Journal of Alzheimer's Disease - Volume 71, issue 2

Authors: Martin, Donel M. | Mohan, Adith | Alonzo, Angelo | Gates, Nicola | Gbadeyan, Oyetunde | Meinzer, Marcus | Sachdev, Perminder | Brodaty, Henry | Loo, Colleen

Article Type: Research Article

Abstract: Background: There is currently no effective intervention for improving memory in people at increased risk for dementia. Cognitive training (CT) has been promising, though effects are modest, particularly at follow-up. Objective: To investigate whether adjunctive non-invasive brain stimulation (transcranial direct current stimulation, tDCS) could enhance the memory benefits of CT in amnestic mild cognitive impairment (aMCI). Methods: Participants with aMCI were randomized to receive CT with either Active tDCS (2 mA for 30 min and 0.016 mA for 30 min) or Sham tDCS (0.016 mA for 60 min) for 15 sessions over a period of 5 weeks in a double-blind, sham-controlled, parallel …group clinical trial. The primary outcome measure was the California Verbal Learning Task 2nd Edition. Results: 68 participants commenced the intervention. Intention-to-treat (ITT) analysis showed that the CT+Active tDCS group significantly improved at post treatment (p  = 0.033), and the CT+Sham tDCS group did not (p  = 0.050), but there was no difference between groups. At the 3-month follow-up, both groups showed large-sized memory improvements compared to pre-treatment (CT+Active tDCS: p  < 0.01, d  = 0.99; CT+Sham tDCS: p  < 0.01, d  = 0.74), although there was no significant difference between groups. Conclusion: This study found that CT+Active tDCS did not produce greater memory improvement compared to CT+Sham tDCS. Large-sized memory improvements occurred in both conditions at follow-up. One possible interpretation, based on recent novel findings, is that low intensity tDCS (used as ‘sham’) may have contributed biological effects. Further work should use a completely inert tDCS sham condition. Show more

Keywords: cognitive training, memory, mild cognitive impairment, randomized controlled trial, transcranial direct current stimulation, treatment

DOI: 10.3233/JAD-190306

Citation: Journal of Alzheimer's Disease, vol. 71, no. 2, pp. 503-512, 2019

Authors: Matsunaga, Shinji | Fujishiro, Hiroshige | Takechi, Hajime

Article Type: Research Article

Abstract: Background: The clinical benefit of cholinesterase inhibitors (ChEIs) for mild cognitive impairment (MCI) remains inconclusive. Objective: We performed a systematic review and meta-analysis of the efficacy/safety of ChEIs on subjects with MCI. Methods: We included randomized controlled trials (RCTs) of ChEIs in subjects with MCI, using cognitive function scores as a primary outcome measure. Results: Fourteen RCTs (six using donepezil, four using galantamine, and four using rivastigmine) with 5,278 subjects were included. We found no significant difference in cognitive function scores between the ChEIs and placebo groups [standardized mean difference (SMD) = –0.06, p  = 0.38, I …2  = 76% ]. However, in the secondary outcomes, ChEIs were associated with a lower incidence of progression to dementia compared with placebo (risk ratio = 0.76, the number needed to treat = 20). For safety outcomes, ChEIs were associated with a lower prevalence of fall than placebo. On the other hand, compared with placebo, ChEIs were associated with a higher incidence of discontinuation due to all causes, discontinuation due to adverse events, at least one adverse event, abnormal dreams, diarrhea, dizziness, headache, insomnia, loose stools, muscle cramps, nausea, vomiting, and weight loss. Conclusions: Although ChEIs have a slight efficacy in the treatment of MCI, there are many safety issues. Therefore, ChEIs are difficult to recommend for MCI. However, the efficacy and safety of ChEIs on MCI with a biomarker-based diagnosis is unclear. Further RCTs are needed to confirm the efficacy and safety of ChEIs when used for individual neuropathological classifications of MCI. Show more

Keywords: Cholinesterase inhibitors, donepezil, galantamine, meta-analysis, mild cognitive impairment, rivastigmine

