Journal of Alzheimer's Disease - Volume 49, issue 3

Authors: Raizes, Meytal | Elkana, Odelia | Franko, Motty | Ravona Springer, Ramit | Segev, Shlomo | Beeri, Michal Schnaider

Article Type: Short Communication

Abstract: We explored the association of plasma glucose levels within the normal range with processing speed in high functioning young elderly, free of type 2 diabetes mellitus (T2DM). A sample of 41 participants (mean age = 64.7, SD = 10; glucose 94.5 mg/dL, SD = 9.3), were examined with a computerized cognitive battery. Hierarchical linear regression analysis showed that higher plasma glucose levels, albeit within the normal range (<110 mg/dL), were associated with longer reaction times (p  <  0.01). These findings suggest that even in the subclinical range and in the absence of T2DM, monitoring plasma glucose levels may have an impact on cognitive function.

Keywords: Plasma glucose level, cognitive function, processing speed, type 2 diabetes

DOI: 10.3233/JAD-150433

Citation: Journal of Alzheimer's Disease, vol. 49, no. 3, pp. 589-592, 2016

Authors: Johnen, Andreas | Frommeyer, Jana | Modes, Fenja | Wiendl, Heinz | Duning, Thomas | Lohmann, Hubertus

Article Type: Research Article

Abstract: Background: Standardized praxis assessments with modern, empirically validated screening tests have substantially improved clinical evaluation of apraxia in patients with stroke. Although apraxia may contribute to early differential diagnosis of Alzheimer’s dementia (AD) and behavioral variant frontotemporal dementia (bvFTD), no comparable test is readily available to clinicians for this purpose to date. Objective: To design a clinically useful apraxia test for the differentiation of AD and bvFTD. Methods: 84 test items pertaining to twelve praxis subdomains were evaluated for their efficacy to discriminate between patients with bvFTD (n  = 24), AD (n  = 28), and elderly healthy controls …(HC; n  = 35). Items were then selected based on discriminative value and psychometric properties. Results: Items indicative of mild AD comprised spatially complex imitation of hand and finger postures and to a lesser degree, pantomime of common object-use. Buccofacial apraxia including imitation of face postures, emblematic face postures, and repetition of multisyllabic pseudowords differentiated bvFTD from HC and AD. The final test version consisting of 20 items proved highly efficient for the discrimination of biologically confirmed dementia patients from HC (sensitivity 91% , specificity 71%) but also for differential diagnosis of bvFTD and AD (sensitivity 74% , specificity 93%). Conclusions: Assessment of praxis profiles effectively contributes to diagnosis and differential diagnosis of AD and bvFTD. The Dementia Apraxia Test (DATE) is a brief and easy to administer cognitive tool for dementia assessment, has a high inter-rater reliability (Cohen’s κ = 0.885) and demonstrates content validity. Show more

Keywords: Apraxia, Alzheimer’s dementia, differential diagnosis, frontotemporal dementia, neuropsychological tests

DOI: 10.3233/JAD-150447

Citation: Journal of Alzheimer's Disease, vol. 49, no. 3, pp. 593-605, 2016

Authors: Elkana, Odelia | Eisikovits, Osnat Reichman | Oren, Noga | Betzale, Vered | Giladi, Nir | Ash, Elissa L.

Article Type: Research Article

Abstract: Highly educated individuals have a lower risk of developing dementia and Alzheimer’s disease (AD). A common assumption is that their “cognitive reserve” protects them from cognitive decline and postpones the clinical manifestation of dementia. These highly educated individuals usually obtain normal scores on cognitive screening tests, although at the same time they can experience subjective cognitive decline and difficulty in multiple cognitive domains. Although comprehensive neuropsychological evaluations usually identify subtle changes in cognition, they demand extensive resources and thus are expensive and difficult to obtain. Therefore, lack of sensitivity of screening tests on the one hand, along with difficulty to …acquire a comprehensive neuropsychological evaluation on the other hand, impede identification of cognitive decline at its earliest stages in this special population. Accordingly, this study aims to identify which neuropsychological tests have the highest sensitivity to detect the earliest stages of cognitive decline among highly educated elderly [n  = 27, ages 66–80 (mean = 72.6 SD = 4.54), mean education level = 17.14 (SD = 3.21 range: 12–24 years)]. Baseline scores and scores at one-year follow up were obtained. We also conducted MRI scans to characterize the relation between brain volume and cognitive performance. Results show significant reductions in RVALT, Semantic verbal Fluency, ROCF copy, and MoCA scores whereas PF, TMT, ROCF delay, digit span, and knowledge tests were not significant. The study stresses the importance of using sensitive neuropsychological tests to examine this special population and the need to create norms that combine an individual’s education with age. Show more

