Journal of Alzheimer's Disease - Volume 40, issue 4

Authors: Walton, J.R.

Article Type: Review Article

Abstract: Industrialized societies produce many convenience foods with aluminum additives that enhance various food properties and use alum (aluminum sulfate or aluminum potassium sulfate) in water treatment to enable delivery of large volumes of drinking water to millions of urban consumers. The present causality analysis evaluates the extent to which the routine, life-long intake, and metabolism of aluminum compounds can account for Alzheimer's disease (AD), using Austin Bradford Hill's nine epidemiological and experimental causality criteria, including strength of the relationship, consistency, specificity, temporality, dose-dependent response, biological rationale, coherence with existing knowledge, experimental evidence, and analogy. Mechanisms that underlie the risk of …low concentrations of aluminum relate to (1) aluminum's absorption rates, allowing the impression that aluminum is safe to ingest and as an additive in food and drinking water treatment, (2) aluminum's slow progressive uptake into the brain over a long prodromal phase, and (3) aluminum's similarity to iron, in terms of ionic size, allows aluminum to use iron-evolved mechanisms to enter the highly-active, iron-dependent cells responsible for memory processing. Aluminum particularly accumulates in these iron-dependent cells to toxic levels, dysregulating iron homeostasis and causing microtubule depletion, eventually producing changes that result in disconnection of neuronal afferents and efferents, loss of function and regional atrophy consistent with MRI findings in AD brains. AD is a human form of chronic aluminum neurotoxicity. The causality analysis demonstrates that chronic aluminum intake causes AD. Show more

Keywords: Aluminum, Alzheimer's disease, amyloidogenesis, animal disease models, causality, disconnection, entorhinal cortex, microtubules, neurofibrillary tangles, transferrin receptors

DOI: 10.3233/JAD-132204

Citation: Journal of Alzheimer's Disease, vol. 40, no. 4, pp. 765-838, 2014

Authors: Silverstein, Jeffrey H.

Article Type: Review Article

Abstract: Since the finding in the 1880 s that elderly patients may experience cognitive decline following surgery, the search for an understanding of this phenomenon has been underway. In the last decade, evidence from biophysical (light scattering and nuclear magnetic resonance), in vitro, in vivo animal studies, retrospective evaluations of human registries, and recently prospective randomized trials have explored the idea that various anesthetic agents play a role in this phenomenon by interacting with the biochemical mechanisms that are also responsible for the development of Alzheimer's disease. In the current review, we examine the evidence available and conclude that there is …significant evidence to suggest an important role for this mechanism. Show more

Keywords: Alzheimer's disease, anesthetics, dementia

DOI: 10.3233/JAD-130815

Citation: Journal of Alzheimer's Disease, vol. 40, no. 4, pp. 839-848, 2014

Authors: Abbate, Carlo | Arosio, Beatrice | Galimberti, Daniela | Nicolini, Paola | Chiara, Lo Russo | Rossi, Paolo Dionigi | Ferri, Evelyn | Gussago, Cristina | Deriz, Milena | Fenoglio, Chiara | Serpente, Maria | Scarpini, Elio | Mari, Daniela

Article Type: Short Communication

Abstract: We describe a sporadic case of frontotemporal lobar degeneration, associated with the C9ORF72 mutation, with prominent behavioral changes and semantic deficits. Predominant deficits in naming, vocabulary, word comprehension, and face and object recognition emerged on neuropsychological assessment. Amnesia, behavioral changes, and isolated psychotic symptoms were also present. Hyposmia was an unspecific prodromal sign. Brain imaging showed basofrontal and temporopolar hypometabolism bilaterally, and predominantly left-sided atrophy. Levels of cerebrospinal fluid biomarkers (amyloid-β, tau and p-tau) were normal. This description further confirms the heterogeneous presentation of the C9ORF72 mutation.

Keywords: C9ORF72, frontotemporal lobar degeneration, hyposmia, phenotype, semantic dementia

DOI: 10.3233/JAD-132075

Citation: Journal of Alzheimer's Disease, vol. 40, no. 4, pp. 849-855, 2014

Authors: Troussière, Anne Cécile | Wallon, David | Mouton-Liger, François | Yatimi, Rachida | Robert, Philippe | Hugon, Jacques | Hannequin, Didier | Pasquier, Florence | Paquet, Claire

Article Type: Short Communication

Abstract: Cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) are well validated in clinical research but less in clinical practice. Using a questionnaire, we evaluated the reasons for prescriptions and clinician's expectations concerning CSF biomarkers. The results show that CSF AD biomarkers are mainly required in case of atypical dementia and diagnosis uncertainty that are different from indications in clinical research. In the future, clinicians wish to get new biomarkers that could improve differential diagnosis and could have a good pronostic value. Further studies in routine practice are necessary to precise the role of these biomarkers in the management of patients.

