March 15, 2016

Alzheimer’s & Dementia: A Journal of the Alzheimer’s


 
 Association. Volume 12, Issue 2, February 2016
 
Jia, et al.DOI: http://dx.doi.org/10.1016/j.jalz.2015.04.010 p89–99

 

Abstract

Introduction
Vascular cognitive impairment without dementia is very common among the aged and tends to progress to dementia, but there have been no proper large-scale intervention trials dedicated to it. Vascular cognitive impairment without dementia caused by subcortical ischemic small vessel disease (hereinafter, subcortical Vascular cognitive impairment without dementia) represents a relatively homogeneous disease process and is a suitable target for therapeutic trials investigating Vascular cognitive impairment without dementia. Preclinical trials showed that dl-3-n-butylphthalide (NBP) is effective for cognitive impairment of vascular origin.
Methods
In this randomized, double-blind, placebo-controlled trial, we enrolled patients aged 50–70 years who had a diagnosis of subcortical Vascular cognitive impairment without dementia at 15 academic medical centers in China. Inclusion criteria included a clinical dementia rating ≥0.5 on at least one domain and global score ≤0.5; a mini-mental state examination score ≥20 (primary school) or ≥24 (junior school or above); and brain magnetic resonance imaging consistent with subcortical ischemic small vessel disease. Patients were randomly assigned to NBP 200 mg three times daily or matched placebo (1:1) for 24 weeks according to a computer-generated randomization protocol. All patients and study personnel were masked to treatment assignment. Primary outcome measures were the changes in Alzheimer's disease assessment scale-cognitive subscale (ADAS-cog) and clinician's interview-based impression of change plus caregiver input (CIBIC-plus) after 24 weeks. All patients were monitored for adverse events (AEs). Outcome measures were analyzed for both the intention-to-treat (ITT) population and the per protocol population.
Results
This study enrolled 281 patients. NBP showed greater effects than placebo on ADAS-cog (NBP change 2.46 vs. placebo 1.39; P = .03; ITT) and CIBIC-plus (80 [57.1%] vs. 59 [42.1%] patients improved; P = .01; ITT). NBP-related AE were uncommon and primarily consisted of mild gastrointestinal symptoms.
Discussion
Over the 6-month treatment period, NBP was effective for improving cognitive and global functioning in patients with subcortical vascular cognitive impairment without dementia and exhibited good safety.
 
 

Prudent diet may attenuate the adverse effects of Western diet on cognitive decline

Shakersain, et al. DOI: http://dx.doi.org/10.1016/j.jalz.2015.08.002p100–109
 

Abstract

Introduction
The influence of mixed dietary patterns on cognitive changes is unknown.
Methods
A total of 2223 dementia-free participants aged ≥60 were followed up for 6 years to examine the impact of dietary patterns on cognitive decline. Mini-mental state examination (MMSE) was administered. Diet was assessed by a food frequency questionnaire. By factor analysis, Western and prudent dietary patterns emerged. Mixed-effect models for longitudinal data with repeated measurements were used.
Results
Compared with the lowest adherence to each pattern, the highest adherence to prudent pattern was related to less MMSE decline (β = 0.106, P = .011), whereas the highest adherence to Western pattern was associated with more MMSE decline (β = 0.156, P < .001). The decline associated with Western diet was attenuated when accompanied by high adherence to prudent pattern.
Discussion
High adherence to prudent diet may diminish the adverse effects of high adherence to Western diet on cognitive decline.
 
