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

Authors: Takahashi, Sho | Mizukami, Katsuyoshi | Arai, Tetsuaki | Ogawa, Ryoko | Kikuchi, Norihiro | Hattori, Satoshi | Darby, David | Asada, Takashi

Article Type: Research Article

Abstract: Background: Studies have shown that developing major depressive disorder (MDD) at 50 years of age or older can predict dementia. Depression is particularly common in dementia with Lewy bodies (DLB), and occasionally occurs before the onset of extrapyramidal symptoms. Moreover, systemic autonomic dysfunction, including an abnormal ventilatory response to hypercapnia (VRH), is common in patients with DLB. Objective: Here, we aimed to determine whether the VRH is useful for distinguishing depression that is predictive of DLB from other types of MDD. Methods: Participants were 35 consecutive patients with first onset MDD at 50 years or older …with bradykinesia. After diagnosing the clinical subtype of MDD according to DSM-IV criteria, each subject underwent a battery of psychological tests, autonomic examinations including VRH, brain magnetic resonance imaging, and 123 I-meta-iodobenzylguanidine scintigraphy. Results: Longitudinal follow-up showed that all 18 patients with abnormal VRH results developed DLB, whereas none of the 17 patients with normal VRH results converted to DLB within the study period (sensitivity: 100% , specificity: 100%). Additionally, over half of the DLB converters showed abnormalities on other autonomic examinations. For converters, the most common MDD subtype had psychotic and melancholic features simultaneously. The frequency of hypersensitivity to psychotropics was higher in converters than it was in non-converters. Conclusion: In the present study, patients with abnormal VRH results were very likely to develop DLB. Thus, for patients with late-onset MDD accompanied by bradykinesia, the VRH in combination with the clinical subtype of MDD or hypersensitivity to psychotropics may be useful for diagnosing prodromal DLB. Show more

Keywords: Autonomic failure, conversion, dementia with Lewy bodies, depression, ventilatory response to hypercapnia

DOI: 10.3233/JAD-150507

Citation: Journal of Alzheimer's Disease, vol. 50, no. 3, pp. 751-758, 2016

Authors: Renard, Dimitri | Wacongne, Anne | Ayrignac, Xavier | Charif, Mahmoud | Fourcade, Genevieve | Azakri, Souhayla | Le Floch, Anne | Bouly, Stephane | Marelli, Cecilia | Arquizan, Caroline | Hirtz, Christophe | Gabelle, Audrey | Thouvenot, Eric | Lehmann, Sylvain

Article Type: Research Article

Abstract: Background: Decreased cerebrospinal fluid (CSF) amyloid-β 1-40 (Aβ40 ) and amyloid-β 1-42 (Aβ42 ) and increased total and phosphorylated tau (t-tau, p-tau) concentrations have been described in cerebral amyloid angiopathy (CAA). Objective: Our aim was to analyze these biomarkers in patients with CAA-related inflammation (CAA-I). Methods: We prospectively recruited nine patients with acute phase CAA-I fulfilling Chung criteria. CSF was analyzed for t-tau, p-tau, Aβ42 , and Aβ40 . Data were compared to controls (n  = 14), patients with Alzheimer’s disease (AD, n  = 42), CAA (n  = 10), and primary angiitis of the central nervous system (PACNS, n … = 3). Results: For the CAA-I group, statistically significant differences were: lower Aβ42 (p  = 0.00053) compared to the control group; lower t-tau (p  = 0.018), p-tau (p  <  0.001), and Aβ40 (p  <  0.001) compared to AD; lower Aβ42 (p  = 0.027) compared to CAA; lower Aβ42 (p  = 0.012) compared to PACNS. Nearly significantly lower Aβ40 (p  = 0.051) and higher t-tau (p  = 0.051) were seen in CAA-I compared to controls. Conclusion: CSF biomarkers profile similar to that of CAA was observed in CAA-I (with even lower levels of Aβ42 compared to CAA). Based on our findings, high p-tau seems more specific for AD, whereas low Aβ42 differentiates CAA-I from CAA, PACNS, and controls, and low Aβ40 differentiates CAA-I from AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, cerebral amyloid angiopathy, cerebrospinal fluid, inflammation, tau

DOI: 10.3233/JAD-150621

Citation: Journal of Alzheimer's Disease, vol. 50, no. 3, pp. 759-764, 2016

Authors: Babić Leko, Mirjana | Borovečki, Fran | Dejanović, Nenad | Hof, Patrick R. | Šimić, Goran