Keywords: Cognitive decline, cognitive reserve, elderly, high education, magnetic resonance imaging, mild cognitive impairment, neuropsychological testing

DOI: 10.3233/JAD-150562

Citation: Journal of Alzheimer's Disease, vol. 49, no. 3, pp. 607-616, 2016

Authors: Dubois, Bruno | Padovani, Alessandro | Scheltens, Philip | Rossi, Andrea | Dell’Agnello, Grazia

Article Type: Research Article

Abstract: Background: Timely diagnosis of Alzheimer’s disease (AD) refers to a diagnosis at the stage when patients come to the attention of clinicians because of concerns about changes in cognition, behavior, or functioning and can be still free of dementia and functionally independent. Objectives: To comprehensively review existing scientific evidence on the benefits and potential challenges of making a timely diagnosis of AD. Methods: Relevant studies were identified by searching electronic databases (Medline, Embase) and bibliographies for studies published in English between 1 January 2000 and 2 June 2014 on the consequences of a timely diagnosis of …AD. Results: Nine studies were identified that investigated the consequences of diagnosing AD at the initial stages; none were specifically focused on prodromal AD. A timely diagnosis potentially offers the opportunities of early intervention, implementation of coordinated care plans, better management of symptoms, patient safety, cost savings, and postponement of institutionalization. Barriers to making a timely diagnosis include stigma, suicide risk, lack of training, diagnostic uncertainty, shortage of specialized diagnostic services, and the reluctance of healthcare providers to make a diagnosis when no effective disease-modifying options are available. Conclusions: Despite its potential benefits, few published studies have explored the advantages or risks of a timely diagnosis of AD. In light of the cultural shift toward diagnosis at the initial stage of the disease continuum, when the patient does not yet have dementia, more investigations are needed to evaluate the benefits and address the barriers that may impede making a timely AD diagnosis. Show more

Keywords: Alzheimer’s disease, diagnosis, pre-dementia, review, timely

DOI: 10.3233/JAD-150692

Citation: Journal of Alzheimer's Disease, vol. 49, no. 3, pp. 617-631, 2016

Authors: Madhavan, Ajay | Schwarz, Christopher G. | Duffy, Joseph R. | Strand, Edythe A. | Machulda, Mary M. | Drubach, Daniel A. | Kantarci, Kejal | Przybelski, Scott A. | Reid, Robert I. | Senjem, Matthew L. | Gunter, Jeffrey L. | Apostolova, Liana G. | Lowe, Val J. | Petersen, Ronald C. | Jack Jr., Clifford R. | Josephs, Keith A. | Whitwell, Jennifer L.

Article Type: Research Article

Abstract: Background: Different clinical syndromes can arise from Alzheimer’s disease (AD) neuropathology, including dementia of the Alzheimer’s type (DAT), logopenic primary progressive aphasia (lvPPA), and posterior cortical atrophy (PCA). Objective: To assess similarities and differences in patterns of white matter tract degeneration across these syndromic variants of AD. Methods: Sixty-four subjects (22 DAT, 24 lvPPA, and 18 PCA) that had diffusion tensor imaging and showed amyloid-β deposition on PET were assessed in this case-control study. A whole-brain voxel-based analysis was performed to assess differences in fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity across groups. …Results: All three groups showed overlapping diffusion abnormalities in a network of tracts, including fornix, corpus callosum, posterior thalamic radiations, superior longitudinal fasciculus, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, and uncinate fasciculus. Subtle regional differences were also observed across groups, with DAT particularly associated with degeneration of fornix and cingulum, lvPPA with left inferior fronto-occipital fasciculus and uncinate fasciculus, and PCA with posterior thalamic radiations, superior longitudinal fasciculus, posterior cingulate, and splenium of the corpus callosum. Conclusion: These findings show that while each AD phenotype is associated with degeneration of a specific structural network of white matter tracts, striking spatial overlap exists among the three network patterns that may be related to AD pathology. Show more

Keywords: Alzheimer’s disease, diffusion tensor imaging, logopenic, posterior cortical atrophy, white matter

DOI: 10.3233/JAD-150502

Citation: Journal of Alzheimer's Disease, vol. 49, no. 3, pp. 633-643, 2016

Authors: Pinnock, Emma C. | Jovanovic, Katarina | Pinto, Maxine G. | Ferreira, Eloise | Dias, Bianca Da Costa | Penny, Clement | Knackmuss, Stefan | Reusch, Uwe | Little, Melvyn | Schatzl, Hermann M. | Weiss, Stefan F.T.

