Journal of Alzheimer's Disease - Volume 50, issue 3

Authors: Dziedzic, Tomasz | Pera, Joanna | Klimkowicz-Mrowiec, Aleksandra | Mroczko, Barbara | Slowik, Agnieszka

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a neurodegenerative, inevitably progressive disease with a rate of cognitive, functional, and behavioral decline that varies highly from patient to patient. Although several clinical predictors of AD progression have been identified, to our mind in clinical practice there is a lack of a reliable biomarker that enables one to stratify the risk of deterioration. Identification of biomarkers that allow the monitoring of AD progression could change the way physicians and caregivers make treatment decisions. This review summarizes the results of studies on potential biochemical and radiological markers related to AD progression.

Keywords: Alzheimer’s disease, biomarkers, cognitive decline, deterioration, progression

DOI: 10.3233/IFS-150578

Citation: Journal of Alzheimer's Disease, vol. 50, no. 3, pp. 623-644, 2016

Authors: Roher, Alex E. | Maarouf, Chera L. | Kokjohn, Tyler A.

Article Type: Research Article

Abstract: Studies of presenilin (PSEN ) gene mutations producing early onset Alzheimer’s disease (AD) have helped elucidate the pathogenic mechanisms of dementia and guided clinical trials of potential therapeutic interventions. Although familial and sporadic forms of AD share features, it is unclear if the two are precisely equivalent. In addition, PSEN mutations do not all produce a single phenotype, but exhibit substantial variability in clinical manifestations, which are related to the position and chemical nature of their amino acid substitutions as well as ratios of critical molecules such as Aβ40 and Aβ42 . These differences complicate the interpretation of …critical clinical trial results and their desired extrapolation to sporadic AD treatment. In this perspective, we examine differences between familial AD and sporadic AD as well as attributes shared by these uniquely arising disturbances in brain biochemical homeostasis that culminate in dementia. Show more

Keywords: Amyloid-β, amyloid cascade hypothesis, dementia, familial Alzheimer’s disease, presenilin, sporadic Alzheimer’s disease

DOI: 10.3233/JAD-150757

Citation: Journal of Alzheimer's Disease, vol. 50, no. 3, pp. 645-658, 2016

Authors: Huang, Fukai | Shang, Ying | Luo, Yuandai | Wu, Peng | Huang, Xue | Tan, Xiaohui | Lu, Xingyi | Zhen, Lifang | Hu, Xianda

Article Type: Research Article

Abstract: Background: The prevalence of dementia differs among racial groups, the highest prevalence being in Latin America (8.5%) compared to sub-Saharan African regions (2–4%). The most common type of dementia is Alzheimer’s disease (AD). Objective: To estimate the prevalence of AD in the Qinghai-Tibet plateau and to investigate the related factors. Methods: This was a cross-sectional, multistage cluster sampling design survey. Data was collected from May 2014 to September 2014 from 4,060 Tibetan aged >60 years. Participants underwent clinical examinations and neuropsychological evaluations. MALDI-TOF was used to test the genotypes of CLU, TFAM, TP53INP1, IGHV1-67, CR1, ApoE, …and BIN1. Logistic regression models were used to ascertain the associations with AD. Results: The prevalence of AD among Tibetan individuals aged >60 years was 1.33% (95% CI: 0.98–1.69). The CLU haplotypes AA+GA (odds ratio (OR) = 4.483; 95% CI: 1.069–18.792) of rs2279590 was correlated with AD. The CLU haplotypes GG+GC (OR = 0.184; 95% CI: 0.038–0.888) of rs9331888 and kowtow (OR = 0.203; 95% CI 0.046–0.896) were negatively correlated with AD. Conclusion: A low prevalence of AD was found in Tibetans from the Qinghai-Tibet plateau. Multivariate analysis might suggest that regular “mind-body” religious meditative activities may be negatively associated with AD in this population, as well as the CLU genotype at rs9331888. Show more

Keywords: Alzheimer’s disease, gene polymorphisms, Qinghai-Tibet Plateau, religion, Tibetan

DOI: 10.3233/JAD-150697

Citation: Journal of Alzheimer's Disease, vol. 50, no. 3, pp. 659-667, 2016

Authors: Qiu, Hongyan | Zhong, Rujia | Liu, Hui | Zhang, Feng | Li, Song | Le, Weidong