Article Type: Research Article

Abstract: Visinin-like protein 1 (VILIP-1) recently emerged as a potential biomarker of Alzheimer’s disease (AD). This neuronal calcium sensor protein previously used as a marker of acute ischemic stroke is elevated in the cerebrospinal fluid (CSF) of AD patients. The goal of this study was to assess CSF VILIP-1 potential in early AD diagnosis and in differentiating mild cognitive impairment (MCI) patients with and without risk of AD. Additionally, we tested VILIP-1 ability to differentiate AD from other primary causes of dementia, and predict the progression of AD-related cognitive decline. VILIP-1 levels were compared with five CSF AD biomarkers (t-tau, Aβ1-42 …, p-tau181 , p-tau199 , and p-tau231 ). VILIP-1 successfully differentiated two MCI patient groups characterized by absence or presence of pathological levels of these CSF biomarkers, except for t-tau. VILIP-1/Aβ1-42 and VILIP-1/p-tau181 ratios also differentiated MCI patients with pathological CSF biomarker levels. However, there was no difference in VILIP-1 levels between AD and MCI patients. VILIP-1/Aβ1-42 and VILIP-1/p-tau231 ratios reached high sensitivities (above 70%) and very high specificities (above 85%) in differentiating AD patients from HC. Additionally, VILIP-1 differentiated AD from patients with Lewy body disease with 77.1% sensitivity and 100% specificity. VILIP-1 potential as a prognostic biomarker of cognitive decline in AD was also proved since VILIP-1/t-tau, VILIP-1/p-tau181 , and VILIP-1/p-tau231 ratios correlated with MMSE scores. These data indicate that VILIP-1 alone or in combination with other AD CSF biomarkers represent a valuable marker for the early diagnosis of AD, recognition of MCI patients at higher risk to develop dementia, and in differentiating AD from LBD. Show more

Keywords: Alzheimer’s disease, biomarker, cerebrospinal fluid, dementia, early diagnosis, mild cognitive impairment, visinin-like protein 1 (VILIP-1)

DOI: 10.3233/JAD-150705

Citation: Journal of Alzheimer's Disease, vol. 50, no. 3, pp. 765-778, 2016

Authors: Nation, Daniel A. | Ho, Jean | Yew, Belinda

Article Type: Research Article

Abstract: Background: Evidence suggests that angiotensin II AT1 -receptor blockers (ARBs) may be protective against dementia, and studies in transgenic animals indicate that this may be due to improved amyloid-β (Aβ) clearance. Objective: We investigated whether taking ARBs was associated with an attenuation of age-related increases in cerebral Aβ retention, and reduced progression to dementia. Methods: Eight hundred seventy-one stroke-free and dementia-free older adults from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study underwent baseline lumbar puncture, and a subgroup (n  = 124) underwent 12 and 24 month follow-up lumbar puncture. Participants were followed at variable intervals for clinical …progression to dementia. Linear mixed models and ANCOVA compared ARBs users with those taking other antihypertensives (O-antiHTN) or no antihypertensives (No-antiHTN) on cerebrospinal fluid (CSF) Aβ and phosphorylated tau (P-tau) levels. Cox regression and chi-square analyses compared groups on progression to dementia. Results: ARBs users exhibited greater vascular risk and lower educational attainment than the No-antiHTN group. Longitudinal analyses indicated higher CSF Aβ and lower P-tau in ARBs users versus other groups. Cross-sectional analyses revealed age-related decreases in CSF Aβ in other groups but not ARBs users. ARBs users were less likely to progress to dementia and showed reduced rate of progression relative to the No-antiHTN group. Discussion: Patients taking ARBs showed an attenuation of age-related decreases in CSF Aβ, a finding that is consistent with studies done in transgenic animals. These findings may partly explain why ARBs users show reduced progression to dementia despite their lower educational attainment and greater vascular risk burden. Show more

Keywords: Amyloid-β, antihypertensive medications, AT1-receptor blockers, blood pressure, CSF biomarkers, tau

DOI: 10.3233/JAD-150487

Citation: Journal of Alzheimer's Disease, vol. 50, no. 3, pp. 779-789, 2016

Authors: Tholen, Susanne | Schmaderer, Christoph | Chmielewski, Stefan | Förstl, Hans | Heemann, Uwe | Baumann, Marcus | Steubl, Dominik | Grimmer, Timo