DOI: 10.3233/JAD-190546

Citation: Journal of Alzheimer's Disease, vol. 71, no. 2, pp. 513-523, 2019

Authors: El-Hayeck, Rita | Baddoura, Rafic | Wehbé, Amine | Bassil, Nazem | Koussa, Salam | Abou Khaled, Karine | Richa, Sami | Khoury, Rita | Alameddine, Abbas | Sellal, François

Article Type: Research Article

Abstract: Background: The Mini-Mental State Examination (MMSE) has not been validated in the Lebanese population and no normative data exist at the national level. Objective: To evaluate the reliability and validity of an Arabic version of MMSE developed by the “Groupe de Travail sur les Démences de l’Université Saint Joseph” (A-MMSE(GTD-USJ)) and to provide normative data by gender, age, and education in adults over 55. Methods: Study design: national cross-sectional survey. Study population: 1,010 literate community-dwelling Lebanese residents aged 55 and above. Outcomes: reproducibility, internal consistency, sensitivity, specificity, predictive values, and area under the curve of the …A-MMSE(GTD-USJ) for the detection of cognitive impairment using the Clinical Dementia Rating (CDR) as the gold standard. Normative data were established from 720 healthy adults. A-MMSE(GTD-USJ) scores corresponding to the 5th, 10th, 15th, and 50th percentiles were identified according to gender, age, and education. Results: Intra-rater and inter-rater test-retest score correlations were 0.89 and 0.72, respectively. Cronbach alpha coefficient for internal consistency of the A-MMSE(GTD-USJ) was 0.71. A threshold value of 23 provided a sensitivity of 80% and a specificity of 89.4%. The area under the curve was 0.92. A-MMSE(GTD-USJ) scores increased with education and decreased with age. Women had significantly lower scores than men. Normative data for A-MMSE(GTD-USJ) stratified by gender, age, and education were generated. Conclusion: In reference to the CDR, the A-MMSE(GTD-USJ) is a valid tool to assess cognitive status among Lebanese subjects aged 55 and above. Normative data will help clinicians in detecting cognitive impairment in this population. Show more

Keywords: Arabic version, dementia, Lebanon, mini-mental state examination, normative data, reliability, validity

DOI: 10.3233/JAD-181232

Citation: Journal of Alzheimer's Disease, vol. 71, no. 2, pp. 525-540, 2019

Authors: Ruano, Luis | Severo, Milton | Sousa, Andreia | Ruano, Catarina | Branco, Mariana | Barreto, Rui | Moreira, Sandra | Araújo, Natália | Pinto, Paula | Pais, Joana | Lunet, Nuno | Cruz, Vítor Tedim

Article Type: Research Article

Abstract: Repeated measurements could be helpful to identify patients with early cognitive decline. We compare the variation of cognitive performance over one year in patients with mild cognitive impairment (MCI) and healthy individuals using the Brain on Track self-applied computerized test (BoT). The study was initiated 30 patients with probable MCI and 377 controls from a population-based cohort, who performed the BoT test from home every three months for one year. The scores were compared using a linear mixed-effects model. All participants increased their scores in the first tests, after 120 days MCI patients started to decline, with a statistically significant …higher rate. The area under the curve to detect MCI was 0.94. We identified a significant decline in cognitive performance over one year in patients with MCI using BoT and the test presented a high discriminative ability. Show more

Keywords: Cognition disorders, cognitive screening, computer-assisted decision making, dementia, mild cognitive impairment

DOI: 10.3233/JAD-190631

Citation: Journal of Alzheimer's Disease, vol. 71, no. 2, pp. 541-548, 2019

Authors: Deckers, Kay | Cadar, Dorina | van Boxtel, Martin P.J. | Verhey, Frans R.J. | Steptoe, Andrew | Köhler, Sebastian