Article Type: Research Article

Abstract: Recently, there is an increasing concern over the association between sleep disorders and Alzheimer’s disease (AD). Clinical observations have reported that chronic sleep deprivation (SD) may serve as a risk factor for AD. However, the pathological evidence for this assumption is still lacking. In the present study, we examined the potential impacts of chronic SD on learning-memory and AD-related pathologies in AβPPswe /PS1 Δ E9 transgenic (TG) mice and their wild-type (WT) littermates. Results indicated that mice (both TG and WT) exposed to 2-month SD showed an altered amyloid-β protein precursor processing, an elevated level of phosphorylated tau protein, …and impaired cognitive performance as compared to non-sleep deprivation (NSD) controls. Moreover, the SD-treated TG mice exhibited more amyloid-β1-42 production and developed more senile plaques in the cortex and hippocampus than NSD-treated TG mice. In addition, SD caused a striking neuronal mitochondrial damage, caspase cascade activation, and neuronal apoptosis in the hippocampus of both TG and WT mice. More importantly, all these behavioral, neuropathological, and biochemical changes induced by chronic SD were long lasting and were irreversible during a 3-month normal housing condition. Collectively, these results indicate that chronic SD impairs learning and memory, exacerbates AD pathologies, and aggravates the mitochondria-mediated neuronal apoptosis in a long-lasting manner. Our findings provide important experimental evidence to prove that chronic SD is a risk factor for AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, apoptosis, chronic sleep deprivation, mitochondria, phosphorylated tau protein, senile plaques

DOI: 10.3233/JAD-150774

Citation: Journal of Alzheimer's Disease, vol. 50, no. 3, pp. 669-685, 2016

Authors: Pistono, Aurélie | Jucla, Mélanie | Barbeau, Emmanuel J. | Saint-Aubert, Laure | Lemesle, Béatrice | Calvet, Benjamin | Köpke, Barbara | Puel, Michèle | Pariente, Jérémie

Article Type: Research Article

Abstract: There is a large body of research on discourse production in Alzheimer’s disease (AD). Some studies have focused on pause production, revealing that patients make extensive use of pauses during speech. This has been attributed to lexical retrieval difficulties, but pausing may also reflect other forms of cognitive impairment as it increases with cognitive load. The aim of the present study was to analyze autobiographical discourse impairment in AD from a broad perspective, looking at pausing behavior (frequency, duration, and location). Our first objective was to characterize discourse changes in mild cognitive impairment (MCI) due to AD. Our second objective …was to determine the cognitive and neuroanatomical correlates of these changes. Fifteen patients with MCI due to AD and 15 matched cognitively normal controls underwent an ecological episodic memory task, a full neuropsychological assessment, and a 3D T1-weighted MRI scans. Autobiographical discourse collected from the ecological episodic memory task was recorded, transcribed, and analyzed, focusing on pausing. Intergroup comparisons showed that although patients did not produce more pauses than controls overall, they did make more between-utterance pauses. The number of these specific pauses was positively correlated with patients’ episodic memory performance. Furthermore, neuroimaging analysis showed that, in the patient group, their use was negatively correlated with frontopolar area (BA 10) grey matter density. This region may therefore play an important role in the planning of autobiographical discourse production. These findings demonstrate that pauses in early AD may reflect a compensatory mechanism for improving mental time travel and memory retrieval. Show more

Keywords: Episodic memory, language, mild cognitive impairment, natural language processing, neuroimaging

DOI: 10.3233/JAD-150408

Citation: Journal of Alzheimer's Disease, vol. 50, no. 3, pp. 687-698, 2016

Authors: Wang, Nan | Allali, Gilles | Kesavadas, Chandrasekharan | Noone, Mohan L. | Pradeep, Vayyattu G. | Blumen, Helena M. | Verghese, Joe

Article Type: Research Article

Abstract: Background: The contribution of cerebral small vessel disease to cognitive decline, especially in non-Caucasian populations, is not well established. Objective: We examined the relationship between cerebral small vessel disease and motoric cognitive risk syndrome (MCR), a recently described pre-dementia syndrome, in Indian seniors. Methods: 139 participants (mean age 66.6 ± 5.4 y, 33.1% female) participating in the Kerala-Einstein study in Southern India were examined in a cross-sectional study. The presence of cerebral small vessel disease (lacunar infarcts and cerebral microbleeds (CMB)) and white matter hyperintensities on MRI was ascertained by raters blinded to clinical information. MCR …was defined by the presence of cognitive complaints and slow gait in older adults without dementia or mobility disability. Results: Thirty-eight (27.3% ) participants met MCR criteria. The overall prevalence of lacunar infarcts and CMB was 49.6% and 9.4% , respectively. Lacunar infarcts in the frontal lobe, but no other brain regions, were associated with MCR even after adjusting for vascular risk factors and presence of white matter hyperintensities (adjusted Odds Ratio (aOR): 4.67, 95% CI: 1.69–12.94). Frontal lacunar infarcts were associated with slow gait (aOR: 3.98, 95% CI: 1.46–10.79) and poor performance on memory test (β: –1.24, 95% CI: –2.42 to –0.05), but not with cognitive complaints or non-memory tests. No association of CMB was found with MCR, individual MCR criterion or cognitive tests. Conclusions: Frontal lacunar infarcts are associated with MCR in Indian seniors, perhaps, by contributing to slow gait and poor memory function. Show more

