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

Authors: Fà, Mauro | Zhang, Hong | Staniszewski, Agnieszka | Saeed, Faisal | Shen, Li W. | Schiefer, Isaac T. | Siklos, Marton I. | Tapadar, Subhasish | Litosh, Vladislav A. | Libien, Jenny | Petukhov, Pavel A. | Teich, Andrew F. | Thatcher, Gregory R.J. | Arancio, Ottavio

Article Type: Research Article

Abstract: Alzheimer’s disease, one of the most important brain pathologies associated with neurodegenerative processes, is related to overactivation of calpain-mediated proteolysis. Previous data showed a compelling efficacy of calpain inhibition against abnormal synaptic plasticity and memory produced by the excess of amyloid-β, a distinctive marker of the disease. Moreover, a beneficial effect of calpain inhibitors in Alzheimer’s disease is predictable by the occurrence of calpain hyperactivation leading to impairment of memory-related pathways following abnormal calcium influxes that might ensue independently of amyloid-β elevation. However, molecules currently available as effective calpain inhibitors lack adequate selectivity. This work is aimed at characterizing the …efficacy of a novel class of epoxide-based inhibitors, synthesized to display improved selectivity and potency towards calpain 1 compared to the prototype epoxide-based generic calpain inhibitor E64. Both functional and preliminary toxicological investigations proved the efficacy, potency, and safety of the novel and selective calpain inhibitors NYC438 and NYC488 as possible therapeutics against the disease. Show more

Keywords: Alzheimer’s disease, amyloid-β, calpain, learning, long-term potentiation, memory

DOI: 10.3233/JAD-150618

Citation: Journal of Alzheimer's Disease, vol. 49, no. 3, pp. 707-721, 2016

Authors: Ahdidan, Jamila | Raji, Cyrus A. | DeYoe, Edgar A. | Mathis, Jedidiah | Noe, Karsten Ø. | Rimestad, Jens | Kjeldsen, Thomas K. | Mosegaard, Jesper | Becker, James T. | Lopez, Oscar

Article Type: Research Article

Abstract: Background: Multiple neurological disorders including Alzheimer’s disease (AD), mesial temporal sclerosis, and mild traumatic brain injury manifest with volume loss on brain MRI. Subtle volume loss is particularly seen early in AD. While prior research has demonstrated the value of this additional information from quantitative neuroimaging, very few applications have been approved for clinical use. Here we describe a US FDA cleared software program, NeuroreaderTM , for assessment of clinical hippocampal volume on brain MRI. Objective: To present the validation of hippocampal volumetrics on a clinical software program. Method: Subjects were drawn (n  = 99) from the …Alzheimer Disease Neuroimaging Initiative study. Volumetric brain MR imaging was acquired in both 1.5 T (n  = 59) and 3.0 T (n  = 40) scanners in participants with manual hippocampal segmentation. Fully automated hippocampal segmentation and measurement was done using a multiple atlas approach. The Dice Similarity Coefficient (DSC) measured the level of spatial overlap between NeuroreaderTM and gold standard manual segmentation from 0 to 1 with 0 denoting no overlap and 1 representing complete agreement. DSC comparisons between 1.5 T and 3.0 T scanners were done using standard independent samples T -tests. Results: In the bilateral hippocampus, mean DSC was 0.87 with a range of 0.78–0.91 (right hippocampus) and 0.76–0.91 (left hippocampus). Automated segmentation agreement with manual segmentation was essentially equivalent at 1.5 T (DSC = 0.879) versus 3.0 T (DSC = 0.872). Conclusion: This work provides a description and validation of a software program that can be applied in measuring hippocampal volume, a biomarker that is frequently abnormal in AD and other neurological disorders. Show more

Keywords: Hippocampus, magnetic resonance imaging, quantification

DOI: 10.3233/JAD-150559

Citation: Journal of Alzheimer's Disease, vol. 49, no. 3, pp. 723-732, 2016

Authors: Bjerke, Maria | Kern, Silke | Blennow, Kaj | Zetterberg, Henrik | Waern, Margda | Börjesson-Hanson, Anne | Östling, Svante | Kern, Jürgen | Skoog, Ingmar