Article Type: Research Article

Abstract: Background: Cognitive impairment in hemodialysis patients is common, but the underlying pathogenesis remains unclear. Alzheimer’s disease is the most common cause of dementia in the general elderly population. Histopathological hallmarks are, among others, senile plaques, which consist of amyloid-β (Aβ). Objective: To measure plasma levels of Aβ42 and Aβ40 during hemodialysis and to examine potential associations with cognitive performance in cognitively impaired hemodialysis patients. Methods: Plasma samples of 26 hemodialysis patients were collected shortly before, after 50% of dialysis time, and at the end of a dialysis session. Aβ42 and Aβ40 levels …were measured by a high-sensitivity ELISA for human amyloid-β. Cognition was tested under standardized conditions using the Montreal Cognitive Assessment (MoCA) as proposed previously. Results: Clearance rates of both peptides during one dialysis session were 22% and 35% for Aβ42 and Aβ40 , respectively. Aβ42 but not Aβ40 baseline levels were significantly associated with MoCA test results (r  = 0.654, p  = 0.001). Conclusion: In cognitively impaired hemodialysis patients plasma Aβ42 levels were associated with cognitive performance and both Aβ42 and Aβ40 plasma levels could be effectively reduced by dialysis. By inducing peripheral Aβ sink, hemodialysis may be considered as an anti-amyloid treatment strategy. Show more

Keywords: Alzheimer’s disease, amyloid-beta, cognitive impairment, hemodialysis

DOI: 10.3233/JAD-150662

Citation: Journal of Alzheimer's Disease, vol. 50, no. 3, pp. 791-796, 2016

Authors: Claus, Jules J. | Staekenborg, Salka S. | Roorda, Jelmen J. | Stevens, Martijn | Herderschee, Dirk | van Maarschalkerweerd, Willy | Schuurmans, Lilly | Tielkes, Caroline E.M. | Koster, Pieter | Bavinck, Chris | Scheltens, Philip

Article Type: Research Article

Abstract: Background: It is generally assumed that with increasing age, pathology in clinically diagnosed Alzheimer’s disease (AD) becomes more mixed, i.e., co-existence of amyloid plaques and cerebrovascular pathology. Objective: To test the hypothesis of increasing prevalence of mixed dementia in late-onset clinically diagnosed Alzheimer’s disease (AD) in a single-center memory clinic population. Methods: Patients included had diagnoses of AD (n  = 832), subjective cognitive impairment (SCI, n  = 333), mild cognitive impairment (MCI, n  = 492), vascular dementia (VaD, n  = 57), other dementia (n  = 53), or other diagnosis (n  = 233). Prevalence of severe white matter lesions (WML) was defined as …a score of 2 or higher on the Fazekas-scale on brain computed tomography to classify AD patients as having mixed dementia. We examined the effect of age on WML using multiple linear regression analysis, and AD patients were compared to SCI to determine the effect of disease on WML. Results: Prevalence of severe WML was 33.6% in AD patients (mixed dementia), 11.4% in SCI, 22.7% in MCI, 75.4% in VaD, 3.8% in other dementia, and 15.5% in other diagnosis. With increasing age there was a significant and similar increase of WML scores in SCI, MCI, AD, other dementia, and other diagnosis, indicating no effect modification by AD. The difference between AD patients and SCI averaged 0.16 on the WML score and difference in percentage severe WML between AD and SCI patients was 15% across all ages. Conclusion: We found a low prevalence of mixed dementia. Furthermore, severe WML in AD was largely explained by age rather than effect of disease. Show more

Keywords: Alzheimer’s disease, computed tomography, Fazekas score, memory clinic, white matter lesions

DOI: 10.3233/JAD-150796

Citation: Journal of Alzheimer's Disease, vol. 50, no. 3, pp. 797-806, 2016

Authors: Spalletta, Gianfranco | Cravello, Luca | Gianni, Walter | Piras, Federica | Iorio, Mariangela | Cacciari, Claudia | Casini, Anna Rosa | Chiapponi, Chiara | Sancesario, Giuseppe | Fratangeli, Claudia | Orfei, Maria Donata | Caltagirone, Carlo | Piras, Fabrizio

