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

Authors: Cross, Donna J. | Meabon, James S. | Cline, Marcella M. | Richards, Todd L. | Stump, Amanda J. | Cross, Chloe G. | Minoshima, Satoshi | Banks, William A. | Cook, David G.

Article Type: Research Article

Abstract: Repetitive mild traumatic brain injury (rmTBI) is known to disturb axonal integrity and may play an important role in the pathogenic cascades leading to neurodegeneration. One critical approach to reduce the future onset of neurodegeneration is to intervene in this process at an early stage following a brain injury. Previously we showed that direct application of the microtubule-stabilizing drug, paclitaxel, on the brain following controlled cortical impact improved motor function and reduced lesion size. Herein, we extended these findings to a model of mild brain injury induced by repeated closed-skull impacts. Paclitaxel was administered intranasally to circumvent its …poor transport across the blood-brain barrier. Mice received five mild closed-skull impacts (one per day for five days). Intranasal paclitaxel was administered once only, immediately after the first impact. We found that paclitaxel prevented injury-induced deficits in spatial memory task in a water tread maze. In vivo magnetic resonance imaging (MRI) and positron emission tomography with 18F-flurodeoxyglucose (FDG-PET) revealed that paclitaxel prevented structural injury and hypometabolism. On MRI, apparent, injury-induced microbleeds were observed in 100% of vehicle-treated rmTBI mice, but not in paclitaxel -treated subjects. FDG-PET revealed a 42% increase in whole brain glucose metabolism in paclitaxel-treated mice as compared to vehicle-treated rmTBI. Immunohistochemistry found reduced evidence of axonal injury and synaptic loss. Our results indicate that intranasal paclitaxel administration imparts neuroprotection against brain injury and cognitive impairment in mice. The results from this study support the idea that microtubule-stabilization strategies hold therapeutic promise in mitigating traumatic brain injury. Show more

Keywords: Axonal injury, imaging, microtubule-stabilizing drug, repeat mild traumatic brain injury, synaptic preservation

DOI: 10.3233/JAD-180871

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2018

Authors: Hornung, Karen | Zampar, Silvia | Engel, Nadine | Klafki, Hans | Liepold, Thomas | Bayer, Thomas A. | Wiltfang, Jens | Jahn, Olaf | Wirths, Oliver

Article Type: Research Article

Abstract: In sporadic Alzheimer’s disease (AD), an imbalance between production and clearance of amyloid-β (Aβ) peptides seems to account for enhanced Aβ accumulation. The metalloprotease neprilysin (NEP) is an important Aβ degrading enzyme as shown by a variety of in vitro and in vivo studies. While the degradation of full-length Aβ peptides such as Aβ1 - 40 and Aβ1 - 42 is well established, it is less clear whether NEP is also capable of degrading N-terminally truncated Aβ species such as the common variant Aβ4 - 42 . In the present report, we confirmed the degradation of Aβ4 - x species by neprilysin using in vitro …digestion and subsequent analysis using gel-based assays and mass spectrometry. By crossing Tg4-42 mice expressing only Aβ4 - 42 peptides with homozygous NEP-knock-out mice (NEP -/-  ), we were able to demonstrate that NEP deficiency increased hippocampal intraneuronal Aβ levels and aggravated neuron loss in the Tg4-42 transgenic mouse model of AD. Show more

Keywords: Alzheimer’s disease, AβPP, intraneuronal amyloid-β, mass spectrometry, neprilysin, neuron loss, transgenic mice, stereology

DOI: 10.3233/JAD-181134

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

Authors: Koop-Nieuwelink, Carolien | Sedaghat, Sanaz | Mutlu, Unal | Licher, Silvan | Franco, Oscar H. | Ikram, M. Arfan | Geerlings, Mirjam I | Ikram, M. Kamran | Bos, Daniel

Article Type: Short Communication

Abstract: Longitudinal population-based data on effects of kidney dysfunction in the development of stroke and dementia remains inconclusive. We investigated associations of kidney function with risk of stroke and dementia in 5,993 community-dwelling individuals (mean age: 69.0 years, 57.2% women). We calculated estimated glomerular filtration rates based on creatinine, cystatin-C, and a combination of these two. During a mean follow-up of 11.6 years (69,790 person-years), 1,360 individuals suffered a stroke (n  = 602) or developed dementia (n  = 758). We found that an impaired kidney function was related to a higher risk of stroke, but not to dementia.

