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March 15, 2016
Alzheimer’s & Dementia: A Journal of the Alzheimer’s
Jia, et al.DOI:
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
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.
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
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.
Shakersain, et al. DOI:
The influence of mixed
dietary patterns on cognitive changes is unknown.
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
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.
High adherence to prudent
diet may diminish the adverse effects of high adherence to Western diet on
Siemers, et al. DOI:
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.
Secondary analyses of efficacy,
biomarker, and safety endpoints in the pooled
(EXPEDTION + EXPEDITION2) mild AD population were performed.
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.
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.2015.08.163p121–129
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.
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.
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.
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
Liu, et al. DOI:
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.
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
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
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
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.
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).
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.
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:
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
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
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.
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
is the current “gold standard” for evaluating the Alzheimer's disease (AD), but
there is no consensus on the methods used.
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
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.
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
Increasing life expectancy
has resulted in a larger population of older individuals at risk of dementia.
The Cardiovascular Health
Study–Cognition Study followed 532 participants from 1998–99 (mean age 79) to
2013 (mean age 93) for death and dementia.
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.
Few survived free of
dementia and disability. Prevention and delay of cognitive decline for this
older population is an imperative.
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:
(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:
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.