Siemers, et al. DOI: http://dx.doi.org/10.1016/j.jalz.2015.06.1893p110–120
 

Abstract

Introduction
EXPEDITION and EXPEDITION2 were identically designed placebo-controlled phase 3 studies assessing effects of solanezumab, an antiamyloid monoclonal antibody binding soluble amyloid-β peptide, on cognitive and functional decline over 80 weeks in patients with mild-to-moderate Alzheimer's disease (AD). Primary findings for both studies have been published.
Methods
Secondary analyses of efficacy, biomarker, and safety endpoints in the pooled (EXPEDTION + EXPEDITION2) mild AD population were performed.
Results
In the mild AD population, less cognitive and functional decline was observed with solanezumab (n = 659) versus placebo (n = 663), measured by Alzheimer's Disease Assessment Scale Cognitive subscale, Mini-Mental State Examination, and Alzheimer's Disease Cooperative Study–Activities of Daily Living functional scale Instrumental ADLs. Baseline-to-endpoint changes did not differ between treatment groups for Alzheimer's Disease Cooperative Study–Activities of Daily Living functional scale, basic items of the ADCS-ADL, and Clinical Dementia Rating Sum of Boxes. Plasma/cerebrospinal fluid biomarker findings indicated target engagement by solanezumab. Solanezumab demonstrated acceptable safety. Efficacy findings for the moderate AD population are also provided.
Discussion
These findings describe solanezumab effects on efficacy/safety measures in a mild AD population. Another phase 3 study, EXPEDITION3, will investigate solanezumab's effects in a mild AD population.
 
Ebbert, et al.DOI: http://dx.doi.org/10.1016/j.jalz.2015.08.163 p121–129
 

Abstract

Introduction
Ebbert et al. reported gene-gene interactions between rs11136000-rs670139 (CLU-MS4A4E) and rs3865444-rs670139 (CD33-MS4A4E). We evaluate these interactions in the largest data set for an epistasis study.
Methods
We tested interactions using 3837 cases and 4145 controls from Alzheimer's Disease Genetics Consortium using meta-analyses and permutation analyses. We repeated meta-analyses stratified by apolipoprotein E (APOE) ε4 status, estimated combined odds ratio (OR) and population attributable fraction (cPAF), and explored causal variants.
Results
Results support the CLU-MS4A4E interaction and a dominant effect. An association between CLU-MS4A4E and APOE ε4 negative status exists. The estimated synergy factor, OR, and cPAF for rs11136000-rs670139 are 2.23, 2.45, and 8.0, respectively. We identified potential causal variants.
Discussion
We replicated the CLU-MS4A4E interaction in a large case-control series and observed APOE ε4 and possible dominant effect. The CLU-MS4A4E OR is higher than any Alzheimer's disease locus except APOE ε4, APP, and TREM2. We estimated an 8% decrease in Alzheimer's disease incidence without CLU-MS4A4E risk alleles and identified potential causal variants.
 
Liu, et al. DOI: http://dx.doi.org/10.1016/j.jalz.2015.05.019p130–143
 

Abstract

Introduction
Environmental factors and epigenetic mechanisms are believed to contribute to Alzheimer's disease (AD). We previously documented that prenatal hypoxia aggravated the cognitive impairment and neuropathology in offspring mice. Here, we investigate the chronic hypoxia-induced epigenetic modifications in AD.
Methods
The 3-month-old APPswe/PS1dE9 mice were exposed to hypoxic environment 6 hour/day for 30 days, followed by learning and memory tests and biochemical and neuropathology measurement at the age of 4, 6, and 9 months.
Results
We found hypoxia exaggerated the neuropathology and cognitive impairment in AD mice. Chronic hypoxia induced demethylation on genomic DNA and decreased the expression of DNA methyltransferase 3b (DNMT3b) in vivo. We further found that DNMTs inhibition elevated the protein levels of amyloid precursor protein, β- and γ-secretases, whereas overexpression of DNMT3b suppressed the levels of them in vitro.
Discussion
Our study suggests chronic hypoxia can aggravate AD progression through demethylation of genes encoding γ-secretase components by downregulation of DNMT3b.
 