Keywords: Aging, cerebral small vessel diseases, cognition, frontal lobe, gait, lacunar infarct, magnetic resonance imaging, memory

DOI: 10.3233/JAD-150523

Citation: Journal of Alzheimer's Disease, vol. 50, no. 3, pp. 699-707, 2016

Authors: Kim, Hee Jin | Cha, Jungho | Lee, Jong-Min | Shin, Ji Soo | Jung, Na-Yeon | Kim, Yeo Jin | Choe, Yearn Seong | Lee, Kyung Han | Kim, Sung Tae | Kim, Jae Seung | Lee, Jae Hong | Na, Duk L. | Seo, Sang Won

Article Type: Research Article

Abstract: Background: Recent advances in resting-state functional MRI have revealed altered functional networks in Alzheimer’s disease (AD), especially those of the default mode network (DMN) and central executive network (CEN). However, few studies have evaluated whether small vessel disease (SVD) or combined amyloid and SVD burdens affect the DMN or CEN. Objective: The aim of this study was to evaluate whether SVD or combined amyloid and SVD burdens affect the DMN or CEN. Methods: In this cross-sectional study, we investigated the resting-state functional connectivity within DMN and CEN in 37 Pittsburgh compound-B (PiB)(+) AD, 37 PiB(–) subcortical …vascular dementia (SVaD), 13 mixed dementia patients, and 65 normal controls. Results: When the resting-state DMN of PiB(+) AD and PiB(–) SVaD patients were compared, the PiB(+) AD patients displayed lower functional connectivity in the inferior parietal lobule while the PiB(–) SVaD patients displayed lower functional connectivity in the medial frontal and superior frontal gyri. Compared to the PiB(–) SVaD or PiB(+) AD, the mixed dementia patients displayed lower functional connectivity within the DMN in the posterior cingulate gyrus. When the resting-state CEN connectivity of PiB(+) AD and PiB(–) SVaD patients were compared, the PiB(–) SVaD patients displayed lower functional connectivity in the anterior insular region. Compared to the PiB(–) SVaD or PiB(+) AD, the mixed dementia patients displayed lower functional connectivity within the CEN in the inferior frontal gyrus. Conclusions: Our findings suggest that in PiB(+) AD and PiB(–) SVaD, there is divergent disruptions in resting-state DMN and CEN. Furthermore, patients with combined amyloid and SVD burdens exhibited more disrupted resting-state DMN and CEN than patients with only amyloid or SVD burden. Show more

Keywords: Alzheimer’s disease, amyloid, central executive network, default mode network, resting-state functional MRI, small vessel disease, subcortical vascular dementia,

DOI: 10.3233/JAD-150637

Citation: Journal of Alzheimer's Disease, vol. 50, no. 3, pp. 709-718, 2016

Authors: Bermejo-Pareja, Félix | Contador, Israel | Trincado, Rocío | Lora, David | Sánchez-Ferro, Álvaro | Mitchell, Alex J. | Boycheva, Elina | Herrero, Alejandro | Hernández-Gallego, Jesús | Llamas, Sara | Villarejo Galende, Alberto | Benito-León, Julián

Article Type: Research Article

Abstract: Background: The predictive value of diverse subtypes of mild cognitive impairment (MCI) for dementia and death is highly variable. Objective: To compare the predictive value of several MCI subtypes in progression to dementia and/or mortality in the NEDICES (Neurological Disorders in Central Spain) elderly cohort. Methods: Retrospect algorithmic MCI subgroups were established in a non-dementia baseline NEDICES cohort using Spanish adaptations of the original Mini-Mental State Examination (MMSE-37) and Pfeffer’s Functional Activities Questionnaire (Pfeffer-11). The presence of MCI was defined according two cognitive criteria: using two cut-offs points on the total MMSE-37 score. Five cognitive domains …were used to establish the MCI subtypes. Functional capacity (Pfeffer-11) was preserved or minimally impaired in all MCI participants. The incident dementia diagnoses were established by specialists and the mortality data obtained from Spanish official registries. Results: 3,411 participants without dementia were assessed in 1994-5. The baseline prevalence of MCI varied according to the MCI definition (4.3%–31.8%). The follow-up was a mean of 3.2 years (1997-8). The dementia incidence varied between 14.9 and 71.8 per 1,000/person-years. The dementia conversion rate was increased in almost all MCI subgroups (p  >  0.01), and mortality rate was raised only in four MCI subtypes. The amnestic-multi-domain MCI (aMd-MCI) had the best dementia predictive accuracy (highest positive likelihood ratio and highest clinical utility when negative). Conclusions: Those with aMd-MCI were at greatest risk of progression to dementia, as in other surveys and might be explored with increased attention in MCI research and in dementia preventive trials. Show more