Keywords: Dementia, epidemiology, glomerular filtration rate, kidney function, stroke

DOI: 10.3233/JAD-181086

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2018

Authors: Wright, John W. | Harding, Joseph W.

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive neuron losses in memory-associated brain structures that rob patients of their dignity and quality of life. Five drugs have been approved by the FDA to treat AD but none modify or significantly slow disease progression. New therapies are needed to delay the course of this disease with the ultimate goal of preventing neuron losses and preserving memory functioning. In this review we describe the renin-angiotensin II (AngII) system (RAS) with specific regard to its deleterious contributions to hypertension, facilitation of neuroinflammation and oxidative stress, reduced cerebral blood flow, tissue remodeling, …and disruption of memory consolidation and retrieval. There is evidence that components of the RAS, AngIV and Ang(1–7), are positioned to counter such damaging influences and these systems are detailed with the goal of drawing attention to their importance as drug development targets. Ang(1–7) binds at the Mas receptor, while AngIV binds at the AT4 receptor subtype, and these receptor numbers are significantly decreased in AD patients, accompanied by declines in brain aminopeptidases A and N, enzymes essential for the synthesis of AngIV. Potent analogs may be useful to counter these changes and facilitate neuronal functioning and reduce apoptosis in memory associated brain structures of AD patients. Show more

Keywords: Alzheimer’s disease, Ang(1–7)/Mas receptor system, angiotensin II/AT1 receptor system, angiotensin IV/AT4 receptor system, insulin-regulated aminopeptidase (IRAP), renin-angiotensin system (RAS)

DOI: 10.3233/JAD-181035

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

Authors: Lutski, Miri | Weinstein, Galit | Goldbourt, Uri | Tanne, David

Article Type: Research Article

Abstract: Background: Lipid levels are associated with an increased risk of cardiovascular disease. Objective: We investigated the association between plasma lipids, apolipoproteins levels, apolipoprotein B/low-density lipoprotein cholesterol (Apo-B/LDL-C), and Apo-B/Apo-A ratios and rate of cognitive decline two decades later in men with coronary heart disease (CHD). Methods: A subset of 337 men (mean age at baseline 56.6±6.4 years) who previously participated in the Bezafibrate Infarction Prevention (BIP) trial (1990–1997) underwent cognitive evaluations 15±3 years (T1) and 19.9±1 years after baseline (T2) as part of the BIP Neurocognitive study. Lipid and apolipoprotein fractions were measured …at baseline. Cognitive function for memory, executive function, visual spatial, attention domains, and composite score were assessed using the NeuroTrax Computerized Battery at T1 and T2 evaluations. Linear mixed models were used to assess change in cognitive function between the two cognitive evaluations. Results: Controlling for confounders, the decline in composite cognitive score (β = –0.161±0.06; p  = 0.013) as well as in memory (β = –0.269±0.10; p  = 0.009) and visual spatial function (β = –0.304±0.12; p  = 0.010) was greater among patients in the upper (≥105 mg/dL) Apo-B tertile as compared to counterparts with <  105 mg/dL. The decline in the composite cognitive score (β = –0.124±0.06; p  = 0.043) was also greater among patients in the estimated LDL-C≥160 mg/dL group compared to counterparts with LDL-C<160 mg/dL. Upper tertile of Apo-B/LDL-C ratio (≥0.75) compared to the lower tertiles was significantly associated with change in memory score (β = –0.210±0.10; p  = 0.041). Conclusion: Our findings suggest that the plasma concentrations of Apo-B, LDL-C, and Apo-B/LDL-C ratio are potential predictors of accelerated late-life cognitive decline among men with CHD. Show more

Keywords: Apolipoproteins, cognitive decline, coronary heart disease, lipid ratios, plasma lipids

DOI: 10.3233/JAD-180849

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

Authors: Oliveira, Deborah | Jun Otuyama, Leonardo | Mabunda, Dirceu | Mandlate, Flavio | Gonçalves-Pereira, Manuel | Xavier, Miguel | Laks, Jerson | Ferri, Cleusa P.