Keywords: Alzheimer's disease, biomarkers, cerebrospinal fluid, clinical practice

DOI: 10.3233/JAD-132672

Citation: Journal of Alzheimer's Disease, vol. 40, no. 4, pp. 857-861, 2014

Authors: Hu, Yueqing | Liang, Jingyao | Yu, Shengyuan

Article Type: Short Communication

Abstract: Huntington's disease (HD) is associated with diabetes mellitus (DM) in population studies, but no case has been reported in a large HD family. We report a case of a five-generation Chinese family who is afflicted by both HD and DM. The prevalence of DM in HD of this family was high (72.7%). The diagnosis of HD in 11 family members was confirmed by the genetic test of the proband who had 42 CAG repeats. Furthermore, the proband's daughter had abnormal locus at G3460T in MT-ND1 among mtDNA genome. Our case report suggests a genetic link between HD and DM.

Keywords: Diabetes mellitus, genes, Huntington disease, pathogenesis

DOI: 10.3233/JAD-131847

Citation: Journal of Alzheimer's Disease, vol. 40, no. 4, pp. 863-868, 2014

Authors: Yakhia, Maja | König, Alexandra | van der Flier, Wiesje M. | Friedman, Leah | Robert, Philippe H. | David, Renaud

Article Type: Research Article

Abstract: Background: Individuals with mild cognitive impairment (MCI) may exhibit changes in motor activity in conducting their activities of daily living. Depression, one of the most frequent neuropsychiatric symptoms, might affect motor activity in MCI. Objective: To assess motor activity in MCI subjects carrying out short functional activity tasks using ambulatory actigraphy. Secondly, we sought to investigate the influence of depressive symptoms on motor activity. Methods: 20 MCI and 14 healthy subjects carried out a 30-minute standardized scenario while wearing a chest actigraph. The protocol consisted of directed activities (execution of motor tasks), semi-directed activities (execution of …Instrumental Activities of Daily Living, IADL), and undirected ‘free’ activities. Several common assessment scales (GDS, MADRS, and NPI) were used to diagnose depression. Results: MCI subjects had significantly reduced mean motor activity while carrying out directed and semi-directed activities, compared to healthy control subjects. No difference was found in motor activity between MCI subjects with or without depression. Conclusion: Actigraphic measurement of motor activity during the evaluation of IADLs and motor tasks is a potential objective tool in detecting early changes in MCI. Depressive symptoms seem not to be associated with motor activity in MCI subjects. Show more

Keywords: Actigraphy, depressive symptoms, mild cognitive impairment, motor activity

DOI: 10.3233/JAD-131691

Citation: Journal of Alzheimer's Disease, vol. 40, no. 4, pp. 869-875, 2014

Authors: Noh, Young | Seo, Sang Won | Jeon, Seun | Lee, Jong Min | Kim, Jung-Hyun | Kim, Geon Ha | Cho, Hanna | Yoon, Cindy W. | Kim, Hee Jin | Ye, Byoung Seok | Kim, Sung Tae | Choe, Yearn Seong | Lee, Kyung-Han | Kim, Jae Seung | Ewers, Michael | Weiner, Michael W. | Lee, Jae-Hong | Werring, David J. | Kang, Dae Ryong | Kim, Chang Soo | Na, Duk L.

Article Type: Research Article

Abstract: Previous preclinical studies have suggested a close relationship between cerebrovascular disease (CVD) and Alzheimer's disease. However, a direct correlation between CVD and amyloid burden has not yet been shown in humans. If there is a relationship between CVD and amyloid burden, it is possible that the apolipoprotein E4 (APOE4) genotype may have an effect on this relationship because APOE4 is a risk factor for the development of AD. We therefore evaluated the effects of APOE4 on the relationship between white matter hyperintensities (WMH), a marker of CVD, and amyloid burden, measured by 11 C-Pittsburgh compound B (PiB) PET. We recruited …53 patients with subcortical vascular cognitive impairments, who had both WMH on MRI and amyloid deposition assessed by PiB PET. Twenty-two of these patients were APOE4 carriers (41.5%). In the APOE4 non-carriers, a significant positive correlation was shown between the volume of WMH and PiB retention (β = 7.0 × 10−3 , p = 0.034) while no significant correlation was found in APOE4 carriers (β = −9.0 × 10−3 , p = 0.085). Statistical parametric mapping analyses in APOE4 non-carriers showed that WMH were associated with PiB retention in the bilateral medial occipitotemporal gyrus, cuneus, and superior cerebellum. Our results suggested that WMH are correlated with amyloid burden especially in the posterior brain regions in APOE4 non-carriers. However, this correlation was not observed in APOE4 carriers, perhaps because in these subjects the influence of APOE4 overrides the effect of CVD. Show more

Keywords: Alzheimer's disease, amyloid burden, apolipoprotein E4, cerebrovascular disease

DOI: 10.3233/JAD-130461

Citation: Journal of Alzheimer's Disease, vol. 40, no. 4, pp. 877-886, 2014

Authors: Hall, James R. | Wiechmann, April R. | Johnson, Leigh A. | Edwards, Melissa | Barber, Robert C. | Cunningham, Rebecca | Singh, Meharvan | O'Bryant, Sid E. | for the Texas Alzheimer's Research and Care Consortium