Vincentius, et al. DOI: http://dx.doi.org/10.1016/j.jalz.2015.08.001p144–153
 

Abstract

Introduction
Although preclinical dementia is characterized by decline in cognition and daily functioning, little is known on their temporal sequence. We investigated trajectories of cognition and daily functioning in preclinical dementia, during 18 years of follow-up.
Methods
In 856 dementia cases and 1712 controls, we repetitively assessed cognition and daily functioning with memory complaints, mini-mental state examination (MMSE), instrumental activities of daily living (IADL), and basic activities of daily living (BADL).
Results
Dementia cases first reported memory complaints 16 years before diagnosis, followed by decline in MMSE, IADL, and finally BADL. Vascular dementia related to earlier decline in daily functioning but later in cognition, compared with Alzheimer's disease. Higher education related to larger preclinical cognitive decline, whereas apolipoprotein E (APOE) ε4 carriers declined less in daily functioning.
Discussion
These results emphasize the long hierarchical preclinical trajectory of functional decline in dementia. Furthermore, they show that various pathologic, environmental, and genetic factors may influence these trajectories of decline.
 
Duits, et al. DOI: http://dx.doi.org/10.1016/j.jalz.2015.08.003p154–163
 

Abstract

Introduction
Lumbar puncture (LP) is increasingly performed in memory clinics. We investigated patient-acceptance of LP, incidence of and risk factors for post-LP complications in memory clinic populations.
Methods
We prospectively enrolled 3868 patients (50% women, age 66 ± 11 years, mini mental state examination 25 ± 5) at 23 memory clinics. We used logistic regression analysis using generalized estimated equations to investigate risk factors for post-LP complications, such as typical postlumbar puncture headache (PLPH) and back pain.
Results
A total of 1065 patients (31%) reported post-LP complaints; 589 patients (17%) reported back pain, 649 (19%) headache, of which 296 (9%) reported typical PLPH. Only few patients needed medical intervention: 11 (0.3%) received a blood patch, 23 (0.7%) were hospitalized. The most important risk factor for PLPH was medical history of headache. An atraumatic needle and age >65 years were preventive. Gender, rest after LP, or volume of cerebrospinal fluid had no effect.
Discussions
The overall risk of complications is relatively low. If risk factors shown in this study are taken into account, LPs can be safely performed in memory clinics.
 
Thomas J. Montine, Sarah E. Monsell, Thomas G. Beach, Eileen H. Bigio, Yunqi Bu, Nigel J. Cairns, Matthew Frosch, Jonathan Henriksen, Julia Kofler, Walter A. Kukull, Edward B. Lee, Peter T. Nelson, Aimee M. Schantz, Julie A. Schneider, Joshua A. Sonnen, John Q. Trojanowski, Harry V. Vinters, Xiao-Hua Zhou, Bradley T. Hyman
DOI: http://dx.doi.org/10.1016/j.jalz.2015.07.492
p164–169
 
 

Abstract

Introduction
Neuropathologic assessment is the current “gold standard” for evaluating the Alzheimer's disease (AD), but there is no consensus on the methods used.
Methods
Fifteen unstained slides (8 brain regions) from each of the 14 cases were prepared and distributed to 10 different National Institute on Aging AD Centers for application of usual staining and evaluation following recently revised guidelines for AD neuropathologic change.
Results
Current practice used in the AD Centers Program achieved robustly excellent agreement for the severity score for AD neuropathologic change (average weighted κ = .88, 95% confidence interval: 0.77–0.95) and good-to-excellent agreement for the three supporting scores. Some improvement was observed with consensus evaluation but not with central staining of slides. Evaluation of glass slides and digitally prepared whole-slide images was comparable.
Discussion
AD neuropathologic evaluation as performed across AD Centers yields data that have high agreement with potential modifications for modest improvements.
 