Article Type: Research Article

Abstract: Background: Increased fatty acid-binding protein 3 (FABP-3) levels have been reported in neurodegenerative diseases, including Alzheimer’s disease (AD). Cerebrospinal fluid (CSF) FABP-3 has therefore been proposed as a putative marker for dementia. Population-based studies examining whether CSF FABP-3 predicts later development of dementia are lacking. Objective: The aim of this study was to examine CSF levels of FABP-3 in relation to later development of dementia in elderly women and in relation to Aβ42, T-tau, P-tau181 , and CSF: serum albumin ratio. Methods: 86 non-demented women aged 70–84 years who participated in the Prospective Population Study …of Women in Gothenburg, Sweden took part in a lumbar puncture in 1992–93. CSF-FABP-3, Aβ42, T-tau, P-tau181 , and the CSF: serum albumin ratio were measured at baseline. Participants were examined with a neuropsychiatric exam at baseline and at follow-up in 2000. Dementia was diagnosed in accordance with DSM-III-R criteria. Results: Between 1992 and 2000, 8 women developed dementia (4 AD, 3 vascular dementia, 1 mixed vascular dementia and AD). Higher levels of CSF-FABP-3 at baseline were related to development of dementia (OR 1.36 CI [1.05–1.76] p  = 0.022) and the subtype AD (OR 1.38 CI [1.06–1.82), p  = 0.019) during follow-up. FABP-3 correlated with CSF T-tau (r  = 0.88, p  <  0.001), P-tau181 (r  = 0.619, p  <  0.001), and CSF:serum albumin ratio (r  = 0.233, p  = 0.031), but not with Aβ42 (r  = –0.08, p  = 0.444) Conclusion: CSF FABP-3 may be an early marker for later development of dementia, probably related to neuronal degeneration, but independent of Aβ metabolism. Show more

Keywords: Cerebrospinal fluid, dementia, fatty acid binding protein-3, older women, population-based, prospective

DOI: 10.3233/JAD-150525

Citation: Journal of Alzheimer's Disease, vol. 49, no. 3, pp. 733-741, 2016

Authors: Chung, Jun Ku | Plitman, Eric | Nakajima, Shinichiro | Chakravarty, M. Mallar | Caravaggio, Fernando | Takeuchi, Hiroyoshi | Gerretsen, Philip | Iwata, Yusuke | Patel, Raihaan | Mulsant, Benoit H. | Graff-Guerrero, Ariel

Article Type: Research Article

Abstract: Previous studies have highlighted that decreased hippocampal volume, an early neural correlate of dementia, is commonly observed in patients with mild cognitive impairment (MCI). However, it is unclear whether neurodegenerative and resultant clinical trajectories are accelerated in MCI patients with concomitant depressive symptoms, leading to a faster conversion to dementia stages than those who are not depressed. No longitudinal study has investigated whether depressed amnestic MCI (DEP+aMCI) patients show an earlier onset of progression to dementia than non-depressed amnestic MCI (DEP-aMCI) patients and whether progressive hippocampal volume reductions are related in the conversion process. Using data from Alzheimer’s Disease Neuroimaging …Initiative, we examined 2-year follow-up data from 38 DEP+aMCI patients and 38 matched DEP-aMCI patients and compared their ages of conversion from aMCI to AD and trajectories of progressive hippocampal volume changes. DEP+ and DEP- patients were defined as having baseline Geriatric Depression Scale scores of 5 or above and 0, respectively. DEP+ converters showed earlier ages of conversion to dementia (p  = 0.009) and greater left hippocampal volume loss than both DEP- converters and DEP+ non-converters over the 2-year period (p  = 0.003, p  = 0.001, respectively). These findings could not be explained by changes in total brain volume, differences in their clinical symptoms of dementia, daily functioning, or apolipoprotein E4 genotypes. No difference in conversion rate to dementia or progressive hippocampal volume change was found between DEP+ patients and DEP-patients, which suggested depressive symptoms themselves may not lead to progression of dementia from MCI. In conclusion, there is a synergistic effect of depressive symptoms and smaller left hippocampal volume in MCI patients that accelerates conversion to dementia. Show more