Article Type: Research Article

Abstract: Homotaurine supplementation may have a positive effect on early Alzheimer’s disease. Here, we investigated its potential neuroprotective effect on the hippocampus structure and episodic memory performances in amnestic mild cognitive impairment (aMCI). Neuropsychological, clinical, and neuroimaging assessment in 11 treated and 22 untreated patients were performed at baseline and after 1 year. Magnetic resonance data were analyzed using voxel-based morphometry to explore significant differences (Family Wise Error corrected) between the two groups over time. Patients treated with homotaurine showed decreased volume loss in the left and right hippocampal tail, left and right fusiform gyrus, and right inferior temporal cortex which …was associated with improved short-term episodic memory performance as measured by the recency effect of the Rey 15-word list learning test immediate recall. Thus, homotaurine supplementation in individuals with aMCI has a positive effect on hippocampus atrophy and episodic memory loss. Future studies should further clarify the mechanisms of its effects on brain morphometry. Show more

Keywords: Amnestic mild cognitive impairment, episodic memory, hippocampus, homotaurine, structural magnetic resonance imaging, tramiprosate

DOI: 10.3233/JAD-150484

Citation: Journal of Alzheimer's Disease, vol. 50, no. 3, pp. 807-816, 2016

Authors: Schuck, Florian | Wolf, Dominik | Fellgiebel, Andreas | Endres, Kristina

Article Type: Research Article

Abstract: ADAM10 is one of the key players in ectodomain-shedding of the amyloid-β protein precursor (Aβ PP). Previous research with postmortem tissue has shown reduced expression and activity of ADAM10 within the central nervous system (CNS) of Alzheimer’s disease (AD) patients. Determination of cerebral ADAM10 in living humans is hampered by its transmembrane property; only the physiological Aβ PP cleavage product generated by ADAM10, sAβ PPα, can be assessed in cerebrospinal fluid. Establishment of surrogate markers in easily accessible material therefore is crucial. It has been demonstrated that ADAM10 is expressed in platelets and that platelet amount is decreased in …AD patients. Just recently it has been shown that platelet ADAM10 and cognitive performance of AD patients positively correlate. In contrast to AD patients, to our knowledge almost no information has been published regarding ADAM10 expression during normal aging. We investigated ADAM10 amount and activity in platelets of cognitively healthy individuals from three different age groups ranging from 22–85 years. Interestingly, we observed an age-dependent increase in ADAM10 levels and activity in platelets. Show more

Keywords: ADAM10, fluorescence activity, normal aging, platelets, resilience factor

DOI: 10.3233/JAD-150737

Citation: Journal of Alzheimer's Disease, vol. 50, no. 3, pp. 817-826, 2016

Authors: Fernández, Gerardo | Manes, Facundo | Politi, Luis E. | Orozco, David | Schumacher, Marcela | Castro, Liliana | Agamennoni, Osvaldo | Rotstein, Nora P.

Article Type: Research Article

Abstract: Patients with Alzheimer’s disease (AD) develop progressive language, visuoperceptual, attentional, and oculomotor changes that can have an impact on their reading comprehension. However, few studies have examined reading behavior in AD, and none have examined the contribution of predictive cueing in reading performance. For this purpose we analyzed the eye movement behavior of 35 healthy readers (Controls) and 35 patients with probable AD during reading of regular and high-predictable sentences. The cloze predictability of words N  – 1, and N  + 1 exerted an influence on the reader’s gaze duration. The predictabilities of preceding words in high-predictable sentences served as task-appropriate cues …that were used by Control readers. In contrast, these effects were not present in AD patients. In Controls, changes in predictability significantly affected fixation duration along the sentence; noteworthy, these changes did not affect fixation durations in AD patients. Hence, only in healthy readers did predictability of upcoming words influence fixation durations via memory retrieval. Our results suggest that Controls used stored information of familiar texts for enhancing their reading performance and imply that contextual-word predictability, whose processing is proposed to require memory retrieval, only affected reading behavior in healthy subjects. In AD patients, this loss reveals impairments in brain areas such as those corresponding to working memory and memory retrieval. These findings might be relevant for expanding the options for the early detection and monitoring in the early stages of AD. Furthermore, evaluation of eye movements during reading could provide a new tool for measuring drug impact on patients’ behavior. Show more