Lewis H. Kuller, Oscar L. Lopez, James T. Becker, Yuefang Chang, Anne B. Newman
DOI: http://dx.doi.org/10.1016/j.jalz.2015.08.165
p170–183
 

Abstract

Introduction
Increasing life expectancy has resulted in a larger population of older individuals at risk of dementia.
Methods
The Cardiovascular Health Study–Cognition Study followed 532 participants from 1998–99 (mean age 79) to 2013 (mean age 93) for death and dementia.
Results
Risk of death was determined by extent of coronary artery calcium, high-sensitivity cardiac troponin, brain natriuretic peptide, and white matter grade. Significant predictors of dementia were age, apolipoprotein-E4, vocabulary raw score, hippocampal volume, ventricular size, cognitive performance, and number of blocks walked. By 2013, 160 of 532 were alive, including 19 cognitively normal. Those with normal cognition had higher grade education, better cognition test scores, greater hippocampal volume, faster gait speed, and number of blocks walked as compared with survivors who were demented.
Discussion
Few survived free of dementia and disability. Prevention and delay of cognitive decline for this older population is an imperative.
 
Manish K. Tiwari, Kasper P. Kepp
DOI: http://dx.doi.org/10.1016/j.jalz.2015.06.1895
p184–194
 

Abstract

Although genetic Aβ variants cause early-onset Alzheimer's disease, literature reports on Aβ properties are heterogeneous, obscuring molecular mechanisms, as illustrated by recent failures of Aβ-level targeting trials. Thus, we combined available data on Aβ levels and ratios, aggregation propensities, toxicities, and patient data for Aβ variants and correlated these data to identify heterogeneity, significant relations, and basis for consensus. Despite heterogeneity, age of disease onset correlates to Aβ levels (R2 = 0.38, P = .018), but not to toxicities, Aβ42 levels, Aβ42/Aβ40 ratios, or aggregation propensities. Cytotoxicity correlates inversely with total Aβ42 (R2 = 0.65, P = .016) and Aβ42/Aβ40 ratios (R2 = 0.76, P = .005), i.e., chemical properties that increase Aβ42 also reduce toxicity. The complexity and heterogeneity of data reveal the need to understand these phenotypes better, e.g., by focusing on the chemical properties of the involved Aβ species.
 
Ismail, et al. DOI: http://dx.doi.org/10.1016/j.jalz.2015.05.017p195–202
 

Abstract

Neuropsychiatric symptoms (NPS) are common in dementia and in predementia syndromes such as mild cognitive impairment (MCI). NPS in MCI confer a greater risk for conversion to dementia in comparison to MCI patients without NPS. NPS in older adults with normal cognition also confers a greater risk of cognitive decline in comparison to older adults without NPS. Mild behavioral impairment (MBI) has been proposed as a diagnostic construct aimed to identify patients with an increased risk of developing dementia, but who may or may not have cognitive symptoms. We propose criteria that include MCI in the MBI framework, in contrast to prior definitions of MBI. Although MBI and MCI can co-occur, we suggest that they are different and that both portend a higher risk of dementia. These MBI criteria extend the previous literature in this area and will serve as a template for validation of the MBI construct from epidemiologic, neurobiological, treatment, and prevention perspectives.
 
Ramirez, et al. DOI: http://dx.doi.org/10.1016/j.jalz.2015.06.1886p203–210
 

Abstract

Given the recent acknowledgement of the complex mixed pathologies that contribute to the clinical expression of dementia, various cohort studies have aimed to examine Alzheimer's disease and cerebrovascular disease as comorbid pathologies, with neuroimaging playing a central role in these studies. Using white matter hyperintensities (WMH) as a biomarker of cerebrovascular disease, we compared WMH burden between the Sunnybrook Dementia Study, the Alzheimer's Disease Neuroimaging Initiative (ADNI-1), the Three-City Study, and various other studies around the world. Based on our findings, it was evident that ADNI-1 had minimal WMH burden relative to other large studies that examine aging and dementia. This low WMH burden in ADNI-1 may be considered as both an advantage, representing a relatively “pure” sample with little confounding vasculopathy, and a disadvantage, as it limits generalizability to “real-world” patient populations with mixed pathologies and to nondemented groups with baseline vascular disease. We explore possible reasons for this distinction, including management of vascular risk factors, gaps in diagnostic criteria, and future directions for clinical research.

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