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

Authors: Strobel, Sabrina | Grünblatt, Edna | Heinsen, Helmut | Riederer, Peter | Espach, Thomas | Meder, Michael | Monoranu, Camelia-Maria

Article Type: Research Article

Abstract: Oxidative stress is implicated in the pathogenesis of neurodegenerative diseases, including sporadic Alzheimer’s disease (AD). Mitochondrial DNA (mtDNA) deletions are markers of oxidative damage with an age-dependent accumulation. In a previous study, we analyzed mtDNA levels in diverse neuronal cell types in order to unravel the impact of oxidative stress in brains of AD patients. The aim of this study was to identify possible correlations between mtDNA deletion levels of selected astrocytes and microglia from three brain regions with different vulnerability to AD pathology and different stages of disease compared to controls. Our results reflect a higher vulnerability of hippocampal …astrocytes and microglia to oxidative stress compared to other brain regions, such as cerebellum and brain stem. Show more

Keywords: Alzheimer’s disease, astrocytes, brainstem, cerebellum, hippocampus, microglia, mitochondrial DNA, oxidative stress, selective vulnerability

DOI: 10.3233/JAD-180661

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2018

Authors: Guven, Gamze | Bilgic, Başar | Tufekcioglu, Zeynep | Erginel Unaltuna, Nihan | Hanagasi, Hasmet | Gurvit, Hakan | Singleton, Andrew | Hardy, John | Emre, Murat | Gulec, Cagri | Bras, Jose | Guerreiro, Rita | Lohmann, Ebba

Article Type: Research Article

Abstract: Progranulin (GRN) gene mutations are a major cause of frontotemporal dementia (FTD). Most mutations identified to date are null mutations, which are predicted to cause the pathology via haploinsufficiency. Decreased peripheral progranulin protein (PGRN) levels are associated with the presence of GRN null mutations and are accepted as reliable biomarkers. In this study, our aim was to test whether the presence of specific GRN splice site mutations (c.– 8+2T>G and c.708+6_9del), could be predicted by peripheral mRNA or protein GRN levels, by studying affected and asymptomatic individuals from FTD families. We also tested four missense GRN …variants to assess if altered GRN levels depended on the type of mutation. Our results confirmed a reduction in both mRNA and protein PGRN levels in the splice site mutation carriers, which is consistent with previous reports for null mutations. Our results also suggested that both decreased peripheral GRN mRNA and serum PGRN levels indicate the presence of pathogenic mutations in affected individuals, and identify the asymptomatic individuals at risk, without previous knowledge of genetic status. Both inferences suggest a potential use of peripheral GRN mRNA or serum PGRN levels as biomarkers for families with FTD. Show more

Keywords: ELISA, frontotemporal dementia, progranulin, serum, splice site mutation

DOI: 10.3233/JAD-180599

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2018

Authors: Rizzo, Giovanni | De Blasi, Roberto | Capozzo, Rosa | Tortelli, Rosanna | Barulli, Maria Rosaria | Liguori, Rocco | Grasso, Daniela | Logroscino, Giancarlo

Article Type: Short Communication

Abstract: We assessed nigral dorsolateral hyperintensity (swallow tail sign) at susceptibility-weighted imaging using 3T-MRI in 15 dementia with Lewy bodies (DLB), 11 Alzheimer’s disease (AD), and 8 frontotemporal dementia (FTD) patients and 10 subjects with subjective memory complaint (SMC). More DLB patients lacked nigral hyperintesity (p  <  0.05). Sensitivity, specificity, and accuracy of DLB diagnosis were, respectively: 80%, 64%, and 73% versus AD; 80%, 75%, and 78% versus FTD; and 80%, 90%, and 84% versus SMC. Considering bilateral loss, sensitivity decreased (53% ) but specificity increased (82–100% ). Swallow tail sign loss, especially if bilateral, can be useful for DLB diagnosis.

Keywords: Dementia with Lewy bodies, magnetic resonance imaging, nigrosome, swallow tail sign, susceptibility-weighted imaging

DOI: 10.3233/JAD-180687

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2018

Authors: Schwarz, Christopher G. | Gunter, Jeffrey L. | Lowe, Val J. | Weigand, Stephen | Vemuri, Prashanthi | Senjem, Matthew L. | Petersen, Ronald C. | Knopman, David S. | Jack Jr , Clifford R.