Keywords: Alzheimer’s disease, eye movements, memory, reading

DOI: 10.3233/JAD-150265

Citation: Journal of Alzheimer's Disease, vol. 50, no. 3, pp. 827-838, 2016

Authors: Nagata, Tomoyuki | Shinagawa, Shunichiro | Nakajima, Shinichiro | Plitman, Eric | Mihashi, Yukiko | Hayashi, Shogo | Mimura, Masaru | Nakayama, Kazuhiko

Article Type: Research Article

Abstract: Background: The Neuropsychiatric Inventory (NPI) comprises 12 items, which were conventionally determined by psychopathological symptoms of patients with dementia. The clinical rating scales with structured questionnaires have been useful to evaluate neuropsychiatric symptoms (NPSs) of patients with dementia over the past twenty year. Objective: The aim of this study was to classify the conventional NPSs in patients with Alzheimer’s disease (AD) requiring antipsychotic treatment for their NPSs into distinct clusters to simplify assessment of these numerous symptoms. Methods: Twelve items scores (product of severity and frequency of each symptom) in the NPI taken from the baseline …visit were classified into subgroups by principle component analysis using data from 421 outpatients with AD enrolled in the Clinical Antipsychotic Trials of Intervention Effectiveness–Alzheimer’s Disease (CATIE-AD) Phase 1. Chi square tests were conducted to examine the co-occurrence of the subgroups. Results: We found four distinct clusters: aggressiveness (agitation and irritabilities), apathy and eating problems (apathy and appetite/eating disturbance), psychosis (delusions and hallucinations), and emotion and disinhibition (depression, euphoria, and disinhibition). Anxiety, aberrant motor behavior, and sleep disturbance were not included by these clusters. Apathy and eating problems, and emotion and disinhibition co-occurred (p  = 0.002), whereas aggressiveness and psychosis occurred independent of the other clusters. Conclusions: Four distinct category clusters were identified from NPSs in patients with AD requiring antipsychotic treatment. Future studies should investigate psychosocial backgrounds or risk factors of each distinct cluster, in addition to their longitudinal course over treatment intervention. Show more

Keywords: Alzheimer’s disease, delusions, neuropsychiatric symptoms, principal component analysis

DOI: 10.3233/JAD-150869

Citation: Journal of Alzheimer's Disease, vol. 50, no. 3, pp. 839-845, 2016

Authors: Ardekani, Babak A. | Convit, Antonio | Bachman, Alvin H.

Article Type: Research Article

Abstract: Background: Hippocampus (HC) atrophy is a hallmark of early Alzheimer’s disease (AD). Atrophy rates can be measured by high-resolution structural MRI. Longitudinal studies have previously shown sex differences in the progression of functional and cognitive deficits and rates of brain atrophy in early AD dementia. It is important to corroborate these findings on independent datasets. Objective: To study temporal rates of HC atrophy over a one-year period in probable AD patients and cognitively normal (CN) subjects by longitudinal MRI scans obtained from the Minimal Interval Resonance Imaging in AD (MIRIAD) database. Methods: We used a novel …algorithm to compute an index of hippocampal (volumetric) integrity (HI) at baseline and one-year follow-up in 43 mild-moderate probable AD patients and 22 CN subjects in MIRIAD. The diagnostic power of longitudinal HI measurement was assessed using a support vector machines (SVM) classifier. Results: The HI was significantly reduced in the AD group (p  <  10–20 ). In addition, the annualized percentage rate of reduction in HI was significantly greater in the AD group (p  <  10–13 ). Within the AD group, the annual reduction of HI in women was significantly greater than in men (p  = 0.008). The accuracy of SVM classification between AD and CN subjects was estimated to be 97% by 10-fold cross-validation. Conclusion: In the MIRIAD patients with probable AD, the HC atrophies at a significantly faster rate in women as compared to men. Female sex is a risk factor for faster descent into AD. The HI measure has potential for AD diagnosis, as a biomarker of AD progression and a therapeutic target in clinical trials. Show more

Keywords: Alzheimer’s disease, atrophy, brain, classification, hippocampus, longitudinal analysis, MRI, sex, support vector machines

DOI: 10.3233/JAD-150780

Citation: Journal of Alzheimer's Disease, vol. 50, no. 3, pp. 847-857, 2016

Authors: Shi, Shi | Liang, Dongli | Bao, Min | Xie, Yilin | Xu, Wangjie | Wang, Lianyun | Wang, Zhaoxia | Qiao, Zhongdong