Article Type: Research Article

Abstract: Research on the link between APOEε4 and neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) has been inconsistent. Previous work has shown a relationship between serum biomarkers of vascular risk and inflammation and NPS in AD. The current study investigated the impact of APOEε4 status on the relationship between biomarkers of cardiovascular risk, systemic inflammation, and NPS. The sample was drawn from the TARCC Longitudinal Research Cohort; the final sample of 190 consisted of 124 females and 66 males meeting the diagnostic criteria for mild to moderate AD. 115 individuals were APOEε4 carriers and 75 were non-carriers. Serum-based clinical biomarkers of …vascular risk and biomarkers of inflammation related to AD were analyzed. NPS data was gathered from caretakers/family members using the Neuropsychiatric Inventory. The significant biomarkers differed for carriers and non-carriers with IL15 being a negative biomarker of total NPS accounting for 12% of the variance for carriers and IL18 and TNFα negative predictors for non-carriers (18% of variance). Patterns related to specific symptoms were similar. Stratification by gender revealed significant biomarkers of total NPS for female carriers were negative IL15 and IL1ra (18% of variance) and for female non-carriers were negative IL18 and positive homocysteine. Total cholesterol was a positive biomarker of total NPS for both male carriers (36% of variance) and non-carriers (negative TNFα and total cholesterol, 32% of variance). These findings suggest that dysregulation of inflammatory activity is related to NPS, that cholesterol is a significant factor in the occurrence of NPS, and that gender and APOE status need to be considered. Show more

Keywords: Alzheimer's disease, APOE, gender, neuropsychiatric symptoms

DOI: 10.3233/JAD-131724

Citation: Journal of Alzheimer's Disease, vol. 40, no. 4, pp. 887-896, 2014

Authors: Walterfang, Mark | Luders, Eileen | Looi, Jeffrey C.L. | Rajagopalan, Priya | Velakoulis, Dennis | Thompson, Paul M. | Lindberg, Olof | Östberg, Per | Nordin, Love E. | Svensson, Leif | Wahlund, Lars-Olof

Article Type: Research Article

Abstract: Morphology of the corpus callosum is a useful biomarker of neuronal loss, as different patterns of cortical atrophy help to distinguish between dementias such as Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). We used a sophisticated morphometric analysis of the corpus callosum in FTLD subtypes including frontotemporal dementia (FTD), semantic dementia (SD), and progressive non-fluent aphasia (PNFA), and compared them to AD patients and 27 matched controls. FTLD patient subgroups diverged in their callosal morphology profiles, with FTD patients showing marked widespread differences, PNFA patients with differences largely in the anterior half of the callosum, and SD patients differences …in a small segment of the genu. AD patients showed differences in predominantly posterior callosal regions. This study is consistent with our previous findings showing significant cortical and subcortical regional atrophy across FTLD subtypes, and suggests that callosal atrophy patterns differentiate AD from FTLD, and FTLD subtypes. Show more

Keywords: Alzheimer's disease, corpus callosum, frontotemporal dementia, white matter

DOI: 10.3233/JAD-131853

Citation: Journal of Alzheimer's Disease, vol. 40, no. 4, pp. 897-906, 2014

Authors: Gharbiya, Magda | Trebbastoni, Alessandro | Parisi, Francesco | Manganiello, Silvia | Cruciani, Filippo | D'Antonio, Fabrizia | De Vico, Umberto | Imbriano, Letizia | Campanelli, Alessandra | De Lena, Carlo

Article Type: Research Article

Abstract: Background: The involvement of retina and its vasculature has been recently described in Alzheimer’s disease (AD). However, none of the previous works have yet investigated the choroid in vivo. Objective: Spectral domain optical coherence tomography (SD-OCT) and enhanced depth imaging (EDI) technique is non-invasively used to assess choroidal thickness in patients with AD and to determine whether the peripapillary retinal nerve fiber layer (RNFL) and central retinal thickness are reduced compared to normal subjects. Methods: Forty-two eyes of 21 patients (mean age, 73.1 ± 6.9 years) with a diagnosis of mild to moderate AD and 42 …eyes of 21 age-matched control subjects (mean age, 70.3 ± 7.3 years) were included in this prospective, cross-sectional study. All the subjects underwent neuropsychological (MMSE, ADAS-Cog, and CDR) and ophthalmological evaluation. The SD-OCT images of the choroid were obtained by EDI modality. Choroidal thickness was assessed by manual measurement. The following parameters, measured automatically by the OCT software, were also analyzed for each eye: 1-mm central subfield (CSF) retinal thickness, peripapillary RNFL thickness. Results: Choroidal thickness was significantly thinner in AD than in control eyes (p < 0.05). No difference in CSF retinal thickness was found between groups (p > 0.05). Mean peripapillary RNFL thickness in all four quadrants was similar between groups (p > 0.05). OCT measurements were not correlated with any of the tested psychometric parameters (p > 0.05). Conclusion: Compared with healthy subjects, patients with AD showed a significant reduction in choroidal thickness. Choroidal thinning may represent an adjunctive biomarker for the diagnosis and follow-up of this disease. Show more

Keywords: Age-related macular degeneration, Alzheimer's disease, biomarker, choroid, choroidal thickness, enhanced depth imaging, optical coherence tomography, peripapillary RNFL thickness, retinal thickness, SD-OCT

