Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Miguel, Laetitia | Frebourg, Thierry | Campion, Dominique | Lecourtois, Magalie

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is neuropathologically defined by two key hallmarks: extracellular senile plaques composed primarily of amyloid-β (Aβ) peptide and intraneuronal neurofibrillary tangles, containing abnormally hyperphosphorylated tau protein. The tau protein is encoded by the MAPT gene. Recently, the H1 and H2 haplotypes of the MAPT gene were associated with AD risk. The minor MAPT H2 haplotype has been linked with a decreased risk of developing late-onset AD (LOAD). MAPT haplotypes show different levels of MAPT/Tau expression with H1 being ∼1.5-fold more expressed than H2, suggesting that MAPT expression level could be related to …LOAD risk. In this study, we investigated whether this moderate difference in MAPT/Tau expression could influence Aβ-induced toxicity in vivo. We show that modest overexpression of tau protein in Drosophila exacerbates neuronal phenotypes in AβPP/BACE1 flies. The exacerbation of neuronal defects correlates with the accumulation of insoluble dTau oligomers, suggesting that the moderate difference in level of tau expression observed between H1 and H2 haplotypes could influence Aβ toxicity through the production of oligomeric tau insoluble species. Show more

Keywords: Alzheimer’s disease, amyloid-β peptide, Drosophila , oligomers, tau

DOI: 10.3233/JAD-190906

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Liguori, Claudio | Spanetta, Matteo | Izzi, Francesca | Franchini, Flaminia | Nuccetelli, Marzia | Sancesario, Giulia Maria | Di Santo, Simona | Bernardini, Sergio | Mercuri, Nicola Biagio | Placidi, Fabio

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common form of dementia. It is mainly characterized by a progressive deterioration of cognition, but sleep-wake cycle disturbances frequently occur. Irregular sleep-wake cycle, insomnia, and daytime napping usually occur in patients with AD in the course of the disease. Objective: The aim of the present study was to verify the sleep-wake cycle in mild to moderate AD patients compared to controls, and to evaluate the relationship between the sleep-wake cycle impairment and the neuropsychological testing, CSF AD biomarkers, and CSF orexin concentrations. Methods: Mild to moderate AD patients were …enrolled and underwent 14-day actigraphic recording, sleep diary, neuropsychological testing, and CSF biomarkers analysis. All patients were compared to controls. Results: Eighteen AD patients were compared to ten controls. AD patients showed the alteration of the sleep-wake cycle, featured by sleep dysregulation and daytime wake fragmentation, with respect to controls. Considering the correlation analysis, we documented the correlation between tau proteins and orexin CSF levels and sleep-wake cycle dysregulation. Conclusion: This study confirmed the dysregulation of sleep-wake cycle in AD patients, as reflected by the daytime wake fragmentation, irregular sleep-wake rhythm, and nocturnal sleep impairment. This sleep-wake cycle disorder correlates with AD neuropathological in vivo features and brain orexin activity. Hence, we suppose that a more marked AD pathology coupled with orexinergic system dysregulation may promote sleep-wake cycle impairment in AD patients. Show more

Keywords: Alzheimer’s disease, cognition, orexin, sleep-wake cycle, tau proteins

DOI: 10.3233/JAD-191124

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2020

Authors: Toniolo, Sofia | Serra, Laura | Olivito, Giusy | Caltagirone, Carlo | Mercuri, Nicola B. | Marra, Camillo | Cercignani, Mara | Bozzali, Marco

Article Type: Research Article

Abstract: The cognitive role of the cerebellum has recently gained much attention, and its pivotal role in Alzheimer’s disease (AD) has now been widely recognized. Diffusion tensor imaging (DTI) has been used to evaluate the disruption of the microstructural milieu in AD, and though several white matter (WM) tracts such as corpus callosum, inferior and superior longitudinal fasciculus, cingulum, fornix, and uncinate fasciculus have been evaluated in AD, data on cerebellar WM tracts are currently lacking. We performed a tractography-based DTI reconstruction of the middle cerebellar peduncle (MCP), and the left and right superior cerebellar peduncles separately (SCPL and SCPR) and …addressed the differences in fractional anisotropy (FA), axial diffusivity (Dax), radial diffusivity (RD), and mean diffusivity (MD) in the three tracts between 50 patients with AD and 25 healthy subjects. We found that AD patients showed a lower FA and a higher RD compared to healthy subjects in MCP, SCPL, and SCPR. Moreover, a higher MD was found in SCPR and SCPL and a higher Dax in SCPL. This result is important as it challenges the traditional view that WM bundles in the cerebellum are unaffected in AD and might identify new targets for therapeutic interventions. Show more

Keywords: Alzheimer’s disease, cerebellum, diffusion tensor imaging, probabilistic tractography, white matter

DOI: 10.3233/JAD-191125

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Hong, Yue | Alvarado, Rachel L. | Jog, Amod | Greve, Douglas N. | Salat, David H.

