Journal of Alzheimer's Disease - Volume 56, issue 4

Authors: N’Songo, Aurelie | Carrasquillo, Minerva M. | Wang, Xue | Nguyen, Thuy | Asmann, Yan | Younkin, Steven G. | Allen, Mariet | Duara, Ranjan | Custo, Maria T. Greig | Graff-Radford, Neill | Ertekin-Taner, Nilüfer

Article Type: Short Communication

Abstract: We conducted a comprehensive screening of rare coding variants in an African American cohort to identify novel pathogenic mutations within the early-onset Alzheimer’s disease (EOAD) genes (APP, PSEN1 , and PSEN2) in this understudied population. Whole-exome sequencing of 238 African American subjects identified 6 rare missense variants within the EOAD genes, which were observed in AD cases but never among controls. These variants were analyzed in an independent cohort of 300 African American subjects in which PSEN2 :NM_000447:exon5:c.T331C:p.Phe111Leu and PSEN1-minilin rs777923890 variants were again not observed, indicating that these novel rare variants, may contribute to AD risk in …this population. Show more

Keywords: African Americans, Alzheimer’s disease, early onset, genetics, presenilins, whole exome sequencing

DOI: 10.3233/JAD-161185

Citation: Journal of Alzheimer's Disease, vol. 56, no. 4, pp. 1215-1222, 2017

Authors: Valenti, Raffaella | Charidimou, Andreas | Xiong, Li | Boulouis, Gregoire | Fotiadis, Panagiotis | Ayres, Alison | Riley, Grace | Kuijf, Hugo J. | Reijmer, Yael D. | Pantoni, Leonardo | Gurol, M. Edip | Davidsdottir, Sigurros | Greenberg, Steven M. | Viswanathan, Anand

Article Type: Short Communication

Abstract: Cerebral amyloid angiopathy (CAA) is a contributor to cognitive impairment in the elderly. We hypothesized that the posterior cortical predilection of CAA would cause visual-processing impairment. We systematically evaluated visuospatial abilities in 22 non-demented CAA patients. Neurocognitive evaluation demonstrated visuoperceptual impairment (23% on Benton Facial Recognition Test [BFRT] and 13.6% on Benton Judgment of Line Orientation Test [BJLO]). BFRT was inversely correlated with white matter hyperintensities volume and BJLO with parietal cerebral microbleeds. This pilot study highlights the presence of visual-processing deficits in CAA. The impairment could be related to global disease severity in addition to local brain injury.

Keywords: Cerebral amyloid angiopathy, neuroimaging markers, neuropsychological assessment, visuospatial functioning

DOI: 10.3233/JAD-160927

Citation: Journal of Alzheimer's Disease, vol. 56, no. 4, pp. 1223-1227, 2017

Authors: Matsunaga, Shinji | Kishi, Taro | Iwata, Nakao

Article Type: Research Article

Abstract: Background: There is uncertainty about the efficacy and tolerability of zonisamide for Parkinson’s disease (PD). Objective: We performed a meta-analysis of zonisamide treatment in PD patients who received antiparkinson drugs such as levodopa. Methods: The primary outcome measures were the Unified Parkinson’s Disease Rating Scale (UPDRS) Part III scores, wearing-off time, and discontinuation rate due to all causes. Secondary outcome measures were UPDRS total and subscale scores; discontinuation rates due to adverse events, inefficacy, and death; and individual adverse events. Results: Four randomized placebo-controlled trials including 1,068 PD patients were analyzed. All studies …were conducted in Japan. UPDRS Part III scores were significantly lower with zonisamide than with placebo (weighted mean difference [WMD], –2.56; 95% confidence interval [CI]; –4.20 to –0.92; p  = 0.002). Further, zonisamide significantly decreased the wearing-off time compared with placebo (standardized mean difference, –0.24; 95% CI, –0.39 to –0.09; p  = 0.001). Discontinuation rates due to all causes were similar between the zonisamide and placebo groups (risk ratio, 1.29; 95% CI, 0.90 to 1.84; p  = 0.16). While zonisamide also decreased both UPDRS Part II (off-time) and UPDRS total scores compared to placebo (UPDRS Part II [off-time] scores: WMD, –0.79; UPDRS total scores: WMD, –2.51), there were no significant differences in other secondary outcomes between the two groups. Conclusions: Our results suggested that zonisamide combination therapy was beneficial in treating motor symptoms in PD patients receiving antiparkinson drugs and was well tolerated in Japanese patients. Future studies in populations other than the Japanese are needed. Show more

Keywords: Meta-analysis, Parkinson’s disease, randomized placebo-controlled trial, systematic review, zonisamide

DOI: 10.3233/JAD-161068

Citation: Journal of Alzheimer's Disease, vol. 56, no. 4, pp. 1229-1239, 2017

Authors: Suhonen, Noora-Maria | Hallikainen, Ilona | Hänninen, Tuomo | Jokelainen, Jari | Krüger, Johanna | Hall, Anette | Pikkarainen, Maria | Soininen, Hilkka | Remes, Anne M.