Article Type: Research Article

Abstract: Recent studies have revealed that the α 7 nicotinic acetylcholine receptor (α 7 nAChR) is a critical link between inflammation and neurodegeneration, which is closely associated with Alzheimer’s disease (AD). The JAK2/STAT3 and PI3K/AKT signaling pathways contribute to the neuroprotective and anti-inflammatory effects of α 7nAChR. Our previous studies have shown that treatment with gx-50 improves cognitive function and is neuroprotective. Here, we investigated the effect of gx-50 on α 7 nAChR and Aβ-induced inflammation in microglia. First, the binding affinity of gx-50 to α 7 nAChR was examined using the fluorescence-based Octet RED system, and the expression of α …7 nAChR was detected using real-time PCR and western blotting. We also investigated downstream events of α 7 nAChR activity, including the translocation of p-STAT3 and the phosphorylation of JAK2, STAT3, PI3K, and AKT. Finally, the effect of gx-50 on Aβ-induced inflammation via α 7 nAChR-mediated signaling pathways was investigated using cytokine assays. The results showed that gx-50 is able to act as a specific ligand to activate α 7 nAChR, which then upregulates the JAK2/STAT3 and PI3K/AKT signaling pathways to inhibit the secretions of pro-inflammatory cytokines, such as IL-1β. In conclusion, the results suggest that gx-50 could inhibit the Aβ-induced inflammatory response in microglia via α 7 nAChR activity, which might be a successful therapeutic target against AD. Show more

Keywords: Alzheimer’s disease, α7 nAChR, gx-50, inflammation, JAK2/STAT3, PI3K/AKT

DOI: 10.3233/JAD-150963

Citation: Journal of Alzheimer's Disease, vol. 50, no. 3, pp. 859-871, 2016

Authors: Melah, Kelsey E. | Lu, Sharon Yuan-Fu | Hoscheidt, Siobhan M. | Alexander, Andrew L. | Adluru, Nagesh | Destiche, Daniel J. | Carlsson, Cynthia M. | Zetterberg, Henrik | Blennow, Kaj | Okonkwo, Ozioma C. | Gleason, Carey E. | Dowling, N. Maritza | Bratzke, Lisa C. | Rowley, Howard A. | Sager, Mark A. | Asthana, Sanjay | Johnson, Sterling C. | Bendlin, Barbara B.

Article Type: Research Article

Abstract: Background: The immune response in Alzheimer’s disease (AD) involves activation of microglia which may remove amyloid-β (Aβ). However, overproduction of inflammatory compounds may exacerbate neural damage in AD. AD pathology accumulates years before diagnosis, yet the extent to which neuroinflammation is involved in the earliest disease stages is unknown. Objective: To determine whether neuroinflammation exacerbates neural damage in preclinical AD. Methods: We utilized cerebrospinal fluid (CSF) and magnetic resonance imaging collected in 192 asymptomatic late-middle-aged adults (mean age = 60.98 years). Neuroinflammatory markers chitinase-3-like protein 1 (YKL-40) and monocyte chemoattractant protein-1 (MCP-1) in CSF were utilized as markers …of neuroinflammation. Neural cell damage was assessed using CSF neurofilament light chain protein (NFL), CSF total tau (T-Tau), and neural microstructure assessed with diffusion tensor imaging (DTI). With regard to AD pathology, CSF Aβ42 and tau phosphorylated at threonine 181 (P-Tau181 ) were used as markers of amyloid and tau pathology, respectively. We hypothesized that higher YKL-40 and MCP-1 in the presence of AD pathology would be associated with higher NFL, T-Tau, and altered microstructure on DTI. Results: Neuroinflammation was associated with markers of neural damage. Higher CSF YKL-40 was associated with both higher CSF NFL and T-Tau. Inflammation interacted with AD pathology, such that greater MCP-1 and lower Aβ42 was associated with altered microstructure in bilateral frontal and right temporal lobe and that greater MCP-1 and greater P-Tau181 was associated with altered microstructure in precuneus. Conclusion: Inflammation may play a role in neural damage in preclinical AD. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid proteins, diffusion tensor imaging, inflammation,

DOI: 10.3233/JAD-150897

Citation: Journal of Alzheimer's Disease, vol. 50, no. 3, pp. 873-886, 2016

Authors: Chatterjee, Pratishtha | Lim, Wei L.F. | Shui, Guanghou | Gupta, Veer B. | James, Ian | Fagan, Anne M. | Xiong, Chengjie | Sohrabi, Hamid R. | Taddei, Kevin | Brown, Belinda M. | Benzinger, Tammie | Masters, Colin | Snowden, Stuart G. | Wenk, Marcus R. | Bateman, Randall J. | Morris, John C. | Martins, Ralph N.