DOI: 10.3233/JAD-132039

Citation: Journal of Alzheimer's Disease, vol. 40, no. 4, pp. 907-917, 2014

Authors: Balasa, Mircea | Sánchez-Valle, Raquel | Antonell, Anna | Bosch, Beatriz | Olives, Jaume | Rami, Lorena | Castellví, Magda | Molinuevo, José Luis | Lladó, Albert

Article Type: Research Article

Abstract: Early-onset cognitive impairment diagnosis is often challenging due to the overlapping symptoms between the different degenerative and non-degenerative conditions. We aimed to evaluate the usefulness of cerebrospinal fluid (CSF) biomarkers in early-onset cognitive impairment differential diagnosis, to assess their contribution to the diagnosis of Alzheimer's disease (AD) based on the new National Institute of Aging-Alzheimer's Association (NIA-AA) workgroup's recommendations and their capacity to predict subsequent decline in early-onset mild cognitive impairment (MCI). 37 controls and 120 patients (clinical onset <65 years) with diagnosis based on criteria available in 2009 (51 MCI, 42 AD, 10 frontotemporal dementia (FTD), 3 posterior cortical …atrophy, and 14 primary progressive aphasia (PPA)) were included. In addition, all subjects were also reclassified according to the revised criteria for MCI, AD, FTD, and PPA, excluding CSF data. We assessed the impact of adding the CSF data to the subject categorization according to the NIA-AA criteria. After inclusion of CSF results, 90% of amnestic and 82% of the non-amnestic AD presentation could be categorized as “high probability”, while 3% of AD patients fit into the category “dementia probably not due to AD”. All the 24 MCI patients who progressed to AD dementia and only 1/27 stable MCI presented pathological CSF at baseline. Only 4% of the FTD clinical diagnosis had pathological CSF levels. CSF biomarkers provide high diagnostic accuracy in a clinical context in differentiating AD, frontotemporal lobar degeneration, and controls in presenile subjects and can be used equally in amnestic and non-amnestic AD. Abnormal CSF-AD biomarker levels predict subsequent progression to AD dementia in subjects with early-onset MCI. Show more

Keywords: CSF biomarkers, early-onset Alzheimer's disease, NIA-AA criteria

DOI: 10.3233/JAD-132195

Citation: Journal of Alzheimer's Disease, vol. 40, no. 4, pp. 919-927, 2014

Authors: Yang, Yi | Chen, Sicong | Zhang, Jiafeng | Li, Chentan | Sun, Yonghong | Zhang, Lihui | Zheng, Xiaoxiang

Article Type: Research Article

Abstract: Autophagy is a lysosomal degradative process essential for neuronal homeostasis, whereas autophagic failure has been linked to accumulating neurodegenerative disorders. However, the precise role of autophagy in axonal and dendritic degeneration in Alzheimer's disease (AD) remains unclear. In this study, we aim to investigate the precise effect of autophagy in amyloid-β peptide (Aβ)25-35 -mediated neurite degeneration. Aβ35-25 , the non-neurotoxic reverse sequence analogue of Aβ25-35 , was used as a negative control. Our results showed that Aβ25-35 dose-dependently suppressed PC12 proliferation and induced autophagy induction in neurites (axons and dendrites). A high proportion of autophagic structures in PC12 neurites …were autolysosomes after 24 h of Aβ25-35 treatment. Autophagy inhibition by 3-methyladenine (3MA), LY294002, and chloroquine (CQ) could not relieve the Aβ25-35 -induced neurite degeneration, while administration of autophagy stimulator rapamycin or AR-12 efficiently suppressed neurite degeneration. Autophagosomes colocalized with fragmented mitochondria after Aβ25-35 treatment. Similar results were obtained using in vitro cultured superior cervical ganglion neurons. These findings demonstrate that autophagy stimulation may prevent neuritic degeneration following Aβ25-35 treatment. Upregulation of autophagic activity may provide a valuable approach for the treatment of axonal and dendritic dystrophy in AD patients. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, autophagy, neuritic degeneration