Article Type: Research Article

Abstract: Background: Differences in dementia risk across the gradient of socioeconomic status (SES) exist, but their determinants are not well understood. Objective: This study investigates whether health conditions and lifestyle-related risk factors explain the SES inequalities in dementia risk. Methods: 6,346 participants from the English Longitudinal Study of Ageing were followed up from 2008/2009 until 2014/2015. We used Cox regression adjusted for age, gender, wealth/education, and clustering at the household level to examine the association between SES markers (wealth, education) and time to dementia in a structural equation model including potential mediation or effect modification by a …weighted compound score of twelve modifiable risk and protective factors for dementia (‘LIfestyle for BRAin health’ (LIBRA) score). Results: During a median follow-up of 6 years, 192 individuals (3.0%) developed dementia. LIBRA scores decreased with increasing wealth and higher educational level. A one-point increase in the LIBRA score was associated with a 13% increase in dementia risk (hazard ratio (HR) = 1.13, 95% confidence interval 1.07–1.19). Higher wealth was associated with a decreased dementia risk (HR = 0.58, 0.39–0.85). Mediation analysis showed that 52% of the risk difference between the highest and lowest wealth tertile was mediated by differences in LIBRA (indirect effect: HR = 0.75, 0.66–0.85). Education was not directly associated with dementia (HR = 1.05, 0.69–1.59), but was a distal risk factor for dementia by explaining differences in wealth and LIBRA scores (indirect effect high education: HR = 0.92, 0.88–0.95). Conclusion: Socioeconomic differences in dementia risk can be partly explained by differences in modifiable health conditions and lifestyle factors. Show more

Keywords: Aging, cohort study, dementia, epidemiology, health inequalities, lifestyle, mediation, prevention, public health, risk factors, socioeconomic status

DOI: 10.3233/JAD-190541

Citation: Journal of Alzheimer's Disease, vol. 71, no. 2, pp. 549-557, 2019

Authors: Su, Ning | Liang, Xinyu | Yao, Ming | Zhou, Li-Xin | Wang, Quan | Jin, Zheng-Yu | Zhang, Shu-Yang | Cui, Li-Ying | Gong, Gaolang | Zhu, Yi-Cheng | Ni, Jun

Article Type: Research Article

Abstract: Background: Few studies have investigated the correlation between cerebral microbleeds (CMBs), a hemorrhagic imaging marker of cerebral small vessel disease (CSVD), and brain volume. Objective: We investigated the association between the burden and locations of CMBs and brain volume in community-dwelling populations. Methods: Data were obtained from 1,029 participants who underwent brain magnetic resonance imaging (MRI) and APOE genotyping. Volumes of the whole brain, subcortical white matter (WM), cortical gray matter (GM), and hippocampus were extracted. Linear regression models were used to investigate the relationship between the CMB burden and their location with structural changes. …Results: Regarding burden, participants with≥3 CMBs had significantly lower whole brain (β= –1.124, p  = 0.0133), subcortical WM (β= –1.020, p  = 0.0043), and hippocampus (β= –0.015, p  = 0.0088) volumes than those without CMBs. Regarding location and burden, the presence of≥3 strictly lobar CMBs was negatively associated with whole brain volume (β= –2.838, p  = 0.0088). Additionally, higher CMB burdens in strictly lobar locations or deep/mixed locations were associated with lower subcortical WM volume (β= –1.689, p  = 0.0482; β= –0.872, p  = 0.0464, respectively). Finally, the presence of≥3 deep/mixed CMBs was associated with lower hippocampus volume (β= –0.018, p  = 0.0088), and these associations were independent of other ischemic markers of CSVD. However, the CMB burden and distributional pattern did not correlate with cortical GM volumes. Conclusion: A higher CMB burden, in specific locations, is associated with decreased brain volumes in community-dwelling populations. Show more

Keywords: brain volumes, cerebral microbleeds, cerebral small vessel disease, hippocampus, white matter

DOI: 10.3233/JAD-190454

Citation: Journal of Alzheimer's Disease, vol. 71, no. 2, pp. 559-567, 2019

Authors: Graham, Charlotte | Santiago-Mugica, Estibaliz | Abdel-All, Zeinab | Li, Mosi | McNally, Richard | Kalaria, Rajesh N. | Mukaetova-Ladinska, Elizabeta B.