Article Type: Research Article

Abstract: Background: Studies have found that individuals with mild cognitive impairment (MCI) exhibit a range of deficits outside the realm of primary explicit memory, yet the role of response speed and implicit learning in older adults with MCI have not been established. Objective: The current study aims to explore and document response speed and implicit learning in older adults with neuropsychologically defined MCI using a simple serial reaction (SRT) task. In addition, the study aims to explore the feasibility of a novel utilization of the simple cognitive task using machine learning procedures as a proof of concept. …Method: Participants were 22 cognitively healthy older adults and 20 older adults with MCI confirmed through comprehensive neuropsychological evaluation. Two-sample t -test, multivariate regression, and mixed-effect models were used to investigate group difference in response speed and implicit learning on the SRT task. We also explored the potential utility of SRT feature analysis through random forest classification. Results: With demographic variables controlled, the MCI group showed overall slower reaction time and higher error rate compared to the cognitively healthy volunteers. Both groups showed significant simple motor learning and implicit learning. The learning patterns were not statistically different between the two groups. Random forest classification achieved overall accuracy of 80.9%. Conclusions: Individuals with MCI demonstrated slower reaction time and higher error rate compared to cognitively healthy volunteers but demonstrated largely preserved motor learning and implicit sequence learning. Preliminary results from random forest classification using features from SRT performance supported further research in this area. Show more

Keywords: Aging, implicit learning, mild cognitive impairment, response speed, supervised machine learning

DOI: 10.3233/JAD-191323

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Rädke, Anika | Michalowsky, Bernhard | Thyrian, Jochen René | Eichler, Tilly | Xie, Feng | Hoffmann, Wolfgang

Article Type: Research Article

Abstract: Background: Dementia care management (DCM) aims to provide optimal treatment for people with dementia (PwD). Treatment and care needs are dependent on patients’ sociodemographic and clinical characteristics and thus, economic outcomes could depend on such characteristics. Objective: To detect important subgroups that benefit most from DCM and for which a significant effect on cost, QALY, and the individual cost-effectiveness could be achieved. Methods: The analysis was based on 444 participants of the DelpHi-trial. For each subgroup, the probability of DCM being cost-effective was calculated and visualized using cost-effectiveness acceptability curves. The impact of DCM on individual …costs and QALYs was assessed by using multivariate regression models with interaction terms. Results: The probability of DCM being cost-effective at a willingness-to-pay of 40,000€ /QALY was higher in females (96% versus 16% for males), in those living alone (96% versus 26% for those living not alone), in those being moderately to severely cognitively (100% versus 3% for patients without cognitive impairment) and functionally impaired (97% versus 16% for patients without functional impairment), and in PwD having a high comorbidity (96% versus 26% for patients with a low comorbidity). Multivariate analyses revealed that females (b = –10,873; SE = 4,775, p  = 0.023) who received the intervention had significantly lower healthcare cost. DCM significantly improved QALY for PwD with mild and moderate cognitive (b = +0.232, SE = 0.105) and functional deficits (b = +0.200, SE = 0.095). Conclusion: Patients characteristics significantly affect the cost-effectiveness. Females, patients living alone, and those being moderately cognitively and functionally impaired benefit most from DCM. For those subgroups, healthcare payers could gain the highest cost savings and the highest effects on QALYs when DCM will be implemented. Show more

Keywords: Alzheimer’s disease, cost-effectiveness acceptability curve, cost-effectiveness analysis, dementia, economic evaluation, health care costs, individual cost-effectiveness ratio, net benefit regression, net monetary benefit