Article Type: Research Article

Abstract: Longitudinal PET studies in aging and Alzheimer’s disease populations rely on accurate and precise measurements of change over time from serial PET scans. Various methods for partial volume correction (PVC) are commonly applied to such studies, but existing comparisons and validations of these PVC methods have focused on cross-sectional measurements. Rate of change measurements inherently have smaller magnitudes than cross-sectional measurements, so levels of noise amplification due to PVC must be smaller, and it is necessary to re-evaluate methods in this context. Here we compare the relative precision in longitudinal measurements from serial amyloid PET scans when using geometric transfer …matrix (GTM) PVC versus the traditional two-compartment (Meltzer-style), three-compartment (Müller-Gärtner-style), and no-PVC approaches. We used two independent implementations of standardized uptake value ratio (SUVR) measurement and PVC (one in-house pipeline based on SPM12 and ANTs, and one using FreeSurfer 6.0). For each approach, we also tested longitudinal-specific variants. Overall, we found that measurements using GTM PVC had significantly worse relative precision (unexplained within-subject variability ≈4–8%) than those using two-compartment, three-compartment, or no PVC (≈2–4%). Longitudinally-stabilized approaches did not improve these properties. This data suggests that GTM PVC methods may be less suitable than traditional approaches when measuring within-person change over time in longitudinal amyloid PET. Show more

Keywords: Amyloid PET, change over time, geometric transfer matrix, partial volume correction, Pittsburgh Compound B, precision, SUVR

DOI: 10.3233/JAD-180749

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2018

Authors: Koseoglu, Mehmet Murat | Norambuena, Andrés | Sharlow, Elizabeth R. | Lazo, John S. | Bloom, George S.

Article Type: Review Article

Abstract: Aberrant neuronal cell cycle re-entry (CCR) is a phenomenon that precedes and may mechanistically lead to a majority of the neuronal loss observed in Alzheimer’s disease (AD). Recent developments concerning the regulation of aberrant neuronal CCR in AD suggest that there are potential intracellular signaling “hotspots” in AD, cancer, and brain insulin resistance, the latter of which is characteristically associated with AD. Critically, these common signaling nodes across different human diseases may represent currently untapped therapeutic opportunities for AD. Specifically, repurposing of existing US Food and Drug Administration-approved pharmacological agents, including experimental therapeutics that target the cell cycle in cancer, …may be an innovative avenue for future AD-directed drug discovery and development. In this review we discuss overlapping aspects of AD, cancer, and brain insulin resistance from the perspective of neuronal CCR, and consider strategies to exploit them for prevention or therapeutic intervention of AD. Show more

Keywords: Alzheimer’s disease, amyloid, cell cycle re-entry, tau

DOI: 10.3233/JAD-180874

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2018

Authors: Helman, Alex M. | Siever, Morgan | McCarty, Katie L. | Lott, Ira T. | Doran, Eric | Abner, Erin L. | Schmitt, Frederick A. | Head, Elizabeth

Article Type: Research Article

Abstract: Cerebrovascular pathology is a significant mediator in Alzheimer’s disease (AD) in the general population. In people with Down syndrome (DS), the contribution of vascular pathology to dementia may play a similar role in age of onset and/or the rate of progression of AD. In the current study, we explored the extent of microbleeds (MBs) and the link between cerebral amyloid angiopathy (CAA) and MBs in the frontal cortex (FCTX) and occipital cortex (OCTX) in an autopsy series from individuals with DS (<40 years), DS with AD pathology (DSAD), sporadic AD, and control cases (2–83 years). Sections were immunostained against Aβ …1 - 40 and an adjacent section stained using Prussian blue for MBs. MBs were both counted and averaged in each case and CAA was scored based on previously published methods. MBs were more frequent in DS cases relative to controls but present to a similar extent as sporadic AD. This aligned with CAA scores, with more extensive CAA in DS relative to controls in both brain regions. CAA was also more frequent in DSAD cases relative to sporadic AD. We found CAA to be associated with MBs and that MBs increased with age in DS after 30 years of age in the OCTX and after 40 years of age in the FCTX. MB and CAA appear to be a significant contributors to the development of dementia in people with DS and are important targets for future clinical trials. Show more

Keywords: Cerebral amyloid angiopathy, microhemorrhages, Prussian blue, trisomy 21