Article Type: Research Article

Abstract: The neuronal perturbations in Alzheimer’s disease are attributed to the formation of extracellular amyloid-β (Aβ) neuritic plaques, composed predominantly of the neurotoxic Aβ42 isoform. Although the plaques have demonstrated a role in synaptic dysfunction, neuronal cytotoxicity has been attributed to soluble Aβ42 oligomers. The 37kDa/67kDa laminin receptor has been implicated in Aβ42 shedding and Aβ42 -induced neuronal cytotoxicity, as well as internalization of this neurotoxic peptide. As the cellular prion protein binds to both LRP/LR and Aβ42 , the mechanism underlying this cytotoxicity may be indirectly due to the PrPc -Aβ42 interaction with LRP/LR. The effects …of this interaction were investigated by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assays. PrPc overexpression significantly enhanced Aβ42 cytotoxicity in vitro , while PrP–/–  cells were more resistant to the cytotoxic effects of Aβ42 and exhibited significantly less cell death than PrPc expressing N2a cells. Although anti-LRP/LR specific antibody IgG1-iS18 significantly enhanced cell viability in both pSFV1-huPrP1-253 transfected and non-transfected cells treated with exogenous Aβ42, it failed to have any cell rescuing effect in PrP–/–  HpL3-4 cells. These results suggest that LRP/LR plays a significant role in Aβ42 -PrPc mediated cytotoxicity and that anti-LRP/LR specific antibodies may serve as potential therapeutic tools for Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, amyloid-β (Aβ), Cellular prion protein (PrPc), 37kDa/67kDa laminin receptor (LRP/LR)

DOI: 10.3233/JAD-150482

Citation: Journal of Alzheimer's Disease, vol. 49, no. 3, pp. 645-657, 2016

Authors: Voyle, Nicola | Keohane, Aoife | Newhouse, Stephen | Lunnon, Katie | Johnston, Caroline | Soininen, Hilkka | Kloszewska, Iwona | Mecocci, Patrizia | Tsolaki, Magda | Vellas, Bruno | Lovestone, Simon | Hodges, Angela | Kiddle, Steven | Dobson, Richard JB.

Article Type: Research Article

Abstract: Background: Recent studies indicate that gene expression levels in blood may be able to differentiate subjects with Alzheimer’s disease (AD) from normal elderly controls and mild cognitively impaired (MCI) subjects. However, there is limited replicability at the single marker level. A pathway-based interpretation of gene expression may prove more robust. Objectives: This study aimed to investigate whether a case/control classification model built on pathway level data was more robust than a gene level model and may consequently perform better in test data. The study used two batches of gene expression data from the AddNeuroMed (ANM) and Dementia Case …Registry (DCR) cohorts. Methods: Our study used Illumina Human HT-12 Expression BeadChips to collect gene expression from blood samples. Random forest modeling with recursive feature elimination was used to predict case/control status. Age and APOE ɛ 4 status were used as covariates for all analysis. Results: Gene and pathway level models performed similarly to each other and to a model based on demographic information only. Conclusions: Any potential increase in concordance from the novel pathway level approach used here has not lead to a greater predictive ability in these datasets. However, we have only tested one method for creating pathway level scores. Further, we have been able to benchmark pathways against genes in datasets that had been extensively harmonized. Further work should focus on the use of alternative methods for creating pathway level scores, in particular those that incorporate pathway topology, and the use of an endophenotype based approach. Show more

Keywords: Alzheimer’s disease, blood, gene expression, pathways

DOI: 10.3233/JAD-150440

Citation: Journal of Alzheimer's Disease, vol. 49, no. 3, pp. 659-669, 2016

Authors: Jacquin-Piques, Agnès | Sacco, Guillaume | Tavassoli, Neda | Rouaud, Olivier | Bejot, Yannick | Giroud, Maurice | Robert, Philippe | Vellas, Bruno | Bonin-Guillaume, Sylvie

