Journal of Alzheimer's Disease - Volume 80, issue 4

Authors: Jouini, Najla | Saied, Zakaria | Ben Sassi, Samia | Nebli, Fatma | Messaoud, Taieb | Hentati, Faycel | Belal, Samir

Article Type: Research Article

Abstract: Background: Iron plays an important role in maintaining cell survival, with normal iron trafficking known to be regulated by the ceruloplasmin-transferrin (Cp-Tf) antioxidant system. Disruption to this system is thought to be detrimental to normal brain function. Objective: To determine whether an imbalance of iron and the proteins involved in its metabolism (ceruloplasmin and transferrin) are linked to Alzheimer’s disease (AD) and to the expression of amyloid-beta (Aβ) peptide 1–42 (Aβ1–42 ), which is a major species of Aβ, and the most toxic. Methods: We evaluated the concentrations of iron, calcium, magnesium, and Aβ1–42 in …the cerebrospinal fluid (CSF) of patients with AD and cognitively normal controls. Correlations between the components of the Cp-Tf antioxidant system in plasma were studied to determine the role of peripheral blood in the onset and/or development of AD. We used commercial ELISA immunoassays to measure Aβ1–42 , immunoturbidimetry to quantify ceruloplasmin and transferrin, and colorimetry to quantify iron, calcium, and magnesium. Results: We found that the AD group had lower CSF concentrations of Aβ1–42 (p  < 0.001) and calcium (p  < 0.001), but a higher CSF concentration of iron (p  < 0.001). Significantly lower plasma concentrations of ceruloplasmin (p  = 0.003), transferrin (mean, p  < 0.001), and iron (p  < 0.001) were observed in the AD group than in cognitively normal adults. Moreover, we found a strong interdependence between most of these components. Conclusion: Iron dyshomeostasis has a crucial role in the onset of AD and/or its development. Correcting metal misdistribution is an appealing therapeutic strategy for AD. Show more

Keywords: Alzheimer’s disease, blood stream, calcium, cerebrospinal fluid, ceruloplasmin, iron metabolism, transferrin

DOI: 10.3233/JAD-201250

Citation: Journal of Alzheimer's Disease, vol. 80, no. 4, pp. 1439-1450, 2021

Authors: Clark, Alexandra L. | Weigand, Alexandra J. | Thomas, Kelsey R. | Solders, Seraphina K. | Delano-Wood, Lisa | Bondi, Mark W. | Bernier, Rachel A. | Sundermann, Erin E. | Banks, Sarah J. | Bangen, Katherine J. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Age-related cerebrovascular and neuroinflammatory processes have been independently identified as key mechanisms of Alzheimer’s disease (AD), although their interactive effects have yet to be fully examined. Objective: The current study examined 1) the influence of pulse pressure (PP) and inflammatory markers on AD protein levels and 2) links between protein biomarkers and cognitive function in older adults with and without mild cognitive impairment (MCI). Methods: This study included 218 ADNI (81 cognitively normal [CN], 137 MCI) participants who underwent lumbar punctures, apolipoprotein E (APOE ) genotyping, and cognitive testing. Cerebrospinal (CSF) levels of eight pro-inflammatory …markers were used to create an inflammation composite, and amyloid-beta 1–42 (Aβ42 ), phosphorylated tau (p-tau), and total tau (t-tau) were quantified. Results: Multiple regression analyses controlling for age, education, and APOE ɛ4 genotype revealed significant PP x inflammation interactions for t-tau (B = 0.88, p  = 0.01) and p-tau (B = 0.84, p  = 0.02); higher inflammation was associated with higher levels of tau within the MCI group. However, within the CN group, analyses revealed a significant PP x inflammation interaction for Aβ42 (B = –1.01, p  = 0.02); greater inflammation was associated with higher levels of Aβ42 (indicative of lower cerebral amyloid burden) in those with lower PP. Finally, higher levels of tau were associated with poorer memory performance within the MCI group only (p s  < 0.05). Conclusion: PP and inflammation exert differential effects on AD CSF proteins and provide evidence that vascular risk is associated with greater AD pathology across our sample of CN and MCI older adults. Show more

