore, the impact of the duration of hypertension is less extensively studied. Objective: To investigate the relationship between hypertension defined using multiple measures and length of hypertension with brain measure and cognition. Methods: Using participants from the UK Biobank MRI visit with blood pressure measurements (n … = 31,513), we examined the cross-sectional relationships between hypertension and duration of hypertension with brain volumes and cognitive tests using generalized linear models adjusted for confounding. Results: Compared with normotensives, hypertensive participants had smaller brain volumes, larger white matter hyperintensities (WMH), and poorer performance on cognitive tests. For total brain, total grey, and hippocampal volumes, those with greatest duration of hypertension had the smallest brain volumes and the largest WMH, ventricular cerebrospinal fluid volumes. For other subcortical and white matter microstructural regions, there was no clear relationship. There were no significant associations between duration of hypertension and cognitive tests. Conclusion: Our results show hypertension is associated with poorer brain and cognitive health however, the impact of duration since diagnosis warrants further investigation. This work adds further insights by using multiple measures defining hypertension and analysis on duration of hypertension which is a substantial advance on prior analyses—particularly those in UK Biobank which present otherwise similar analyses on smaller subsets. Show more

Keywords: Cardiovascular, cognitive decline, dementia, epidemiology, hypertension

DOI: 10.3233/JAD-210512

Citation: Journal of Alzheimer's Disease, vol. 84, no. 3, pp. 1373-1389, 2021