Article Type: Research Article

Abstract: Background: Most people with dementia live in low- and middle-income countries and little is known about the potential for reducing these numbers by reducing key risk factors. Objective: To investigate the potential for dementia incidence reduction in Brazil, Mozambique, and Portugal (a culturally related, high-income country). Methods: We replicated previously published methods and based on the relative risks from previous studies, we estimated the population-attributable risk (PAR) of dementia in Mozambique, Brazil, and Portugal for seven modifiable risk factors associated with dementia (low educational attainment, physical inactivity, midlife hypertension, midlife obesity, depression, smoking, …and diabetes mellitus). The combined PAR was calculated and adjusted for associations between risk factors. The potential for risk factor reduction was assessed by examining the effect of relative reductions of 10% and 20% per decade for each of the risk factors on projections for dementia cases for each decade until 2050. Results: After adjusting for non-independence of risk factors, 24.4%, 32.3%, and 40.1% of dementia cases could be related to seven potentially modifiable risk factors in Mozambique, Brazil, and Portugal, respectively. Reducing the prevalence of each risk factor by 20% per decade could, by 2050, potentially reduce the prevalence of dementia in Mozambique, Brazil, and Portugal by 12.9%, 16.2%, and 19.5%, respectively. Conclusion: There is a substantial difference between the countries on in the percentage of dementia cases that could be attributable to the seven potentially modifiable risk factors. The proportion of cases that could be prevented by 2050 if measures were taken to address these main risk factors was higher in Portugal than in Brazil and Mozambique. Each country or region should consider their unique risk factor profile when developing dementia risk reduction programs. Show more

Keywords: Alzheimer’s disease, dementia, low- and middle-income countries, prevention, risk reduction

DOI: 10.3233/JAD-180636

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

Authors: Ben Jemaa, Sonia | Marzouki, Yousri | Ben Fredj, Mohamed | Le Gall, Didier | Bellaj, Tarek

Article Type: Research Article

Abstract: Background: Depression is a major disorder that can be triggering, co-occurring, or exacerbating dementia symptoms. Its assessment is paramount to achieve diagnostic, prognostic, and therapeutic decisions. The Cornell Scale for Depression in Dementia (CSDD) is purposely designed to address clinically this issue. Objective: To examine the reliability and validity of an Arabic version of the CSDD (A-CSDD) in the Tunisian population. Methods: Fifty-seven participants took part in this study: 20 as a control group (NC), 18 as dementia patients with depression (DD), and 19 as depressed patients without dementia (DND); all patients met the DSM IV …criteria for depression and/or dementia. A translated, back-translated and adapted Arabic version of the CSDD was administered in parallel with the Geriatric Depression Scale (GDS), the non-cognitive part of the Alzheimer’s disease Assessment Scale, and the Mini-Mental State Examination. Results: The A-CSDD had good internal consistency (Cronbach’s alpha = 0.85) and high test-retest reliability (Rho  = 0.897, p  <  0.001). The A-CSDD had excellent discriminatory power to diagnose depression in dementia patients (AUC = 0.90, p  <  0.001) and good concurrent validity with the GDS (Rho  = 0.70, p  <  0.001). A principal component analysis with varimax rotation, performed on the DD group, led to a configuration of five factors explaining 75% of the variance. Conclusions: The results showed that this Arabic-Tunisian version of the A-CSDD is reliable and valid for diagnosing depression in an elderly Tunisian population with dementia and can be used in clinical and research settings. Show more

Keywords: Arabic version, Cornell Scale for Depression in Dementia, culture, dementia, depression, normative data, reliability, test adaptation, validity

DOI: 10.3233/JAD-180448

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

Authors: Alfini, Alfonso J. | Weiss, Lauren R. | Nielson, Kristy A. | Verber, Matthew D. | Smith, J. Carson

Article Type: Research Article

Abstract: Background: Exercise training has been associated with greater cerebral blood flow (CBF) in cognitively normal older adults (CN). Alterations in CBF, including compensatory perfusion in the prefrontal cortex, may facilitate changes to the brain’s neural infrastructure. Objective: To examine the effects of a 12-week aerobic exercise intervention on resting CBF and cognition in CN and those with mild cognitive impairment (MCI). We hypothesized individuals with MCI (versus CN) would exhibit greater whole brain CBF at baseline and that exercise would mitigate these differences. We also expected CBF changes to parallel cognitive improvements. Methods: Before and after …a 12-week exercise intervention, 18 CN and 17 MCI participants (aged 61–88) underwent aerobic fitness testing, neuropsychological assessment, and an MRI scan. Perfusion-weighted images were collected using a GE 3T MR system. Repeated measures analyses of covariance were used to test within- and between-group differences over time, followed by post-hoc analyses to examine links between CBF changes and cognitive improvement. Results: At baseline, individuals with MCI (versus CN) exhibited significantly elevated perfusion in the left insula. Twelve weeks of aerobic exercise reversed this discrepancy. Additionally, exercise improved working memory (measured by the Rey Auditory Verbal Learning Test) and verbal fluency (measured by the Controlled Oral Word Association Test) and differentially altered CBF depending on cognitive status. Among those with MCI, decreased CBF in the left insula and anterior cingulate cortex was associated with improved verbal fluency. Conclusions: Exercise training alters CBF and improves cognitive performance in older adults with and without cognitive impairment. Future studies must evaluate the mediating effects of CBF on the association between exercise training and cognition. Show more