Keywords: Cerebrospinal fluid, inflammation, mild cognitive impairment, tau, vascular dysfunction

DOI: 10.3233/JAD-201382

Citation: Journal of Alzheimer's Disease, vol. 80, no. 4, pp. 1451-1463, 2021

Authors: Beauchet, Olivier | Sekhon, Harmehr | Launay, Cyrille P. | Gaudreau, Pierrette | Morais, José A. | Allali, Gilles

Article Type: Research Article

Abstract: Background: Motoric cognitive risk syndrome (MCR) and mild cognitive impairment (MCI) are two pre-dementia stages with an overlap, which may influence the risk for dementia. Objective: The study aims to examine the association of MCR, MCI, and their combination with incident dementia in Quebec community-dwelling older adults. Methods: 1,063 older adults (i.e., ≥65) were selected from a population-based observational cohort study known as the “Nutrition as a determinant of successful aging: The Quebec longitudinal study ” (NuAge). Participants were separated into four groups at the baseline assessment: those without MCR and MCI (i.e., cognitively healthy individual; …CHI), those with MCR alone, those with MCI alone, and those with MCR plus MCI. Incident dementia was recorded at each annual visit during a 3-year follow-up. Results: The prevalence of CHI was 87.2%, MCR 3.0%, MCI 8.8%, and MCR plus MCI 0.9%. The overall incidence of dementia was 2.4% and was significantly associated with MCR alone (Odd Ratio (OR) = 5.00 with 95% Confidence interval (CI) = [1.01;24.59] and p  = 0.049), MCI alone (OR = 6.04 with 95% CI = [2.36;15.47] and p ≤0.001), and the combination of MCR and MCI (OR = 25.75 with 95% CI = [5.32;124.66] and p ≤0.001). Conclusion: Combining MCR and MCI increased the risk for incident dementia. These results also demonstrated that this combination is a better predictor of dementia than MCI or MCR alone. Show more

Keywords: Cohort study, dementia, epidemiology, incidence, older adults

DOI: 10.3233/JAD-201571

Citation: Journal of Alzheimer's Disease, vol. 80, no. 4, pp. 1465-1470, 2021

Authors: Zingel, Rebecca | Bohlken, Jens | Kostev, Karel

Article Type: Research Article

Abstract: Background: The critical role of inflammatory processes in the pathogenesis of dementia has recently been established. Objective: The aim of this study was to investigate the association between inflammatory bowel disease (IBD) and dementia risk in patients followed in general practices in Germany. Methods: This study included patients aged over 60 with an initial diagnosis of IBD (Crohn’s Disease (CD), ulcerative colitis (UC)) who were followed in 1,159 German general practices between January 1995 and December 2014. IBD patients were matched to healthy patients using propensity scores based on age, gender, index year, insurance type and …comorbidities. Kaplan-Meier curves were used to study the development of dementia in patients with or without IBD within up to 15 years of the index date. Cox proportional hazard regression models were used to estimate the relationship between IBD and dementia. Results: The study included 3,850 patients with and 3,850 patients without IBD and revealed a higher cumulative incidence of dementia in IBD patients than in non-IBD patients after the follow-up period. The cumulative incidence of dementia differed within IBD subtypes; it was significantly higher in UC patients than in CD patients. Cox proportional hazard models showed that IBD is associated with a 1.22-fold increase in the risk (95% CI: 1,07–1,39) of developing dementia. UC patients had a 1.25-fold higher risk of developing dementia (95% CI: 1.07–1.46). CD is not significantly associated with an increased risk of dementia (HR: 1.17, 95% CI: 0.93–1.47). Conclusion: A positive association between IBD and dementia was found in patients followed in general practices in Germany. Show more

Keywords: Crohn’s disease, dementia, inflammatory bowel disease, ulcerative colitis