Keywords: Amnesic multidomain MCI, dementia, dementia conversion, MCI mortality, MCI subtypes, MMSE-37, NEDICES, Pfeffer’s FAQ

DOI: 10.3233/JAD-150625

Citation: Journal of Alzheimer's Disease, vol. 50, no. 3, pp. 719-731, 2016

Authors: Yasue, Ichiro | Matsunaga, Shinji | Kishi, Taro | Fujita, Kiyoshi | Iwata, Nakao

Article Type: Research Article

Abstract: Background: There is uncertainty about the efficacy and tolerability of serotonin 2A (5-HT2A ) receptor negative modulators for Parkinson’s disease psychosis (PDP). Objective: This is the first meta-analysis of randomized placebo-controlled trials (RCTs) testing negative modulators of the 5-HT2A receptor as a treatment for PDP. Methods: The primary outcome was the Scale for Assessment of Positive Symptoms (SAPS)-hallucinations (H) and -delusions (D) scores (SAPS-H+D). Other outcome measures were SAPS-H, SAPS-D, the Unified Parkinson’s Disease Rating Scale Part II and III (UPDRS-II+III), discontinuation rates, and individual adverse events. Results: Four RCTs were identified that …met inclusion criteria, all assessing the 5-HT2A inverse agonist pimavanserin (including 417 drug-treated and 263 placebo-treated PDP patients). Pimavanserin significantly decreased SAPS-H+D scores compared to placebo [weighted mean differences (WMD) = –2.26, 95% confidence interval (95% CI) = –3.86 to –0.67, p  = 0.005, I 2  = 30% , N  = 4 studies, n  = 502 patients]. Moreover, pimavanserin was superior to placebo for reducing SAPS-H (WMD = –2.15, 95% CI = –3.45 to –0.86, p  = 0.001, I 2  = 0% , N  = 2, n  = 237) and SAPS-D scores (WMD = –1.32, 95% CI = –2.32 to –0.32, p  = 0.010, I 2  = 0% , N  = 2, n  = 237). Pimavanserin was associated with less orthostatic hypotension than placebo (risk ratio = 0.33, 95% CI = 0.15–0.75, p  = 0.008, I 2  = 0% , number needed to harm = 17, p  = 0.01, N  = 3, n  = 476). There were no significant differences in rates of all-cause discontinuation, adverse events, and death, UPDRS-II+III scores, and incidences of individual adverse events (other than orthostatic hypotension) between pimavanserin and placebo groups. Conclusions: Pooled RCT results suggest that pimavanserin is beneficial for the treatment of PDP and is well tolerated. We did not identify other negative modulators of the 5-HT2A receptor for the treatment of PDP. Show more

Keywords: 5-HT2A, meta-analysis, Parkinson’s disease, pimavanserin, psychosis

DOI: 10.3233/JAD-150818

Citation: Journal of Alzheimer's Disease, vol. 50, no. 3, pp. 733-740, 2016

Authors: Maes, Annemarie | Anthonissen, Roel | Wambacq, Sheleen | Simons, Koen | Verschaeve, Luc

Article Type: Research Article

Abstract: Exposure to extremely low frequency magnetic fields (ELF-MF) has been identified as one of the potential environmental risk factors for Alzheimer’s disease (AD). However, this is far from being established. So far there is no experimental evidence supporting this alleged association. We have performed an in vitro cytogenetic laboratory investigation to explore the plausibility of such association. Our investigation was based on possible similarities found in cells from AD patients and in cells exposed to ELF-MF. We especially found that 50 Hz ELF-MF increase the frequency of cells with (large) micronuclei and nuclear buds indicating that fields above 50 μT …may induce chromosome instabilities as those found in AD patients. It should be stressed yet that results from the few published experimental studies on ELF-MF and AD are rather reassuring. Thus, our findings certainly do not prove anything. They only suggest that further investigations might be necessary. Show more

Keywords: 50 Hz, Alzheimer’s disease, apoptosis, C3A cells, cytome assay, magnetic fields, micronuclei, nuclear bridges, nuclear buds

DOI: 10.3233/JAD-150669

Citation: Journal of Alzheimer's Disease, vol. 50, no. 3, pp. 741-749, 2016