DOI: 10.3233/JAD-132270

Citation: Journal of Alzheimer's Disease, vol. 40, no. 4, pp. 929-939, 2014

Authors: Cavedo, Enrica | Redolfi, Alberto | Angeloni, Francesco | Babiloni, Claudio | Lizio, Roberta | Chiapparini, Luisa | Bruzzone, Maria G. | Aquino, Domenico | Sabatini, Umberto | Alesiani, Marcella | Cherubini, Andrea | Salvatore, Elena | Soricelli, Andrea | Vernieri, Fabrizio | Scrascia, Federica | Sinforiani, Elena | Chiarati, Patrizia | Bastianello, Stefano | Montella, Patrizia | Corbo, Daniele | Tedeschi, Gioacchino | Marino, Silvia | Baglieri, Annalisa | De Salvo, Simona | Carducci, Filippo | Quattrocchi, Carlo C. | Cobelli, Milena | Frisoni, Giovanni B. | for the Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: The North American Alzheimer’s Disease Neuroimaging Initiative (NA-ADNI) was the first program to develop standardized procedures for Alzheimer’s disease (AD) imaging biomarker collection. Objective: We describe the validation of acquisition and processing of structural magnetic resonance imaging (MRI) in different Italian academic AD clinics following NA-ADNI procedures. Methods: 373 patients with subjective memory impairment (n = 12), mild cognitive impairment (n = 92), Alzheimer’s dementia (n = 253), and frontotemporal dementia (n = 16) were enrolled in 9 Italian centers. 22 cognitively healthy elderly controls were also included. MRI site qualification and MP-RAGE quality assessment …was applied following the NA-ADNI procedures. Indices of validity were: (i) NA-ADNI phantom’s signal-to-noise and contrast-to-noise ratio, (ii) proportion of images passing quality control, (iii) comparability of automated intracranial volume (ICV) estimates across scanners, and (iv) known-group validity of manual hippocampal volumetry. Results: Results on Phantom and Volunteers scans showed that I-ADNI acquisition parameters were comparable with those one of the ranked-A ADNI scans. Eighty-seven percent of I-ADNI MPRAGE images were ranked of high quality in comparison of 69% of NA-ADNI. ICV showed homogeneous variances across scanners except for Siemens scanners at 3.0 Tesla (p = 0.039). A significant difference in hippocampal volume was found between AD and controls on 1.5 Tesla scans (p < 0.001), confirming known group validity test. Conclusion: This study has provided standardization of MRI acquisition and imaging marker collection across different Italian clinical units and equipment. This is a mandatory step to the implementation of imaging biomarkers in clinical routine for early and differential diagnosis. Show more

Keywords: Alzheimer's disease, hippocampus, intracranial volume, magnetic resonance imaging, mild cognitive impairment, standardized operating procedures

DOI: 10.3233/JAD-132666

Citation: Journal of Alzheimer's Disease, vol. 40, no. 4, pp. 941-952, 2014

Authors: Zhong, Xiaomei | Shi, Haishan | Shen, Zhiwei | Hou, Le | Luo, Xinni | Chen, Xinru | Liu, Sha | Zhang, Yuefeng | Zheng, Dong | Tan, Yan | Huang, Guimao | Fang, Yaxiu | Zhang, Hui | Mu, Nan | Chen, Jianping | Wu, Renhua | Ning, Yuping

Article Type: Research Article

Abstract: FDG-PET and SPECT studies suggest that hypometabolism and hypoperfusion in occipital lobe and posterior cingulate gyrus (PCG) are prominent features of dementia with Lewy bodies (DLB) and Alzheimer's disease (AD), respectively. Cerebral blood flow and glucose metabolism are tightly linked to brain energy metabolism. 1 H-MRS is a useful tool to directly detect energy metabolism. We aimed to use 1 H-MRS to characterize metabolite concentrations in the occipital lobe and PCG in DLB and AD patients, and estimate their usefulness in the diagnosis of DLB. Nineteen DLB, 21 AD, and 18 normal control (NC) subjects underwent 1 H-MRS with the …voxels placed in bilateral occipital lobes and left PCG. The N-acetylaspartate (NAA) and glutamate (Glu) concentrations in occipital lobe in DLB were lower than those in AD and NC. Concentrations of these two metabolites in PCG in DLB were lower than those in NC, and were the same as those in AD. These results remained robust after correcting for relative gray matter volume in the region of interest. The NAA and Glu concentrations in occipital lobe in DLB were found correlated with global cognitive function. From the ROC curves with Glu concentrations in occipital lobe, the mean areas under the curve were 0.845 for the DLB/control (with sensitivity 83.3% and specificity 84.2%) and 0.773 for the DLB/AD (with sensitivity 66.7% and specificity 84.2%). Our study suggests that 1 H-MRS investigation is valuable to detect the characteristic patterns of metabolite concentrations and is helpful in the diagnostic process and assessing dementia severity in DLB. Show more

Keywords: Dementia with Lewy bodies, Alzheimer's disease, diagnosis, differential diagnosis, hydrogen proton magnetic resonance spectroscopy, occipital lobe, posterior cingulate gyrus

DOI: 10.3233/JAD-131517

Citation: Journal of Alzheimer's Disease, vol. 40, no. 4, pp. 953-966, 2014

Authors: Ito, Kaori | Hutmacher, Matthew M. | for the Alzheimer's Disease Neuroimaging Initiative (ADNI)

Article Type: Research Article

Abstract: Background: Growing interest in treating Alzheimer’s disease (AD) patients in the earliest stages requires new clinical endpoints. Currently, there is no established clinical endpoint or treatment duration for mild cognitive impairment (MCI) trials. Objective: This analysis attempts to answer “how long the MCI clinical trial would be necessary” using the Clinical Dementia Rating Sum of Boxes (CDR-SB) as a clinical endpoint, where CDR-SB is an example of a suitable tool to assess both cognition and function as a single primary efficacy outcome. Methods: A longitudinal model was developed to predict the CDR-SB time-profile. The CDR-SB is …considered ideal to assess both cognition and function as a single primary endpoint in MCI trials. The median time for clinically “worsening”, defined using several thresholds for change from baseline, was calculated using individual CDR-SB predictions. Covariates predictive of worsening were also evaluated. Results: The median time to a 1-point change in CDR-SB was approximately 2 years in MCI patients. Higher baseline severity in disease, lower hippocampal volume, and ApoE4 carrier status were significant covariates predicting shorter times to worsening (faster progress). The results indicate that at least a 2-year trial would be necessary with 30% (or more) disease modifying drug with a sample size of n = 350 to detect the significant difference from placebo (80% power) and to achieve the target mean effect size of 0.5 point change in CDR-SB. Conclusion: Predictions of CDR-SB changes from a longitudinal model are able to inform study design and possible enrichment strategies, based on covariate analyses, for prospective planning of clinical trials in MCI patients. Show more