DOI: 10.3233/JAD-190578

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2020

Authors: Jung, Na-Yeon | Kim, Eun Soo | Kim, Hyang-Sook | Jeon, Sumin | Lee, Myung Jun | Pak, Kyoungjune | Lee, Jae-Hyeok | Lee, Young Min | Lee, Kangyoon | Shin, Jin-Hong | Ko, Jun Kyeung | Lee, Jae Meen | Yoon, Jin A | Hwang, Chungsu | Choi, Kyung-Un | Lee, Eun Chong | Seong, Joon-Kyung | Huh, Gi Yeong | Kim, Dae-Seong | Kim, Eun-Joo

Article Type: Research Article

Abstract:  The diagnostic performances of cerebrospinal fluid (CSF) biomarkers and amyloid positron emission tomography (PET) were compared by examining the association and concordance or discordance between CSF Aβ1-42 and amyloid PET, after determining our own cut-off values for CSF Alzheimer’s disease (AD) biomarkers. Furthermore, we evaluated the ability of CSF biomarkers and amyloid PET to predict clinical progression. CSF Aβ1-42 , t-tau, and p-tau levels were analyzed in 203 individuals [27 normal controls, 38 mild cognitive impairment (MCI), 62 AD dementia, and 76 patients with other neurodegenerative diseases] consecutively recruited from two dementia clinics. We used both visual and standardized …uptake value ratio (SUVR)-based amyloid PET assessments for analyses. The association of CSF biomarkers with amyloid PET SUVR, hippocampal atrophy, and cognitive function were investigated by linear regression analysis, and the risk of conversion from MCI to AD dementia was assessed using a Cox proportional hazards model. CSF p-tau/Aβ1-42 and t-tau/Aβ1-42 exhibited the best diagnostic accuracies among the CSF AD biomarkers examined. Correlations were observed between CSF biomarkers and global SUVR, hippocampal volume, and cognitive function. Overall concordance and discordance between CSF Aβ1-42 and amyloid PET was 77% and 23%, respectively. Baseline positive CSF Aβ1-42 for MCI demonstrated a 5.6-fold greater conversion risk than negative CSF Aβ1-42 .  However, amyloid PET findings failed to exhibit significant prognostic value. Therefore, despite presence of a significant correlation between the CSF Aβ1-42 level and SUVR of amyloid PET, and a relevant concordance between CSF Aβ1-42 and amyloid PET, baseline CSF Aβ1-42 better predicted AD conversion. Show more

Keywords: Alzheimer disease, amyloid, cerebrospinal fluid, mild cognitive impairment, positron emission tomography, tau

DOI: 10.3233/JAD-191109

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2020

Authors: Koch, Manja | Costanzo, Simona | Fitzpatrick, Annette L. | Lopez, Oscar L. | DeKosky, Steven | Kuller, Lewis H. | Price, Julie | Mackey, Rachel H. | Jensen, Majken K. | Mukamal, Kenneth J.

Article Type: Research Article

Abstract: Background: Light to moderate alcohol consumption has been variably associated with lower or higher risk of dementia, but effects on Alzheimer’s disease pathology are less clear. Objective: We determined whether late-life alcohol consumption was associated with Alzheimer’s disease pathology among older adults. Methods: We assessed the associations of alcohol consumption self-reported in 2000–2002 with brain amyloid-β deposition on PET scans, and white matter lesion and hippocampal volume on MRIs measured 7–9 years later in 189 participants of the Ginkgo Evaluation of Memory Study (age 75–87 years at baseline) who were free of clinical dementia, using multivariable-adjusted …and inverse probability-weighted robust linear regression models. Results: Alcohol consumption was not statistically significantly associated with amyloid-β deposition (standardized uptake value ratio difference per drink: –0.013 [95% CI: –0.027, 0.002]). Both non-drinkers and participants consuming ≥1 drink(s)/week had higher white matter lesion volume (% intracranial volume) than did the reference group of those consuming <1 drink/week (differences: 0.25 % [95% CI: 0.01, 0.50]; 0.26 % [95% CI: 0.02, 0.50]). The association of alcohol consumption and hippocampal volume was modified by age (p  = 0.02). Among participants younger than 77 years, participants consuming 1–7 drinks/week had larger hippocampal volume compared with participants consuming <1 drink/week. Conclusions: Alcohol consumption was not statistically significantly associated with amyloid-β deposition 7–9 years later. Non-drinking and greater alcohol consumption were associated with higher white matter lesion volume compared with drinking <1 drink/week. Moderate drinking was associated with higher hippocampal volume in younger individuals. Given the selective nature of this population and adverse health effects of excessive alcohol consumption, these findings warrant further investigation, but cannot be translated into clinical recommendations. Show more