DOI: 10.3233/JAD-180589

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2018

Authors: Jovicich, Jorge | Babiloni, Claudio | Ferrari, Clarissa | Marizzoni, Moira | Moretti, Davide V. | Del Percio, Claudio | Lizio, Roberta | Lopez, Susanna | Galluzzi, Samantha | Albani, Diego | Cavaliere, Libera | Minati, Ludovico | Didic, Mira | Fiedler, Ute | Forloni, Gianluigi | Hensch, Tilman | Molinuevo, José Luis | Bartrés Faz, David | Nobili, Flavio | Orlandi, Daniele | Parnetti, Lucilla | Farotti, Lucia | Costa, Cinzia | Payoux, Pierre | Rossini, Paolo Maria | Marra, Camillo | Schönknecht, Peter | Soricelli, Andrea | Noce, Giuseppe | Salvatore, Marco | Tsolaki, Magda | Visser, Pieter Jelle | Richardson, Jill C. | Wiltfang, Jens | Bordet, Régis | Blin, Olivier | Frisoniand, Giovanni B.

Article Type: Research Article

Abstract: Auditory “oddball” event-related potentials (aoERPs), resting state functional magnetic resonance imaging (rsfMRI) connectivity, and electroencephalographic (rsEEG) rhythms were tested as longitudinal functional biomarkers of prodromal Alzheimer’s disease (AD). Data were collected at baseline and four follow-ups at 6, 12, 18, and 24 months in amnesic mild cognitive impairment (aMCI) patients classified in two groups: “positive” (i.e., “prodromal AD”; n  = 81) or “negative” (n  = 63) based on a diagnostic marker of AD derived from cerebrospinal samples (Aβ 42 /P-tau ratio). A linear mixed model design was used to test functional biomarkers for Group, Time, and Group×Time effects adjusted by nuisance …covariates (only data until conversion to dementia was used). Functional biomarkers that showed significant Group effects (“positive” versus “negative”, p  <  0.05) regardless of Time were 1) reduced rsfMRI connectivity in both the default mode network (DMN) and the posterior cingulate cortex (PCC), both also giving significant Time effects (connectivity decay regardless of Group); 2) increased rsEEG source activity at delta (<4 Hz) and theta (4–8 Hz) rhythms and decreased source activity at low-frequency alpha (8–10.5 Hz) rhythms; and 3) reduced parietal and posterior cingulate source activities of aoERPs. Time×Group effects showed differential functional biomarker progression between groups: 1) increased rsfMRI connectivity in the left parietal cortex of the DMN nodes, consistent with compensatory effects and 2) increased limbic source activity at theta rhythms. These findings represent the first longitudinal characterization of functional biomarkers of prodromal AD relative to “negative” aMCI patients based on 5 serial recording sessions over 2 years. Show more

Keywords: Alpha rhythms, amnesic mild cognitive impairment, biomarkers, clinical trial, electroencephalography, functional magnetic resonance imaging, oddball event-related potentials, PharmaCog project, prodromal Alzheimer’s disease, resting state

DOI: 10.3233/JAD-180158

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-21, 2018

Authors: Cox, Kay L. | Cyarto, Elizabeth V. | Ellis, Kathryn A. | Ames, David | Desmond, Patricia | Phal, Pramit | Sharman, Matthew J. | Szoeke, Cassandra | Rowe, Christopher C. | Masters, Colin L. | You, Emily | Burrows, Sally | Lai, Michelle M.Y. | Lautenschlager, Nicola T.

Article Type: Research Article

Abstract: Background: Previous studies have demonstrated that physical activity (PA) interventions can improve physical and cognitive outcomes in older adults, but most have been relatively short in duration (<1 year) with a few having specifically targeting individuals at risk of developing Alzheimer’s disease. Objective: To examine adherence and physical health outcomes in a 24-month home-based PA intervention in older adults at risk of Alzheimer’s disease. Methods: Participants 60 years and older with mild cognitive impairment (MCI) or subjective memory complaints (SMC) with at least 1 cerebrovascular risk factor recruited from The Australian Imaging Biomarkers and Lifestyle Flagship …Study of Aging (AIBL) were randomized to a PA or control group (n  = 106). The control group continued with their usual lifestyle. The PA group received a 24-month home-based program with a target of 150 minutes/week of moderate PA and a behavioral intervention. Retention (participants remaining) and PA adherence (PA group only, percent PA completed to the PA prescribed) were determined at 6, 12, 18, and 24 months. Assessments at baseline, 6, 12, and 24 months included, PA; fitness; body composition and fat distribution. Key outcome measures were PA adherence and PA. Results: The 24-month retention rate (97.2%) and the median PA adherence 91.67% (Q1–Q3, 81.96, 100.00) were excellent. In the long-term the intervention group achieved significantly better improvements in PA levels, leg strength, fat mass and fat distribution compared to the control. Conclusion: This study demonstrates that in this target group, long-term PA adherence is achievable and has physical health benefits. Show more