Keywords: Aging, cerebral blood flow, exercise, magnetic resonance imaging, mild cognitive impairment, neuroimaging

DOI: 10.3233/JAD-180728

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2018

Authors: Huisa, Branko N. | Thomas, Ronald G. | Jin, Shelia | Oltersdorf, Tilman | Taylor, Curtis | Feldman, Howard H.

Article Type: Research Article

Abstract: Background: Acetylcholinesterase inhibitors (AChEIs) and memantine are commonly prescribed medications for Alzheimer’s disease (AD). Their concurrent use in AD randomized clinical trials (RCTs) is generally allowed but their effect in outcome measures is unsettled. Objective: To evaluate whether use of AChEIs and/or memantine across AD RCTs are associated with different rates of cognitive/functional decline. Methods: We pooled data from 5 RCTs of mild to moderate AD conducted by the Alzheimer’s Disease Cooperative Study (ADCS) between 2002-2013. 1,423 participants with MMSE of 14–26 and completion of 12–18 months follow-up visits were analyzed. Trials did …not randomize with respect to AChEIs or memantine. We defined 4 groups: AChEI (27%), memantine (16%), AChEIs+memantine (46%), and non-users (11%). Outcome measures were change in ADAS-cog-11, ADCS-ADL, and MMSE from baseline to 18 months. Fisher’s exact test, Wilcoxon signed rank, and Spearman’s tests were used to identify confounding variables. Mixed model repeated measures were used for adjustments and pairwise tests for comparing change in scores. Results: Age, apolipoprotein E, and initial MMSE were identified as covariates. Memantine and/or AChEIs users had greater impairment at entry than non-users. There was a significant decline on the ADAS-cog-11 in the memantine (estimate –4.2 p  <  0.0001) and AChEIs+memantine groups (estimate –3.5 p  <  0.0001) than non-users, while there was significantly more decline in MMSE (estimate 2.5 p  <  0.0001) and ADCS-ADL in the AChEIs+memantine group (estimate 4.3 p  <  0.0001) Conclusion: Memantine monotherapy or combined with AChEIs are associated with more rapid cognitive and functional decline than non-users. We postulated a potential selection bias by indication. Show more

Keywords: Acetylcholinesterase inhibitors, Alzheimer’s disease, memantine, randomized clinical trials

DOI: 10.3233/JAD-180684

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2018

Authors: Khoonsari, Payam Emami | Shevchenko, Ganna | Herman, Stephanie | Remnestål, Julia | Giedraitis, Vilmantas | Brundin, RoseMarie | Gunnarsson, Malin Degerman | Kilander, Lena | Zetterberg, Henrik | Nilsson, Peter | Lannfelt, Lars | Ingelsson, Martin | Kultima, Kim

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is diagnosed based on a clinical evaluation as well as analyses of classical biomarkers: Aβ 42 , total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF). Although the sensitivities and specificities of the classical biomarkers are fairly good for detection of AD, there is still a need to develop novel biochemical markers for early detection of AD. Objective: We explored if integration of novel proteins with classical biomarkers in CSF can better discriminate AD from non-AD subjects. Methods: We applied ELISA, mass spectrometry, and multivariate modeling …to investigate classical biomarkers and the CSF proteome in subjects (n  = 206) with 76 AD patients, 74 mild cognitive impairment (MCI) patients, 11 frontotemporal dementia (FTD) patients, and 45 non-dementia controls. The MCI patients were followed for 4–9 years and 21 of these converted to AD, whereas 53 remained stable. Results: By combining classical CSF biomarkers with twelve novel markers, the area of the ROC curves (AUROCS) of distinguishing AD and MCI/AD converters from non-AD were 93% and 96%, respectively. The FTDs and non-dementia controls were identified versus all other groups with AUROCS of 96% and 87%, respectively. Conclusions: Integration of new and classical CSF biomarkers in a model-based approach can improve the identification of AD, FTD, and non-dementia control subjects. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, ELISA, mass spectrometry, mild cognitive impairment, proteomics

DOI: 10.3233/JAD-180855

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2018