DOI: 10.3233/JAD-210103

Citation: Journal of Alzheimer's Disease, vol. 80, no. 4, pp. 1471-1478, 2021

Authors: Moussavi Nik, Seyyed Hani | Porter, Tenielle | Newman, Morgan | Bartlett, Benjamin | Khan, Imran | Sabale, Miheer | Eccles, Melissa | Woodfield, Amy | Groth, David | Dore, Vincent | Villemagne, Victor L. | Masters, Colin L. | Martins, Ralph N. | Laws, Simon M. | Lardelli, Michael | Verdile, Giuseppe

Article Type: Research Article

Abstract: Background: The PRESENILIN genes (PSEN1 , PSEN2 ) encoding for their respective proteins have critical roles in many aspects of Alzheimer’s disease (AD) pathogenesis. The PS2V transcript of PSEN2 encodes a truncated protein and is upregulated in AD brains; however, its relevance to AD and disease progression remains to be determined. Objective: Assess transcript levels in postmortem AD and non-AD brain tissue and in lymphocytes collected under the Australian Imaging Biomarker and Lifestyle (AIBL) study. Methods: Full length PSEN2 and PS2V transcript levels were assessed by quantitative digital PCR in postmortem …brain tissue (frontal cortex and hippocampus) from control, AD, frontotemporal dementia (FTD), and Lewy body dementia (LBD). Transcript levels were also assessed in lymphocytes obtained from the Perth subset of the AIBL study (n  = 160). Linear regression analysis was used to assess correlations between transcript copy number and brain volume and neocortical amyloid load. Results: PS2V levels increased in AD postmortem brain but PS2V was also present at significant levels in FTD and LBD brains. PS2V transcript was detected in lymphocytes and PS2V /PSEN2 ratios were increased in mild cognitive impairment (p  = 0.024) and AD (p  = 0.019) groups compared to control group. Increased ratios were significantly correlated with hippocampal volumes only (n  = 62, β= –0.269, p  = 0.03). Conclusion: Taken together, these results suggest that PS2V may be a marker of overall neurodegeneration. Show more

Keywords: Alzheimer’s disease, frontotemporal dementia, Lewy body dementia, lymphocytes, neurodegeneration, Presenilin 2

DOI: 10.3233/JAD-201133

Citation: Journal of Alzheimer's Disease, vol. 80, no. 4, pp. 1479-1489, 2021

Authors: Zamarian, Laura | Karner, Elfriede | Bodner, Thomas | Djamshidian, Atbin | Delazer, Margarete

Article Type: Research Article

Abstract: Background: Education has a protective effect toward cognitive decline in advanced age and is an important factor contributing to cognitive reserve. Objective: To elucidate the interaction effect of education and global mental status on cognitive performance of older patients with progressive cognitive decline. Methods: This retrospective study included 1,392 patients. We performed moderation regressions to examine the interaction between education and global mental status (Mini-Mental State Examination (MMSE) score) on performance in episodic memory, executive functions (EF), language, and constructional praxis tests. Significant interaction effects were further explored through separate linear regressions by MMSE level (inferior: …≤24; intermediate: 25–27; superior: 28–30). Results: There was an interaction between MMSE and education for some but not all variables. At intermediate and superior MMSE levels, high-educated people had a clear advantage relative to low-educated people in verbal memory and EF tests. This advantage was not significant at an inferior MMSE level. In object naming, constructional praxis recall, and constructional praxis, high-educated people performed better than low-educated people, independently of MMSE level. Conclusion: Education has a differential effect on cognitive performance in patients with cognitive decline. While high education is not helpful for episodic memory and EF at low cognitive levels, it is still beneficial for retrieving words or other semantic knowledge. These findings suggest an interaction between global mental status and education on different cognitive domains and have strong clinical implications. Diagnostic judgments should be based on the knowledge of such interaction. This study highlights the beneficial but selective effects of high education. Show more

Keywords: Aging, cognition, cognitive dysfunction, cognitive reserve, diagnosis, education, neuropsychology