Article Type: Research Article

Abstract: Background: Discovering biomarkers for dementia is a pivotal step toward successful early diagnosis and treatment. Although plasma biomarkers have been explored, no consensus has been reached. Alpha-synuclein (AS), a 14 kDa synaptic protein associated with several neurodegenerative diseases, exists natively within erythrocytes (ERC). This protein is characteristic of Lewy body diseases, in which it aggregates into toxic Lewy bodies. As ERC are implicated in dementia, they are a potential target for future biomarkers. Objective: The aims of this study were to assess AS levels within ERC and whether AS can be used as a peripheral biomarker to differentiate between …dementia and aged matched healthy control subjects. Methods: A total of 114 samples (60 aging controls, 36 Alzheimer’s disease, 12 vascular dementia (VaD) and 6 dementia with Lewy bodies (DLB) subjects) were analyzed. We used Bradford assay to measure protein concentration, indirect ELISA to detect levels of AS, and immunoblotting to identify AS composition. Data were analyzed with nonparametric tests. Results: AS oligomers were present in dementia blood samples, whereas in controls, AS was largely monomeric. There was a significant increase in AS levels in DLB whole blood (p  = 0.005; Kruskal-Wallis test), with a sensitivity and specificity of 100.0% and 93.9%. Protein concentrations in ERC isolated at pH 5.7 were significantly increased in dementia patients compared to controls (17.58 versus 40.33μ g/ml; p ≤0.005; Mann-Whitney test). In the VaD group, the protein concentration in the pH5.7 ERC fraction had sensitivity and specificity of 91.7% and 62.1%. Conclusions: ERC protein concentration and AS levels have a potential for development of a novel diagnostic dementia blood test. Show more

Keywords: Alzheimer’s disease, alpha-synuclein, biomarker, blood, dementia, dementia with Lewy bodies, erythrocytes, vascular dementia

DOI: 10.3233/JAD-190567

Citation: Journal of Alzheimer's Disease, vol. 71, no. 2, pp. 569-580, 2019

Authors: Qiu, Ruolun | Ahn, Jae Eun | Alexander, Robert | Brodney, Michael A. | He, Ping | Leurent, Claire | Mancuso, Jessica | Margolin, Richard A. | Tankisheva, Ekaterina | Chen, Danny

Article Type: Research Article

Abstract: PF-06751979 is a selective inhibitor of the beta-site amyloid precursor protein cleaving enzyme-1, which is a key aspartyl protease in the generation of amyloid-β (Aβ) peptides, thought to be critical for the cerebral degeneration observed in Alzheimer’s disease. Two Phase I studies (NCT02509117, NCT02793232) investigated the safety/tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of PF-06751979. Single-ascending doses up to 540 mg and multiple-ascending doses up to 275 mg once daily (QD) in healthy adults, and multiple doses of 50 mg or 125 mg QD in healthy older subjects were assessed. PF-06751979 was well tolerated at all doses given, and all treatment-related adverse events (AEs) were …mild to moderate. PK parameters remained consistent across the PF-06751979 QD dosing regimens, and no notable food effects were observed. PD analysis showed that PF-06751979 reduced the cerebrospinal fluid (CSF) and plasma levels of Aβ peptides in a dose-dependent manner, with the greatest reductions observed in subjects treated with 275 mg QD (approximately 92% and 93% reduction in CSF Aβ1–40 and Aβ1–42 observed at 24 h after Day 14 dose, respectively). A drug interaction study (NCT03126721) using midazolam indicated that there was no clinically meaningful effect of multiple doses of PF-06751979 100 mg QD on the PK of single-dose midazolam in healthy adults. Overall, these data suggest that PF-06751979 with daily dosing is favorable for further clinical development. Show more

Keywords: Alzheimer’s disease, amyloid-β peptides, BACE1 protein-human, pharmacodynamics, pharmacokinetics, Phase I, safety, tolerability

DOI: 10.3233/JAD-190228

Citation: Journal of Alzheimer's Disease, vol. 71, no. 2, pp. 581-595, 2019

Authors: Liang, Tao | Xue, Feixiao | Hang, Weijian | Wen, Bin | Zhang, Qianying | Chen, Jiehui | Liu, Xiaofeng | Chen, Juan