Keywords: Dementia, depression, hippocampus, mild cognitive impairment

DOI: 10.3233/JAD-150679

Citation: Journal of Alzheimer's Disease, vol. 49, no. 3, pp. 743-754, 2016

Authors: Wu, Helen Zong Ying | Ong, Kwok Leung | Seeher, Katrin | Armstrong, Nicola J. | Thalamuthu, Anbupalam | Brodaty, Henry | Sachdev, Perminder | Mather, Karen

Article Type: Research Article

Abstract: Background: In recent years, microRNAs (miRNA), a class of non-coding RNA known to regulate protein expression post-transcriptionally, have been recognized as novel biomarkers of diseases. Objective: In this systematic review, we identify miRNAs that are differentially expressed in Alzheimer’s disease (AD) and/or mild cognitive impairment (MCI) and evaluate their accuracy as potential blood biomarkers. Methods: Eligible studies of miRNAs in peripheral blood distinguishing patients with AD or MCI from cognitively normal controls were identified through standardized search strategies in Medline, PubMed, and Embase. MiRNAs that were differentially expressed were identified and where available their sensitivity and …specificity for AD or MCI extracted from the retrieved studies. Results: Eighteen studies investigated the diagnostic value of miRNAs as peripheral biomarkers of AD/MCI. Twenty miRNAs were significantly upregulated and 32 miRNAs downregulated in AD compared to controls in ten AD studies. Nine miRNAs were consistently dysregulated in more than one study. Of the 8 MCI studies, only one miRNA, miR-132, was consistently upregulated in three independent studies. Of the studies that reported diagnostic accuracy data, the majority of miRNA panels and individual miRNAs had a sensitivity and specificity greater than 0.75. Conclusion: Individual studies suggest that miRNAs can differentiate patients with AD/MCI from cognitively normal controls with modest accuracy. However, the literature is constrained by methodological differences between studies, with few studies assessing the same miRNAs. To become potential biomarkers for AD, further studies with standardized study designs for replication and validation are required. Results from this review may help researchers select candidate miRNAs for further investigation. Show more

Keywords: Alzheimer’s disease, biomarkers, dementia, mild cognitive impairment, microRNAs

DOI: 10.3233/JAD-150619

Citation: Journal of Alzheimer's Disease, vol. 49, no. 3, pp. 755-766, 2016

Authors: Särkämö, Teppo | Laitinen, Sari | Numminen, Ava | Kurki, Merja | Johnson, Julene K. | Rantanen, Pekka

Article Type: Research Article

Abstract: Recent evidence suggests that music-based interventions can be beneficial in maintaining cognitive, emotional, and social functioning in persons with dementia (PWDs). Our aim was to determine how clinical, demographic, and musical background factors influence the cognitive and emotional efficacy of caregiver-implemented musical activities in PWDs. In a randomized controlled trial, 89 PWD-caregiver dyads received a 10-week music coaching intervention involving either singing or music listening or standard care. Extensive neuropsychological testing and mood and quality of life (QoL) measures were performed before and after the intervention (n  = 84) and six months later (n  = 74). The potential effects of six key …background variables (dementia etiology and severity, age, care situation, singing/instrument playing background) on the outcome of the intervention were assessed. Singing was beneficial especially in improving working memory in PWDs with mild dementia and in maintaining executive function and orientation in younger PWDs. Music listening was beneficial in supporting general cognition, working memory, and QoL especially in PWDs with moderate dementia not caused by Alzheimer’s disease (AD) who were in institutional care. Both music interventions alleviated depression especially in PWDs with mild dementia and AD. The musical background of the PWD did not influence the efficacy of the music interventions. Our findings suggest that clinical and demographic factors can influence the cognitive and emotional efficacy of caregiver-implemented musical activities and are, therefore, recommended to take into account when applying and developing the intervention to achieve the greatest benefit. Show more