Article Type: Research Article

Abstract: While behavioral symptoms are both early and prevalent features of behavioral variant frontotemporal dementia (bvFTD), they can be present in other types of dementia as well, including Alzheimer’s disease (AD) and even mild cognitive impairment (MCI). The Frontal Behavioral Inventory (FBI) was specifically developed to capture the behavioral and personality changes in bvFTD; it has also been modified into a self-administered caregiver questionnaire (FBI-mod). We examined the utility of the FBI-mod in differentiating bvFTD (n  = 26), primary progressive aphasia (PPA) (n  = 7), AD (n  = 53), and MCI (n  = 50) patients, and investigated how the FBI-mod may be associated with neuropsychological …measures. The bvFTD patients scored significantly higher as compared to all other patient groups on the FBI-mod Total (p  < 0.005), Negative (p  < 0.005), and Positive (p  < 0.01) scores. The cut-off point for the FBI-mod Total score that best discriminated the bvFTD and AD patients in our sample was 16, thus substantially lower than reported for the original FBI. For the bvFTD group, only mild correlations emerged between the FBI-mod and the cognitive measures. However, significant correlations between the FBI-mod and depressive symptoms as measured by the BDI-II were found for bvFTD. This suggests that while behavioral symptoms appear independent from cognitive deficits in bvFTD, they may nevertheless be interrelated with depressive symptoms. We conclude that the FBI-mod is an easily administered behavioral scale that can aid in differential diagnosis of bvFTD and should be used in clinical practice. The FBI-mod may further be considered as an outcome measure in clinical trials. Show more

Keywords: Behavioral rating scale, behavioral symptoms, dementia, depressive symptoms, frontotemporal dementia, neuropsychological tests

DOI: 10.3233/JAD-160983

Citation: Journal of Alzheimer's Disease, vol. 56, no. 4, pp. 1241-1251, 2017

Authors: Kuriyama, Nagato | Ihara, Masafumi | Mizuno, Toshiki | Ozaki, Etsuko | Matsui, Daisuke | Watanabe, Isao | Koyama, Teruhide | Kondo, Masaki | Tokuda, Takahiko | Tamura, Aiko | Yamada, Kei | Akazawa, Kentaro | Takeda, Kazuo | Takada, Akihiro | Mizuno, Shigeto | Nakagawa, Masanori | Watanabe, Yoshiyuki

Article Type: Research Article

Abstract: Background: Adrenomedullin (ADM) is a vasoreactive physiological peptide with anti-inflammatory effects and vasodilative and immunomodulatory actions that is widely distributed throughout the vascular system of the brain. Objective: To investigate mid-regional proADM (MR-proADM), a stable fragment of the ADM precursor, and cerebral deep white matter lesions (DWMLs) in association with cognitive decline. Methods: The study participants were 288 patients (194 men, 94 women) who gave consent to participate in a 5-year longitudinal survey on arteriosclerosis from 2008 to 2013. The Fazekas classification system (Grade [G] 0 [normal] to G3 [severe]) was used for the evaluation …of DWMLs on brain magnetic resonance imaging (MRI). In addition, all participants were asked to undergo cognitive function tests regarding word/letter fluency, the results of which were assessed for correlations with MR-proADM levels. Results: MR-proADM levels significantly increased with DWML grade progression. The odds ratio for high MR-proADM levels was 3.08 (95% confidence interval: 1.49–5.17) in the groups graded G3 on brain MRI, suggesting that a high level of MR-proADM is an independent risk factor for DWMLs. A significant inverse correlation was observed between MR-proADM levels and cognitive test scores. MR-proADM levels were significantly increased in the G3 group in 2013 compared with 2008. Conclusion: MR-proADM levels were significantly different between the DWML groups and inversely correlated with cognitive function test scores, suggesting that high MR-proADM levels and DWMLs are associated with cognitive decline. Therefore, the MR-proADM level may be an effective candidate as a potential diagnostic surrogate marker of cognitive decline. Show more

Keywords: Deep white matter lesion, dementia, magnetic resonance imaging, mid-regional proadrenomedullin