DOI: 10.3233/JAD-201608

Citation: Journal of Alzheimer's Disease, vol. 80, no. 4, pp. 1491-1501, 2021

Authors: Chen, Yongjie | Du, Yue | Sun, Zhuoyu | Liu, Qian | Sun, Changqing | Lin, Hongyan | Jin, Mengdi | Fu, Jingzhu | Ma, Fei | Li, Wen | Liu, Huan | Zhang, Xumei | Wang, Guangshun | Huang, Guowei

Article Type: Research Article

Abstract: Background: Handgrip strength (HGS) and serum folate and homocysteine (Hcy) levels were associated with cognitive function. However, little was known whether there were interactions between HGS and serum folate and Hcy levels on cognitive function. Objective: To examine the interactions between HGS and serum folate and Hcy levels on cognitive function. Methods: This study analyzed the baseline data of the Tianjin Elderly Nutrition and Cognition Cohort study. All participants aged ≥60 years were potential eligible. HGS was measured using a grip strength dynamometer. Serum folate and Hcy levels were assayed using standard laboratory protocol. A Mini-Mental …State Examination was used to assess cognitive function. Linear regressions were employed to examine the interactions between HGS and serum folate and Hcy levels on cognitive function. Results: 4,484 participants were included in this study. There were interactions between HGS and serum folate and Hcy levels on cognitive function. Furthermore, subjects with strong HGS and sufficient folate level had the best cognitive function (β= 2.018), sequentially followed by those with strong HGS and insufficient folate level (β= 1.698) and with poor HGS and sufficient folate level (β= 0.873). Similarly, cognitive function was ranked in the descending order of subjects with strong HGS and normal Hcy level (β= 1.971), strong HGS and high Hcy level (β= 1.467), and poor HGS and normal Hcy level (β= 0.657). Conclusion: There were interactions between HGS and serum folate and Hcy levels on cognitive function. However, the temporal associations cannot be examined in a cross-sectional study. Further cohort study should be conducted to confirm these associations in the future. Show more

Keywords: Alzheimer’s disease, cognitive function, handgrip strength, serum folate, serum homocysteine

DOI: 10.3233/JAD-201537

Citation: Journal of Alzheimer's Disease, vol. 80, no. 4, pp. 1503-1513, 2021

Authors: Gervais, Frederic | Dauphinot, Virginie | Mouchoux, Christelle | Krolak-Salmon, Pierre

Article Type: Research Article

Abstract: Background: Literature supports an increasing number of older patients living with neurocognitive disorders alongside with their annual worldwide costs. Therapeutic management of behavioral and psychological symptoms includes the use of anticholinergic and sedative drugs for which significant exposure is negatively associated with clinical outcomes. Objective: The aim of this study was to assess the healthcare costs differences related to an increase in the exposure to anticholinergic and sedative drugs in older patients with neurocognitive disorder. Methods: A longitudinal study was conducted during 3 years on 1,604 participants of the MEMORA cohort linked with both regional public …health insurance and hospital discharge databases between 2012 and 2017. Direct medical and non-medical costs were included. Exposure to anticholinergic and sedative drugs was measured by the drug burden index (DBI). Results: Costs difference associated with a DBI≥0.5 were + 338€ (p  < 0.001). After adjustment on comorbidities, NCD stage, cognitive impairment, functional limitation, polypharmacy, and sociodemographic characteristics, a DBI≥0.5 was found to be an independent predictor of an increase of total healthcare costs by 22%(p  < 0.001). Conclusion: Anticholinergic and sedative drugs have a substantial economic burden among older patients with neurocognitive disorder. More studies are required to assess the clinical and economic impact of an efficient strategy based on the reduction of the exposure to anticholinergic and sedative drugs and the promotion of non-pharmacological interventions. Show more

Keywords: Adverse effects, aging, cholinergic antagonists, cost of illness, drug effects, hypnotics and sedatives, longitudinal studies

DOI: 10.3233/JAD-201127

Citation: Journal of Alzheimer's Disease, vol. 80, no. 4, pp. 1515-1524, 2021

Authors: Ten Brinke, Lisanne F. | Hsu, Chun Liang | Erickson, Kirk I. | Handy, Todd C. | Liu-Ambrose, Teresa