Keywords: ADNI, biomarkers, bounded outcome, Clinical Dementia Rating Sum of Boxes (CDR-SB), clinical trial, enrichment strategy, longitudinal data, median time to worsening, mild cognitive impairment

DOI: 10.3233/JAD-132090

Citation: Journal of Alzheimer's Disease, vol. 40, no. 4, pp. 967-979, 2014

Authors: Rodrigues, Diana I. | Gutierres, Jessié | Pliássova, Anna | Oliveira, Catarina R. | Cunha, Rodrigo A. | Agostinho, Paula

Article Type: Research Article

Abstract: Amyloid-β protein precursor (AβPP) is a large transmembrane protein highly expressed in the central nervous system and cleavage of it can produce amyloid-β peptides (Aβ) involved in synaptic dysfunction and loss associated with cognitive impairment in Alzheimer's disease (AD). Surprisingly, little is known about the synaptic and sub-synaptic distribution of AβPP in different types of nerve terminals. We used total, synaptic, sub-synaptic, and astrocytic membrane preparations obtained from the hippocampus of adult rats to define the localization of AβPP, using two different antibodies against different AβPP epitopes. Western blot analysis revealed that AβPP was not significantly enriched in synaptosomal as …compared to total membranes. Within synapses, AβPP immunoreactivity was more abundant in pre- (60 ± 4%) than post- (30 ± 5%) or extra-synaptic fractions (10 ± 2%). Immunocytochemical analysis of purified nerve terminals indicated that AβPP was more frequently associated with glutamatergic (present in 31 ± 4% of glutamatergic terminals) rather than with GABAergic (16 ± 3%) or cholinergic terminals (4 ± 1%, n = 4). We also observed a general lack of co-localization of AβPP and GFAP immunoreactivities in the hippocampus of sections of adult rat brain, albeit we could detect the presence of AβPP in gliosomes (vesicular specializations of astrocytic membranes), suggesting that AβPP has a heterogeneous localization restricted to certain regions of astrocytes. These results provide the first direct demonstration that AβPP is mostly distributed among glutamatergic rather than GABAergic or cholinergic terminals of the adult rat hippocampus, in remarkable agreement with the particular susceptibility to dysfunction and degeneration of glutamatergic synapses in early AD. Show more

Keywords: Alzheimer's disease, amyloid-β protein precursor, gliosomes, nerve terminals, sub-synaptic fractions, synaptosomes

DOI: 10.3233/JAD-132030

Citation: Journal of Alzheimer's Disease, vol. 40, no. 4, pp. 981-992, 2014

Authors: Wu, Liyong | Soder, Ricardo Bernardi | Schoemaker, Dorothée | Carbonnell, Felix | Sziklas, Viviane | Rowley, Jared | Mohades, Sara | Fonov, Vladmir | Bellec, Pierre | Dagher, Alain | Shmuel, Amir | Jia, Jianping | Gauthier, Serge | Rosa-Neto, Pedro

Article Type: Research Article

Abstract: Executive dysfunction is frequently associated with episodic memory decline in amnestic mild cognitive impairment (aMCI) patients. Resting state executive control network (RS-ECN) represents a novel approach to interrogate the integrity of brain areas underlying executive dysfunction. The present study aims to investigate RS-ECN in aMCI and examine a possible link between changes in brain functional connectivity and declines in executive function. aMCI individuals (n = 13) and healthy subjects (n = 16) underwent cognitive assessment including executive function and high field functional magnetic resonance imaging. Individual RS-ECN maps were estimated using a seed-based cross-correlation method. Between groups RS-ECN functional connectivity …comparison was assessed using voxel-wise statistic parametric mapping. aMCI individuals had reduced RS-ECN connectivity in the anterior cingulate cortex (ACC) and dorsal lateral prefrontal cortex (DLPFC), bilaterally. In contrast, aMCI showed increased connectivity in ventral lateral and anterior prefrontal cortex, bilaterally. Connectivity strength was associated with executive function in the ACC (r = 0.6213, p = 0.023) and right DLPFC (r = 0.6454, p = 0.017). Coexistence between connectivity declines and recruitment of brain regions outside the RS-ECN as reported here fits a brain reserve conceptual framework in which brain networks undergo remodeling in aMCI individuals. Show more

Keywords: Executive control network, executive function, functional MRI, mild cognitive impairment, neural plasticity