Keywords: Alcohol, brain amyloid-β , epidemiology, hippocampal volume, white matter lesions

DOI: 10.3233/JAD-190834

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: de Heus, Rianne A.A. | Reumers, Stacha F.I. | van der Have, Alba | Tumelaire, Maxime | Tully, Phillip J. | Claassen, Jurgen A.H.R.

Article Type: Research Article

Abstract: Background: High visit-to-visit blood pressure variability (BPV) has been associated with cognitive decline and cerebral small vessel disease (cSVD), in particular cerebrovascular lesions. Whether day-to-day BPV also relates to cSVD has not been investigated. Objective: To investigate the cross-sectional association between day-to-day BPV and total cSVD MRI burden in older memory clinic patients. Methods: We included outpatients referred to our memory clinic, who underwent cerebral MRI as part of their diagnostic assessment. We determined the validated total cSVD score (ranging from 0–4) by combining four markers of cSVD that were visually rated. Home blood pressure (BP) …measurements were performed for one week, twice a day, according to international guidelines. BPV was defined as the within-subject coefficient of variation (CV; standard deviation/mean BP*100). We used multivariable ordinal logistic regression analyses adjusted for age, sex, smoking, diabetes, antihypertensive medication, history of cardiovascular disease, and mean BP. Results: For 82 patients (aged 71.2±7.9 years), mean home BP was 140/79±15/9 mmHg. Dementia and mild cognitive impairment were diagnosed in 46% and 34%, respectively. 78% had one or more markers of cSVD. Systolic CV was associated with cSVD burden (adjusted odds ratio per point increase in CV = 1.29, 95% confidence interval = 1.04–1.60, p  = 0.022). There were no differences in diastolic CV and mean BP between the cSVD groups. When we differentiated between morning and evening BP, only evening BPV remained significantly associated with total cSVD burden. Conclusion: Day-to-day systolic BPV is associated with cSVD burden in memory clinic patients. Future research should indicate whether lowering BPV should be included in BP management in older people with memory complaints. Show more

Keywords: Blood pressure, blood pressure variability, cerebrovascular damage, cognition, dementia, home monitoring, small vessel disease

DOI: 10.3233/JAD-191134

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Fleiner, Tim | Dauth, Hannah | Zijlstra, Wiebren | Haussermann, Peter

Article Type: Short Communication

Abstract:  Physical exercise is an effective treatment approach for neuropsychiatric symptoms (NPS), but it is unknown whether the reduction of NPS has an impact on professional caregiver burden. A randomized controlled trial in acute dementia care with N  = 70 patients, n  = 35 per group, was conducted. The intervention group (IG) received an exercise program, the control group a social stimulation program. The RM-ANOVA showed a significant group x time interaction with time effects for the IG and decreased caregiver burden due to the exercise program at follow-up. Physical exercise programs may not only be beneficial for the patients but also for …their professional caregivers. Show more

Keywords: dementia, hospital care, neuropsychiatric symptoms, professional caregiver burden, structured exercise, DRKS00006740 (German Clinical Trial Register)

DOI: 10.3233/JAD-191102

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2020

Authors: Bharadwaj, Prashant | Martins, Ralph N.

Article Type: Research Article

Abstract: Increased amyloid-β (Aβ) accumulation associated with abnormal autophagy-lysosomal activity and nutrient kinase dysregulation are common features in Alzheimer’s disease (AD) brain. Recent studies have identified PRKAG2 and TIPRL genes that control nutrient kinase regulated autophagy, and here we determined if their expression is altered in postmortem AD brains. Gene and protein expression of TIPRL were unchanged. However, gene expression of PRKAG2 was increased 3-fold and its protein levels positively correlated with Aβ accumulation in the AD brain. In summary, our findings suggest that increased PRKAG2 is an important contributing factor to Aβ accumulation in the AD brain.

Keywords: Alzheimer’s disease, amyloid-β , autophagy, PRKAG2, TIPRL

DOI: 10.3233/JAD-190948

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2020