Article Type: Research Article

Abstract: Background: Psychotropic drugs are frequently prescribed in nursing homes (NH). Nonetheless, we hoped that institutionalization decreases the number of psychotropic drug classes prescribed, because NH residents may have more psychosocial interventions than patients living at home. Objective: The aim was to compare the type and number of psychotropic drugs prescribed in elderly NH residents with dementia with those in community-living patients. Methods: This cross-sectional study included elderly patients (at least 75 years old) with dementia recorded in the National Alzheimer’s data Bank (“Banque Nationale Alzheimer”) during the year 2012 and who were taking at least one …psychotropic drug. Psychotropic drugs were classified as follows: antidepressant, anxiolytic, hypnotic, and antipsychotic drugs. Patients were classified into three categories of dementia severity according to the MMSE score. Results: Among the 50,932 patients with dementia recorded in the BNA, 40.1% had at least one psychotropic drug prescribed. Most of the patients who were treated by at least one psychotropic drug class had antidepressant therapy (69.0%), whatever their residence type, and 16.1% were treated with antipsychotics. Among the study population, 51.9% of the NH residents and 67.4% of the patients living at home had only one psychotropic drug class prescribed. Living in a NH was significantly associated with the more frequent prescription of anxiolytic, hypnotic, and antipsychotic drugs, and with a greater number of psychotropic drug classes prescribed, whatever the severity of the dementia. Conclusion: We underlined the more frequent prescription of psychotropic drugs in NH residents regardless of MMSE scores. Show more

Keywords: Dementia, National Alzheimer’s data Bank, nursing home, psychotropic drug

DOI: 10.3233/JAD-150280

Citation: Journal of Alzheimer's Disease, vol. 49, no. 3, pp. 671-680, 2016

Authors: Banerjee, Priyanjalee | Sahoo, Arghyadip | Anand, Shruti | Bir, Aritri | Chakrabarti, Sasanka

Article Type: Research Article

Abstract: The altered metabolism of iron impacts the brain function in multiple deleterious ways during normal aging as well as in Alzheimer’s disease. We have shown in this study that chelatable iron accumulates in the aged rat brain along with overexpression of transferrin receptor 1 (TfR1) and ferritin, accompanied by significant alterations in amyloid-β (Aβ) peptide homeostasis in the aging brain, such as an increased production of the amyloid-β protein precursor, a decreased level of neprilysin, and increased accumulation of Aβ42 . When aged rats are given daily the iron chelator, deferasirox, over a period of more than 4 months starting …from the 18th month, the age-related accumulation of iron and overexpression of TfR1 and ferritin in the brain are significantly prevented. More interestingly, the chelator treatment also considerably reverses the altered Aβ peptide metabolism in the aging brain implying a significant role of iron in the latter phenomenon. Further, other results indicate that iron accumulation results in oxidative stress and the activation of NF-κB in the aged rat brain, which are also reversed by the deferasirox treatment. The analysis of the results together suggests that iron accumulation and oxidative stress interact at multiple levels that include transcriptional and post-transcriptional mechanisms to bring about changes in the expression levels of TfR1 and ferritin and also alterations in Aβ peptide metabolism in the aging rat brain. The efficacy of deferasirox in preventing age-related changes in iron and Aβ peptide metabolism in the aging brain, as shown here, has obvious therapeutic implications for Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, amyloid-β 42, brain aging, ferritin, iron, oxidative stress, transferrin receptor

DOI: 10.3233/JAD-150514

Citation: Journal of Alzheimer's Disease, vol. 49, no. 3, pp. 681-693, 2016

Authors: Bergeron, David | Beauregard, Jean-Mathieu | Guimond, Jean | Fortin, Marie-Pierre | Houde, Michèle | Poulin, Stéphane | Verret, Louis | Bouchard, Rémi W. | Laforce Jr, Robert

Article Type: Research Article

Abstract: Diagnosis of atypical/unclear dementia is often difficult and this delays treatment initiation. Several authors have shown that beyond standard dementia workup, 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) reduces the number of unclear diagnoses, leads to earlier treatment, and has a beneficial impact on families. However, it is not uncommon that the FDG-PET findings are equivocal in this setting. For those cases, a repeat FDG-PET may clarify the diagnosis and prevent treatment delay. We retrospectively assessed the clinical impact of a repeat FDG-PET in 59 patients with atypical/unclear dementia syndromes and inconclusive initial FDG-PET. Changes in primary diagnosis, diagnostic confidence, and …management following the second FDG-PET were examined. Conducting a second FDG-PET reduced the number of unclear diagnoses from 80% to 34% , led to diagnostic change in 24% of cases, and treatment modification in 22% of patients. Overall, the clinical impact was higher when initial diagnostic confidence was low and the second FDG-PET repeated ≥12 months after the first one. In tertiary care memory clinic settings, when diagnostic incertitude persists despite extensive evaluation and an equivocal FDG-PET, repeating the FDG-PET 12 months later can greatly clarify the diagnosis and improve management. Show more

Keywords: Atypical dementia, brain imaging, differential diagnosis, FDG-PET

DOI: 10.3233/JAD-150302

Citation: Journal of Alzheimer's Disease, vol. 49, no. 3, pp. 695-705, 2016