Keywords: Adherence, cerebrovascular disease, mild cognitive impairment, physical activity, subjective memory complaints

DOI: 10.3233/JAD-180521

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2018

Authors: Sacre, Julian W | Magliano, Dianna J. | Zimmet, Paul Z. | Polkinghorne, Kevan R. | Chadban, Steven J. | Anstey, Kaarin J. | Shaw, Jonathan E.

Article Type: Research Article

Abstract: Background: The role of chronic kidney disease (CKD) as a risk factor for cognitive impairment independent of their shared antecedents remains controversial. Objective: To determine whether kidney damage (indicated by albuminuria) or kidney dysfunction (estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m2 ) predict future (12-year) cognitive function independently of their shared risk factors. Methods: We studied 4,128 individuals from the 1999/00 population-based Australian Diabetes, Obesity, and Lifestyle (AusDiab) Study who returned in 2011/12 for follow-up cognitive function testing. Albuminuria was defined by urinary albumin:creatinine≥3.5 (women) or≥2.5 mg/mmol (men). Kidney dysfunction was indicated by eGFR <60 ml/min/1.73 m2 . Cognitive function …domains assessed included memory (California Verbal Learning Test [CVLT]) and processing speed (Symbol Digit Modalities Test [SDMT]). Results: Baseline albuminuria and kidney dysfunction were identified in 142 (3.4%) and 39 (0.9%) individuals, respectively, with minimal overlap (n  = 7). Those with albuminuria demonstrated concurrently reduced 12-year SDMT (p  = 0.084) and CVLT scores (p  = 0.005) following adjustment for age, sex, and education. However, only CVLT performance remained worse (p  = 0.027) following additional adjustment for myocardial infarction, stroke, and related risk factors (hypertension, diabetes, dyslipidemia, smoking, BMI, physical activity, and alcohol intake). Indeed, these collective covariates were responsible for 47% of the effect of albuminuria on SDMT, but only 21% of its effect on CVLT. Kidney dysfunction was not associated with either SDMT or CVLT performance (p  >  0.10). Conclusions: Albuminuria predicted worse memory function at 12 years follow-up, whereas its effect on processing speed was driven largely by differences in cardiovascular risk. Kidney dysfunction based on eGFR predicted neither cognitive domain. Show more

Keywords: Cardiovascular diseases, cognition disorders, cognitive decline, cognitive impairment, cohort studies, kidney diseases

DOI: 10.3233/JAD-180498

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2018

Authors: Evans, Isobel E.M. | Martyr, Anthony | Collins, Rachel | Brayne, Carol | Clare, Linda

Article Type: Research Article

Abstract: Background: There is some evidence to suggest that social isolation may be associated with poor cognitive function in later life. However, findings are inconsistent and there is wide variation in the measures used to assess social isolation. Objective: We conducted a systematic review and meta-analysis to investigate the association between social isolation and cognitive function in later life. Methods: A search for longitudinal studies assessing the relationship between aspects of social isolation (including social activity and social networks) and cognitive function (including global measures of cognition, memory, and executive function) was conducted in PsycInfo, CINAHL, PubMed, …and AgeLine. A random effects meta-analysis was conducted to assess the overall association between measures of social isolation and cognitive function. Sub-analyses investigated the association between different aspects of social isolation and each of the measures of cognitive function. Results: Sixty-five articles were identified by the systematic review and 51 articles were included in the meta-analysis. Low levels of social isolation characterized by high engagement in social activity and large social networks were associated with better late-life cognitive function (r  = 0.054, 95% CI: 0.043, 0.065). Sub-analyses suggested that the association between social isolation and measures of global cognitive function, memory, and executive function were similar and there was no difference according to gender or number of years follow-up. Conclusions: Aspects of social isolation are associated with cognitive function in later life. There is wide variation in approaches to measuring social activity and social networks across studies which may contribute to inconsistencies in reported findings. Show more

Keywords: Aging, cognition, cognitive reserve, social isolation

DOI: 10.3233/JAD-180501

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-26, 2018