Article Type: Research Article

Abstract: Background: Evidence suggests that computerized cognitive training (CCT) can improve cognitive function in older adults, particularly executive functions. However, the underlying mechanisms by which CCT may improve executive functions are not well established. Objective: To determine: 1) inter-network functional connectivity correlates of changes in executive functions; and 2) the effect of CCT on these functional connectivity correlates. Methods: This secondary analysis included a subset of 124 adults aged 65–85 years enrolled in an 8-week randomized controlled trial of CCT. Participants were randomized to either: 1) group-based CCT 3x/week for 1 hour plus 3x/week home-based training; 2) …group-based CCT preceded by brisk walking (Ex+CCT) 3x/week for 1 hour plus 3x/week home-based training; or 3) group-based balanced and toned (BAT) classes 3x/week for 1 hour (control). At baseline and trial completion, 65 of the 124 participants completed resting-state functional magnetic resonance imaging and neuropsychological tests of executive functions, specifically the Stroop Colour-Word Test and Flanker Test. Results: Improved performance on the Stroop Colour-Word Test and Flanker Test were associated with decreased correlation between the default mode network (DMN) and the fronto-parietal network (FPN) (p  < 0.05). Compared with BAT, CCT alone significantly decreased correlation between the left dorsolateral prefrontal cortex and both the left and right medial temporal gyrus (–0.143, 95%CI [–0.256,–0.030], p  = 0.014, and –0.123, 95%CI [–0.242,–0.004], p  = 0.043, respectively). Conclusion: Decreased correlation between DMN and FPN, indicating less connection between these networks, may be an underlying mechanism by which CCT improves executive functions. Future studies are needed to replicate this finding. Show more

Keywords: Clinical trial, cognitive aging, executive function, magnetic resonance imaging

DOI: 10.3233/JAD-200844

Citation: Journal of Alzheimer's Disease, vol. 80, no. 4, pp. 1525-1537, 2021

Authors: Tanner, Jared J. | Hanchate, Shivani | Price, Catherine C. | Garvan, Cynthia | Lai, Song | Staud, Roland | Deshpande, Hrishikesh | Deutsch, Georg | Goodin, Burel R. | Fillingim, Roger B. | Sibille, Kimberly T.

Article Type: Research Article

Abstract: Background: Non-Hispanic black (NHB) individuals have increased risk of Alzheimer’s disease (AD) relative to non-Hispanic whites (NHW). Ethnicity/race can serve as a proxy sociodemographic variable for a complex representation of sociocultural and environmental factors. Chronic pain is a form of stress with high prevalence and sociodemographic disparities. Chronic pain is linked to lower cognition and accelerated biological aging. Objective: The purpose of this study is to seek understanding of potential cognitive and temporal lobe structural brain AD vulnerabilities based on chronic pain stage and ethnicity/race. Methods: Participants included 147 community dwelling NHB and NHW adults without …dementia between 45–85 years old who had or were at risk of knee osteoarthritis. All participants received an MRI (3T Philips), the Montreal Cognitive Assessment (MoCA), and assessment of clinical knee pain stage. Results: There were ethnic/race group differences in MoCA scores but no relationships with chronic knee pain stage. Ethnicity/race moderated the relationship between AD-related temporal lobe thickness and chronic pain stage with quadratic patterns suggesting thinner cortex in high chronic pain stage NHB adults. Conclusion: There appear to be complex relationships between chronic knee pain stage, temporal lobe cortex, and sociodemographic variables. Specifically, NHB participants without dementia but with high chronic knee pain stage appeared to have thinner temporal cortex in areas associated with AD. Understanding the effects of sociocultural and socioeconomic factors on health outcomes is the first step to challenging the disparities in healthcare that now appear to link disease conditions to neurodegenerative processes. Show more

Keywords: Alzheimer’s disease, chronic pain, ethnic groups, magnetic resonance imaging, race factors, risk factors, socioeconomic factors, temporal lobe

DOI: 10.3233/JAD-201345

Citation: Journal of Alzheimer's Disease, vol. 80, no. 4, pp. 1539-1551, 2021