Keywords: Caregivers, cognition, dementia, depression, intervention studies, music, quality of life, singing

DOI: 10.3233/JAD-150453

Citation: Journal of Alzheimer's Disease, vol. 49, no. 3, pp. 767-781, 2016

Authors: Jul, Pia | Volbracht, Christiane | de Jong, Inge E.M. | Helboe, Lone | Elvang, Anders Brandt | Pedersen, Jan Torleif

Article Type: Research Article

Abstract: Tauopathies, such as Alzheimer’s disease (AD) and frontotemporal dementia (FTD), are characterized by formation of neurofibrillary tangles consisting of hyperphosphorylated tau. In addition to memory loss, patients experience behavioral symptoms such as agitation, aggression, depression, and insomnia. We explored the behavioral phenotype of a mouse model (rTg4510) carrying the human tau P301L mutation found in a familial form of FTD. We tested these mice in locomotor activity assays as well as in the Morris water maze to access spatial memory. In addition to cognitive impairments, rTg4510 mice exhibited a hyperactivity phenotype which correlated with progression of tau pathology and was …dependent on P301L tau transgene expression. The hyperactive phenotype was characterized by significantly increased locomotor activity in a novel and in a simulated home cage environment together with a disturbed day/night cycle. The P301L-tau-dependent hyperactivity and agitative-like phenotype suggests that these mice may form a correlate to some of the behavioral disturbances observed in advanced AD and FTD. Show more

Keywords: Agitation, Alzheimer’s disease, frontotemporal dementia, hyperactivity, P301L, rTg4510

DOI: 10.3233/JAD-150292

Citation: Journal of Alzheimer's Disease, vol. 49, no. 3, pp. 783-795, 2016

Authors: Winkler, Angela | Weimar, Christian | Jöckel, Karl-Heinz | Erbel, Raimund | Dragano, Nico | Broecker-Preuss, Martina | Moebus, Susanne | Führer-Sakel, Dagmar | Dlugaj, Martha

Article Type: Research Article

Abstract: Background: Although some studies reported on the association of serum thyroid-stimulating hormone (TSH) concentration and cognition, only one population-based study investigated the association of TSH concentration and mild cognitive impairment (MCI). Objective: To investigate the gender-specific association of low- and high-normal TSH concentrations with MCI in euthyroid participants. Methods: Analysis sample 1 included 2,563 euthyroid participants (aged 50–80 years) from the second examination of the population-based Heinz Nixdorf Recall study. Gender-specific TSH quintiles (Q1 low, Q2-Q4 middle, Q5 high TSH concentration) were determined and group comparisons of age- and education-adjusted mean scores were performed for all …cognitive subtests. Analysis sample 2 included 378 participants with MCI and 931 cognitively normal participants. MCI was diagnosed according to previously published MCI criteria. Multivariate logistic regression models were performed using TSH quintiles (Q2-Q4 as reference) to assess the association of low- and high-normal TSH concentration with MCI. Models were performed unadjusted and adjusted for sociodemographic and cardiovascular risk factors. Results: Group comparisons showed significant differences only in the immediate recall of the verbal memory task in women. Only women showed a strong association of high-normal TSH concentration with MCI (unadjusted: odds ratio 2.09, 95% confidence interval 1.29–3.37, full adjusted: 1.86, 1.06–3.27). There was no association with low-normal TSH concentration in women and no association of either low- or high-normal TSH concentration with MCI in men. Conclusions: These results suggest that women with high-normal TSH concentration might be at higher risk of cognitive decline. This needs to be confirmed in the longitudinal analysis. Show more

Keywords: Aging, gender, mild cognitive impairment, population-based studies, thyroid function, thyroid-stimulating hormone