DOI: 10.3233/JAD-160901

Citation: Journal of Alzheimer's Disease, vol. 56, no. 4, pp. 1253-1262, 2017

Authors: Hu, Chen | Xu, Junjie | Zeng, Linlin | Li, Ting | Cui, Mei-Zhen | Xu, Xuemin

Article Type: Research Article

Abstract: Presenilin-1 (PS1) or presenilin-2 (PS2), nicastrin (NCT), anterior pharynx-defective 1 (Aph-1), and presenilin enhancer-2 (Pen-2) have been considered the minimal essential subunits required to form an active γ -secretase complex. Besides PS, which has been widely believed to function as the catalytic subunit of the complex, the functional roles of the other subunits in the γ -secretase complex remain debatable. In the current study, we set out to determine the role of Pen-2 in γ -secretase activity. To this end, using knockout cells in combination with siRNA and immunoprecipitation approaches, our results revealed that Pen-2 together with presenilin are sufficient …to form a functionally active enzyme to process Notch. Specifically, our data demonstrated that Pen-2 plays a crucial role in substrate binding, a mechanism by which Pen-2 contributes directly to the catalytic mechanism of γ -secretase activity. Our data also suggested that there may be different requirements for components to process AβPP and Notch. This information would be important for therapeutic strategy aimed at inhibition or modulation of γ -secretase activity. Show more

Keywords: AβPP, Alzheimer’s disease, Aph-1, γ-secretase, nicastrin, Notch, Pen-2, presenilin

DOI: 10.3233/JAD-161094

Citation: Journal of Alzheimer's Disease, vol. 56, no. 4, pp. 1263-1269, 2017

Authors: Ferrari, Raffaele | Grassi, Mario | Graziano, Francesca | Palluzzi, Fernando | Archetti, Silvana | Bonomi, Elisa | Bruni, Amalia C. | Maletta, Raffaele G. | Bernardi, Livia | Cupidi, Chiara | Colao, Rosanna | Rainero, Innocenzo | Rubino, Elisa | Pinessi, Lorenzo | Galimberti, Daniela | Scarpini, Elio | Serpente, Maria | Nacmias, Benedetta | Piaceri, Irene | Bagnoli, Silvia | Rossi, Giacomina | Giaccone, Giorgio | Tagliavini, Fabrizio | Benussi, Luisa | Binetti, Giuliano | Ghidoni, Roberta | Singleton, Andrew | Hardy, John | Momeni, Parastoo | Padovani, Alessandro | Borroni, Barbara

Article Type: Research Article

Abstract: In frontotemporal dementia (FTD), age at disease onset (AAO) is unpredictable in both early and late-onset cases; AAO variability is found even in autosomal dominant FTD. The present study was aimed at identifying genetic modifiers modulating AAO in a large cohort of Italian FTD patients. We conducted an association analysis on 411 FTD patients, belonging to 7 Italian Centers, and for whom AAO was available. Population structure was evaluated by principal component analysis to infer continuous axes of genetic variation, and single linear regression models were applied. A genetic score (GS) was calculated on the basis of suggestive single nucleotide …polymorphisms (SNPs) found by association analyses. GS showed genome-wide significant slope decrease by –3.86 (95% CI: –4.64 to –3.07, p  < 2×10–16 ) per standard deviation of the GS for 6 SNPs mapping to genes involved in neuronal development and signaling, axonal myelinization, and glutamatergic/GABA neurotransmission. An increase of the GS was associated with a decrease of the AAO. Our data indicate that there is indeed a genetic component that underpins and modulates up to 14.5% of variability of AAO in Italian FTD. Future studies on genetic modifiers in FTD are warranted. Show more

Keywords: Age at onset, frontotemporal dementia, GWAS, polymorphism

DOI: 10.3233/JAD-160949

Citation: Journal of Alzheimer's Disease, vol. 56, no. 4, pp. 1271-1278, 2017

Authors: Buccarello, Lucia | Grignaschi, Giuliano | Castaldo, Anna Maria | Di Giancamillo, Alessia | Domeneghini, Cinzia | Melcangi, Roberto Cosimo | Borsello, Tiziana