DOI: 10.3233/JAD-131574

Citation: Journal of Alzheimer's Disease, vol. 40, no. 4, pp. 993-1004, 2014

Authors: Farr, Susan A. | Erickson, Michelle A. | Niehoff, Michael L. | Banks, William A. | Morley, John E.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disease. Currently, there are no therapies to stop or reverse the symptoms of AD. We have developed an antisense oligonucleotide (OL-1) against the amyloid-β protein precursor (AβPP) that can decrease AβPP expression and amyloid-β protein (Aβ) production. This antisense rapidly crosses the blood-brain barrier, reverses learning and memory impairments, reduces oxidative stress, and restores brain-to-blood efflux of Aβ in SAMP8 mice. Here, we examined the effects of this AβPP antisense in the Tg2576 mouse model of AD. We administered the OL-1 antisense into the lateral ventricle 3 times at 2week intervals. Seventy-two hours …after the third injection, we tested learning and memory in T-maze foot shock avoidance. In the second study, we injected the mice with OL-1 antisense 3 times at 2-week intervals via the tail vein. Seventy-two hours later, we tested learning and memory T-maze, novel object recognition, and elevated plus maze. At the end of behavioral testing, brain tissue was collected. OL-1 antisense administered centrally improved acquisition and retention of T-maze foot shock avoidance. OL-1 antisense administered via tail vein improved learning and memory in both T-maze foot shock avoidance and novel object-place recognition. In the elevated plus maze, the mice which received OL-1 antisense spent less time in the open arms and had fewer entries into the open arms indicating reduced disinhibitation. Biochemical analyses reveal significant reduction of AβPP signal and a reduction of measures of neuroinflammation. The current findings support the therapeutic potential of OL-1 AβPP antisense. Show more

Keywords: Antisense oligonucleotide, Tg2576, learning, memory, T-maze, object recognition, oxidative stress, blood brain barrier, cytokines

DOI: 10.3233/JAD-131883

Citation: Journal of Alzheimer's Disease, vol. 40, no. 4, pp. 1005-1016, 2014

Authors: Tan, Lin | Yu, Jin-Tai | Tan, Meng-Shan | Liu, Qiu-Yan | Wang, Hui-Fu | Zhang, Wei | Jiang, Teng | Tan, Lan

Article Type: Research Article

Abstract: Recent findings that human serum contains stably expressed microRNAs (miRNAs) have revealed a great potential of serum miRNA signature as disease fingerprints to diagnosis. Here we used genome-wide serum miRNA expression analysis to investigate the value of serum miRNAs as biomarkers for the diagnosis of Alzheimer's disease (AD). Illumina HiSeq 2000 sequencing followed by individual quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) assays was used to test the difference in levels of serum miRNAs between 50 AD patients and 50 controls in the screening stages. The detected serum miRNAs then were validated by qRT-PCR in 158 patients and 155 controls. …MiR-98-5p, miR-885-5p, miR-483-3p, miR-342-3p, miR-191-5p, and miR-let-7d-5p displayed significantly different expression levels in AD patients compared with controls. Among the 6 miRNAs, miR-342-3p has the best sensitivity (81.5%) and specificity (70.1%) and was correlated to Mini-Mental State Examination score. This study identified six serum miRNAs that distinguish AD patients from healthy controls with high sensitivity and specificity. Serum miRNA panel (or miR-342-3p alone) may serve as a novel, noninvasive biomarker for AD. Show more

Keywords: Alzheimer's disease, biomarker, diagnosis, genome-wide sequencing, microRNA, serum

DOI: 10.3233/JAD-132144

Citation: Journal of Alzheimer's Disease, vol. 40, no. 4, pp. 1017-1027, 2014

Authors: Jacquin, Agnès | Binquet, Christine | Rouaud, Olivier | Graule-Petot, Anny | Daubail, Benoit | Osseby, Guy-Victor | Bonithon-Kopp, Claire | Giroud, Maurice | Béjot, Yannick

Article Type: Research Article

Abstract: Background: Because of the aging population and a rise in the number of stroke survivors, the prevalence of post-stroke cognitive impairment (PSCI) is increasing. Objective: To identify the factors associated with 3-month PSCI. Methods: All consecutive stroke patients without pre-stroke dementia, mild cognitive disorders, or severe aphasia hospitalized in the Neurology Department of Dijon, University Hospital, France (November 2010 – February 2012) were included in this prospective cohort study. Demographics, vascular risk factors, and stroke data were collected. A first cognitive evaluation was performed during the hospitalization using the Mini-Mental State Exam (MMSE) and the Montreal …Cognitive Assessment (MOCA). Patients assessable at 3 months were categorized as cognitively impaired if the MMSE score was ≤26/30 and MOCA <26/30 or if the neuropsychological battery confirmed PSCI when the MMSE and MOCA were discordant. Multivariable logistic models were used to determine factors associated with 3-month PSCI. Results: Among the 280 patients included, 220 were assessable at 3 months. The overall frequency of 3-month PSCI was 47.3%, whereas that of dementia was 7.7%. In multivariable analyses, 3-month PSCI was associated with age, low education level, a history of diabetes mellitus, acute confusion, silent infarcts, and functional handicap at discharge. MMSE and MOCA scores during hospitalization were associated with 3-month PSCI (OR = 0.63; 95% CI: 0.54–0.74; p < 0.0001 and OR = 0.67; 95% CI: 0.59–0.76; p < 0.0001, respectively). Conclusion: Our study underlines the high frequency of PSCI in a cohort of mild stroke. The early cognitive diagnosis of stroke patients could be useful by helping physicians to identify those at a high risk of developing PSCI. Show more