Article Type: Research Article

Abstract: Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer’s disease (AD). It is shown that apoE4 preferentially undergoes aberrant cleavage in neurons, yielding neurotoxic C-terminal-truncated apoE4 fragment. Endoplasmic reticulum (ER) stress has also been known to be involved in the pathogenesis of AD. However, little is known about the contribution of ER stress to the neurotoxicity of apoE4 fragment. In the present study, we established the neuron-specific expression human C-terminal-truncated apoE4(1–272) fragment transgenic mice and also transfected apoE4(1–272) fragment in neuroblastoma N2a cells. We found that human apoE4(1–272) fragment could trigger ER stress as evidenced by increasing the …expression of ER stress markers both in vivo and in vitro . Meanwhile, the apoE4(1–272) transgenic mice presented obviously AD-like neuropathological changes, including the impairment of spatial learning and memory, prominent axonal morphological changes, and hyperphosphorylation of tau. At the same time, we also found that glycogen synthase kinase-3 activities were significantly increased. Furthermore, these neuropathological changes, especially tau hyperphosphorylation and axonal transport impairment, were significantly rescued by the ER stress protector 4-phenylbutyric acid (4-PBA) in apoE4(1–272)-transfected N2a cells. Pretreatment with 4-PBA not only decreased the protein expression of immunoglobulin binding protein (BiP) and C/EBP-homologous protein (CHOP), but also significantly reversed these defects in axonal transport. These results suggested that the neurotoxic effects of apoE4(1–272) fragment found in AD subjects, at least in part, through triggering ER stress and inducing tau hyperphosphorylation, led to the enduring impairment of axonal transport. Show more

Keywords: Alzheimer’s disease, apolipoprotein E4 (1–272), axonopathy, endoplasmic reticulum stress, tau phosphorylation

DOI: 10.3233/JAD-190419

Citation: Journal of Alzheimer's Disease, vol. 71, no. 2, pp. 597-611, 2019

Authors: Laurens, Brice | Planche, Vincent | Cubizolle, Stéphanie | Declerck, Léa | Dupouy, Sandrine | Formaglio, Maïté | Koric, Lejla | Seassau, Magali | Tilikete, Caroline | Vighetto, Alain | Ceccaldi, Mathieu | Tison, Françcois

Article Type: Research Article

Abstract: Background/Objective: Performances on spatial decision eye-tracking tasks are known to be impaired in patients with moderate Alzheimer’s disease (AD), but the clinical relevance of this deficit during earlier stages of AD remains unclear. Methods: This study recruited patients with amnestic mild cognitive impairment (aMCI, prodromal AD), patients with mild AD, and age-matched controls from three French memory clinics. Participants’ ability to make spatial judgments and decisions was assessed with an eye-tracking system, and cognitive performance on conventional neuropsychological tests was evaluated. Results: We enrolled 26 controls, 25 aMCI patients (median Mini-Mental State Exam [MMSE] 26), and …23 mild-AD patients (median MMSE 23). Patients with mild AD had higher error rates on the spatial decision task than aMCI patients and controls (32.4% versus 23.5%; p  < 0.01 and 32.4% versus 22.2%; p  < 0.05, respectively), but there were no differences among the groups in anticipation rate or the percentage of express saccades. Additionally, error rates on the spatial decision task were inversely correlated with performance on visual memory tests (immediate and delayed recall on the DMS- 48: r  =–0.44, p  = 0.0019 and r  =–0.43, p  = 0.0020, respectively), semantic fluency (r  =–0.44, p  = 0.0016), and global cognition (MMSE: r  =–0.44, p  = 0.0019). Performance on the spatial decision task was not correlated with anti-saccades, processing speed, or attentional performance. Conclusions: Patients with mild AD made more errors on a spatial decision task than aMCI patients and controls. We hypothesize that impaired visuospatial judgment may explain these results and distinguish aMCI patients from mild AD patients. Show more

Keywords: Alzheimer’s disease, eye-tracking, mild cognitive impairment, spatial decision

DOI: 10.3233/JAD-190549

Citation: Journal of Alzheimer's Disease, vol. 71, no. 2, pp. 613-621, 2019