Article Type: Research Article

Abstract: P301L transgenic (tg) mice well mimic features of human tauopathies and provide a good model for investigating the role of tau in neurodegenerative events. We here analyzed the possible interactions among phosphorylation of tau (p-tau), spine injury, neuronal death, and sex in the P301L mouse model of tauopathy. When compared to control mice (ctr), P301L transgenic mice (tg) presented a lower body weight, reduced survival rate, hyperphosphorylated tau, spine injury, and neuronal loss in both cerebral cortex and hippocampus at 15 months of age. Importantly, we found that pathological features were more pronounced in female than male tg mice. Recent …reports underline that tau may be localized within both pre- and post-synaptic compartments, suggesting that it may possibly induce or contribute to synaptic dysfunction. Therefore, we focused our attention on tau localization at dendritic spines. We detected high levels of both tau and p-tau in dendritic spine of P301L transgenic mice. In addition, p-tau correlated with a significant reduction of post-synaptic markers, such as GluN2A, GluN2B, GluA1, GluA2, Drebrin, and PSD-95, in P301L mice. The p-tau levels are higher in female than in male mice, and the increased p-tau was consistent with a proportional decrease in the post-synaptic marker levels analyzed. The P301L-tg females showed a more severe synaptopathy compared to males. Future investigations on the postsynaptic role of p-tau will be necessary to understand its toxic effects and provide insights into new therapeutic targets for maintaining spine integrity, highlighting the importance of tau toxicity as well as the impact of sex on tau-pathology. Show more

Keywords: Hyperphosphorylated tau, post-synaptic markers, sex, synaptopathy, tauopathy

DOI: 10.3233/JAD-161087

Citation: Journal of Alzheimer's Disease, vol. 56, no. 4, pp. 1279-1292, 2017

Authors: Molad, Jeremy | Kliper, Efrat | Korczyn, Amos D. | Ben Assayag, Einor | Ben Bashat, Dafna | Shenhar-Tsarfaty, Shani | Aizenstein, Orna | Shopin, Ludmila | Bornstein, Natan M. | Auriel, Eitan

Article Type: Research Article

Abstract: Background: White matter hyperintensities (WMH) were shown to predict cognitive decline following stroke or transient ischemic attack (TIA). However, WMH are only one among other radiological markers of cerebral small vessel disease (SVD). Objective: The aim of this study was to determine whether adding other SVD markers to WMH improves prediction of post-stroke cognitive performances. Methods: Consecutive first-ever stroke or TIA patients (n  = 266) from the Tel Aviv Acute Brain Stroke Cohort (TABASCO) study were enrolled. MRI scans were performed within seven days of stroke onset. We evaluated the relationship between cognitive performances one year …following stroke, and previously suggested total SVD burden score including WMH, lacunes, cerebral microbleeds (CMB), and perivascular spaces (PVS). Results: Significant negative associations were found between WMH and cognition (p  < 0.05). Adding other SVD markers (lacunes, CMB, PVS) to WMH did not improve predication of post-stroke cognitive performances. Negative correlations between SVD burden score and cognitive scores were observed for global cognitive, memory, and visual spatial scores (all p  < 0.05). However, following an adjustment for confounders, no associations remained significant. Conclusion: WMH score was associated with poor post-stroke cognitive performance. Adding other SVD markers or SVD burden score, however, did not improve prediction. Show more

Keywords: Cognition, stroke, small vessel disease burden, TABASCO, white matter hyperintensities

DOI: 10.3233/JAD-160939

Citation: Journal of Alzheimer's Disease, vol. 56, no. 4, pp. 1293-1299, 2017

Authors: Ienca, Marcello | Fabrice, Jotterand | Elger, Bernice | Caon, Maurizio | Scoccia Pappagallo, Alessandro | Kressig, Reto W. | Wangmo, Tenzin

Article Type: Research Article

Abstract: Intelligent assistive technologies (IATs) have the potential of offering innovative solutions to mitigate the global burden of dementia and provide new tools for dementia care. While technological opportunities multiply rapidly, clinical applications are rare as the technological potential of IATs remains inadequately translated into dementia care. In this article, the authors present the results of a systematic review and the resulting comprehensive technology index of IATs with application in dementia care. Computer science, engineering, and medical databases were extensively searched and the retrieved items were systematically reviewed. For each IAT, the authors examined their technological type, application, target population, model …of development, and evidence of clinical validation. The findings reveal that the IAT spectrum is expanding rapidly in volume and variety over time, and encompasses intelligent systems supporting various assistive tasks and clinical uses. At the same time, the results confirm the persistence of structural limitations to successful adoption including partial lack of clinical validation and insufficient focus on patients’ needs. This index is designed to orient clinicians and relevant stakeholders involved in the implementation and management of dementia care across the current capabilities, applications, and limitations of IATs and to facilitate the translation of medical engineering research into clinical practice. In addition, a discussion of the major methodological challenges and policy implications for the successful and ethically responsible implementation of IAT into dementia care is provided. Show more

Keywords: Ambient assisted living, assistive technology, cognitive assistance, dementia, pervasive computing, robotics, technology index

DOI: 10.3233/JAD-161037

Citation: Journal of Alzheimer's Disease, vol. 56, no. 4, pp. 1301-1340, 2017