Keywords: Cognitive impairment, early cognitive assessment, prevalence, stroke

DOI: 10.3233/JAD-131580

Citation: Journal of Alzheimer's Disease, vol. 40, no. 4, pp. 1029-1038, 2014

Authors: Qiang, Min | Xiao, Rong | Su, Tao | Wu, Bei-Bei | Tong, Zhi-Qian | Liu, Ying | He, Rong-Qiao

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is the most common form of dementia, affecting millions of people worldwide. Increasing evidence suggests that formaldehyde might be one of the various pathological mechanisms involved in the process of AD onset. Here, we use an AD mouse model, senescence accelerated mouse-prone 8 strain (SAMP8), to study the relationship between endogenous formaldehyde and impairment of cognition. The Morris water maze test was used to evaluate the spatial learning and memory ability of 3-month-old SAMP8 mice, and we correlated the results with endogenous formaldehyde concentrations in the brain. To investigate the underlying reasons for formaldehyde elevation in neurodegenerative …diseases, the expression levels of enzymes involved in formaldehyde metabolism were analyzed, including (anabolic) semicarbazide sensitive amine oxidase (SSAO) and (catabolic) alcohol dehydrogenase III (ADH3). When compared with age-matched SAMR1 mice, we found that in 3-month-old SAMP8 mice the capacity for spatial learning and memory was lower, while brain formaldehyde levels were higher. By using real-time PCR, western blotting, enzyme assay, and immunohistochemistry techniques, we discovered that SSAO expression levels were increased, whereas ADH3 exhibited reduced expression levels of mRNA, protein, and enzyme activity. The imbalance of these metabolic enzymes may represent a causal explanation for the observed formaldehyde elevation in the SAMP8 brain. Such increase could be responsible for the observed tau hyperphosphorylation assumed to result in protein aggregation, ultimately leading to cognitive impairment. Taken together, our study gives new insights into the role of metabolic enzymes in age-related accumulation of formaldehyde, and thus the establishment of neurodegenerative diseases. Show more

Keywords: Alzheimer's disease, enzymes, formaldehyde, metabolism, SAMP8, SAMR1, SSAO, ADH3

DOI: 10.3233/JAD-131595

Citation: Journal of Alzheimer's Disease, vol. 40, no. 4, pp. 1039-1053, 2014

Authors: Zimmermann, Ruediger | Huber, Ellen | Schamber, Christine | Lelental, Natalia | Mroczko, Barbara | Brandner, Sebastian | Maler, Juan Manuel | Oberstein, Timo | Szmitkowski, Maciej | Rauh, Manfred | Kornhuber, Johannes | Lewczuk, Piotr

Article Type: Research Article

Abstract: Changes in the concentrations of amyloid-β (Aβ) in the body fluids are the earliest alterations observed in Alzheimer's disease (AD), however, there is a lack of data about how early these alterations occur, before the onset of the clinical symptoms. APOE genotype is the most recognized genetic risk/protective factor of AD, meaning that a group of non-demented persons carrying ε4 allele is enriched in the subjects who will develop AD, compared to the group of non-carriers. Therefore, we studied the plasma concentrations of Aβ peptides (Aβ1-42 , Aβ1-40 , Aβx-42 , and Aβx-40 ), and the APOE genotype in 173 …young volunteers (average age, 28 ± 7.6 years) without memory deficits, in order to see whether the non-demented group of subjects at risk already characterize with Aβ changes three-to-four decades before the age at which dementia usually occurs. We did not find statistically significant differences among the groups of ε4 carriers, ε3 homozygotes, and ε2 carriers. We conclude that the APOE genotype does not influence the metabolism of the Aβ peptides in young persons without memory deficits. Show more

Keywords: Amyloid-β, APOE genotype, blood biomarkers, non-demented volunteers

DOI: 10.3233/JAD-132687

Citation: Journal of Alzheimer's Disease, vol. 40, no. 4, pp. 1055-1060, 2014

Authors: George, Daniel R. | D'Alton, Simon

Article Type: Review Article

DOI: 10.3233/JAD-140707

Citation: Journal of Alzheimer's Disease, vol. 40, no. 4, pp. 1061-1062, 2014

Article Type: Correction

DOI: 10.3233/JAD-149003

Citation: Journal of Alzheimer's Disease, vol. 40, no. 4, pp. 1063-1063, 2014

Article Type: Other

DOI: 10.3233/JAD-132688

Citation: Journal of Alzheimer's Disease, vol. 40, no. 4, pp. 1065-1067, 2014

Article Type: Other

DOI: 10.3233/JAD-2014-40426

Citation: Journal of Alzheimer's Disease, vol. 40, no. 4, pp. 1069-1080, 2014