Article Type: Research Article

Abstract: Background and Objective: Aberrant lipid metabolism has been implicated in sporadic Alzheimer’s disease (AD). The current study investigated plasma phospholipid and sphingolipid profiles in individuals carrying PSEN1 mutations responsible for autosomal dominant AD (ADAD). Methods: Study participants evaluated were from the Perth and Melbourne sites of the Dominantly Inherited Alzheimer Network (DIAN) study. Plasma phospholipid and sphingolipid profiles were measured using liquid chromatography coupled with mass spectrometry in 20 PSEN1 mutation carriers (MC; eight of whom were symptomatic and twelve asymptomatic, based on Clinical Dementia Rating scores) and compared with six non carriers (NC) using linear …mixed models. Further, AD gold standard biomarker data obtained from the DIAN database were correlated with lipid species significantly altered between MC and NC, using Spearman’s correlation coefficient. Results: One-hundred and thirty-nine plasma phospholipid and sphingolipid species were measured. Significantly altered species in MC compared to NC primarily belonged to choline and ethanolamine containing phospholipid classes and ceramides. Further phosphatidylcholine species (34:6, 36:5, 40:6) correlated with cerebrospinal fluid tau (p  <  0.05), and plasmalogen ethanolamine species (34:2, 36:,4) correlated with both cerebrospinal fluid tau and brain amyloid load within the MC group (p  <  0.05). Conclusion: These findings indicate altered phospholipid and sphingolipid metabolism in ADAD and provide insight into the pathomolecular changes occurring with ADAD pathogenesis. Further, findings reported in this study allow comparison of lipid alterations in ADAD with those reported previously in sporadic AD. The findings observed in the current pilot study warrant validation in the larger DIAN cohort. Show more

Keywords: Alzheimer’s disease, biomarkers, familial Alzheimer’s disease, phospholipids, sphingolipids

DOI: 10.3233/JAD-150948

Citation: Journal of Alzheimer's Disease, vol. 50, no. 3, pp. 887-894, 2016

Authors: Porter, Tenielle | Bharadwaj, Prashant | Groth, David | Paxman, Adrian | Laws, Simon M. | Martins, Ralph N. | Verdile, Giuseppe

Article Type: Research Article

Abstract: Latrepirdine (Dimebon™) has been demonstrated to be a neuroprotective and cognition improving agent in neurodegenerative diseases that feature protein aggregation and deposition, such as Alzheimer’s disease (AD). The accumulation of amyloid-β (Aβ) protein aggregates is a key event in the neurodegenerative process in AD. This study explores if latrepirdine modulation of protein aggregation contributes to its neuroprotective mechanism of action. Assessment of neuronal cell death showed that there was a significant reduction in lactate dehydrogenase release at an equimolar ratio of Aβ:latrepirdine and with lower concentrations of latrepirdine. The ability of latrepirdine to alter the formation of Aβ42 aggregates …was assessed by thioflavin-T fluorescence, western immunoblotting and atomic force microscopy (AFM). Despite showing a reduction in thioflavin-T fluorescence with latrepirdine treatment, indicating a decrease in aggregation, immunoblotting and AFM showed a modest increase in both the formation and size of Aβ aggregates. The discrepancies between thioflavin-T and the other assays are consistent with previous evidence that cyclic molecules can interfere with thioflavin-T binding of amyloid protein preparations. The ability of latrepirdine to modulate Aβ aggregation appears to be independent of its neuroprotective effects, and is unlikely to be a mechanism by which latrepirdine offers protection. This study investigates the effect of latrepirdine on Aβ aggregation, and presents evidence suggesting that caution should be applied in the use of thioflavin-T fluorescence based assays as a method for screening compounds for protein aggregation altering properties. Show more

Keywords: Alzheimer’s disease, amyloid-beta, latrepirdine, neurotoxicity, Thiofavin T

DOI: 10.3233/JAD-150790

Citation: Journal of Alzheimer's Disease, vol. 50, no. 3, pp. 895-905, 2016

Article Type: Other

DOI: 10.3233/JAD-151107

Citation: Journal of Alzheimer's Disease, vol. 50, no. 3, pp. 907-911, 2016