DOI: 10.3233/JAD-150561

Citation: Journal of Alzheimer's Disease, vol. 49, no. 3, pp. 797-807, 2016

Authors: Saarelainen, Laura | Taipale, Heidi | Koponen, Marjaana | Tanskanen, Antti | Tolppanen, Anna-Maija | Tiihonen, Jari | Hartikainen, Sirpa

Article Type: Research Article

Abstract: Background: Benzodiazepines and related drugs (BZDR) are occasionally used to treat certain symptoms of Alzheimer’s disease (AD). However, the risks related to BZDR use are high in older persons. Although frequent BZDR use has been reported in persons with AD, no previous study has focused specifically on the incidence of BZDR use in this population. Objective: We investigated the incidence of BZDR use in persons with and without AD during a five-year follow-up. Methods: The Finnish nationwide, register-based MEDALZ cohort includes all AD cases who received a clinically verified AD diagnosis in 2005–2011 (n  = 70,718) and …their matched comparison persons. Incidence of BZDR, including benzodiazepines (lorazepam, oxazepam, temazepam, alprazolam, chlordiazepoxide, diazepam, and nitrazepam) and Z-drugs (zolpidem and zopiclone), use was investigated in the cohort from two years before to three years after the diagnosis of AD. Further, initial BZDRs were investigated. Results: The incidence of BZDR use was higher in persons with AD starting from 12 months before the diagnosis and peaked at six months after the diagnosis of AD (incidence rate ratio [IRR] = 2.6, 95% confidence interval [CI] = 2.5–2.8). Benzodiazepines were more frequently initiated by persons with AD, with the incidence peaking at six months after the diagnosis (IRR = 4.5, 95% CI = 4.1–4.9) and remaining over three times higher than in comparison persons until three years after the diagnosis. Conclusion: Early symptomatic treatment with BZDRs is contrary to AD treatment guidelines. As BZDRs impair cognition, the observed early treatment with BZDRs may complicate the monitoring of AD treatment effectiveness. Show more

Keywords: Alzheimer’s disease, benzodiazepines, drug utilization, registries

DOI: 10.3233/JAD-150630

Citation: Journal of Alzheimer's Disease, vol. 49, no. 3, pp. 809-818, 2016

Authors: Pimouguet, Clément | Le-Goff, Mélanie | Rizzuto, Debora | Berr, Claudine | Leffondré, Karen | Pérès, Karine | Dartigues, Jean FranÇois | Helmer, Catherine

Article Type: Research Article

Abstract: Background: Although early diagnosis has been hypothesized to benefit both patients and caregivers, until now studies evaluating the effect of early dementia diagnosis are lacking. Objective: To investigate the influence of early specialist referral for dementia on the risk of institutionalization and functional decline in Activity of Daily Living (ADL). Methods: Incident dementia cases were screened in a prospective population-based cohort, the Three-City Study, and initial specialist consultation for cognitive complaint was assessed at dementia diagnosis. Proportional hazard regression and illness-death models were used to test the association between specialist referral and, respectively, institutionalization and functional …decline. Results: Only one third of the incident individuals with dementia had consulted a specialist for cognitive problems early (36%). After adjustment on potential confounders (including cognitive and functional decline) and competing risk of death, participants who had consulted a specialist early in the disease course presented a higher rate of being institutionalized than those who did not (Hazard Ratio = 2.00, 95% Confidence Interval (CI): 1.09– 3.64). But early specialist referral was not associated with further functional decline (HR = 1.09, 95% CI: 0.71– 1.67). Conclusions: Early specialist referral in dementia is associated with increased risk of institutionalization but not with functional decline in ADL. These findings suggest that early care referral in dementia may be a marker of concern for patients and/or caregivers; subsequent medical and social care could be suboptimal or inappropriate to allow patients to stay longer at home. Show more

Keywords: Dementia, dependency, institutionalization, population-based study, secondary care

DOI: 10.3233/JAD-150574

Citation: Journal of Alzheimer's Disease, vol. 49, no. 3, pp. 819-828, 2016