Journal of Alzheimer's Disease - Volume 65, issue 1

Authors: Watad, Abdulla | Bragazzi, Nicola L. | Tiosano, Shmuel | Yavne, Yarden | Comaneshter, Doron | Cohen, Arnon D. | Amital, Howard

Article Type: Research Article

Abstract: Background: Neurological features are often overlooked in systemic sclerosis (SSc) patients and little is known about the link between dementia and SSc. Objectives: We sought to investigate whether an association exists between Alzheimer’s disease (AD) and SSc, as well as assess the impact of a dual diagnosis on mortality rates, by performing an extensive data analysis on a large subject sample. Methods: We utilized the medical database of the Clalit-Health-Services in a case-control study. Patients with SSc were compared with age- and sex-matched controls with regard to the prevalence of AD and its impact on their …mortality. Results: Our study included 2,431 SSc patients and 12,377 age- and sex-matched controls. The mean age of the study population was 63.32±18.06 years and the female to male ratio was 4.5:1. 134 (5.5%) cases had AD as a co-morbidity in comparison with 749 (5.9%) of the controls. The mortality rate was 12.5% among controls and 26.2% among SSc cases. On the Cox multivariate survival analysis, diagnosis of SSc and AD demonstrated significant HRs (2.35 (95% CI 2.05–2.69, p < 0.0001) and 2.19 (95% CI 1.94–2.48, p < 0.0001), respectively). SSc patients with AD had a relative risk of death of 2.35 (95% CI: 1.44–3.83) in comparison with SSc patients without AD. Conclusion: AD is a predictor of death in SSc and therefore preemptive screening may be warranted. Further studies are needed to evaluate whether improvements in the medical regimen for SSc may lead to a reduction in AD development and possibly to increased survival as well. Show more

Keywords: Alzheimer’s disease, autoimmune diseases, dementia, scleroderma, systemic sclerosis

DOI: 10.3233/JAD-180516

Citation: Journal of Alzheimer's Disease, vol. 65, no. 1, pp. 117-124, 2018

Authors: Malandrino, Noemi | Capristo, Esmeralda | Taveira, Tracey H. | Mingrone, Geltrude | Wu, Wen-Chih

Article Type: Research Article

Abstract: Background/Objective: Normal weight obesity (NWO) is associated with increased risk of metabolic syndrome, cardiovascular- and all-cause mortality. However, no data have been reported on the relationship between adiposity and cognitive performance in NWO. We therefore studied the association between cognitive function and body fat percentage (BF%) in NWO, using a representative sample of the United States population. Methods: A cross-sectional study was performed using the nationwide 1988 to 1994 data set from the Third National Health and Nutrition Examination Survey. Cognitive function was measured by three validated cognitive tests: simple reaction time test (SRTT), symbol digit substitution test …(SDST), and serial digit learning test (SDLT). The association between BF% and cognitive performance was evaluated in 2,039 adults aged 20–59 years and with a body mass index ranging from 18.5 to 24.9 kg/m2 . Linear regression modeling was used to adjust for potential confounders. Results: Increased BF% was significantly associated with poorer performance on SDLT in the entire study sample (coefficient [95% CI]: 0.15 [0.01, 0.29]) and with poorer performance on SDST in the age group 20–29 years (coefficient [95% CI]: 0.30 [0.10, 0.49]). Increased BF% did not significantly predict poorer performance on SRTT. Conclusion: Higher BF% is significantly associated with poorer cognitive function in a nationally representative sample of US adults with NWO. The identification of possible complications associated with increased adipose tissue underlines the need to measure body fat content in NWO individuals, whose metabolic and cognitive dysfunction could go undetected for years due to their young age and normal body weight. Show more

Keywords: Adipose tissue, body composition, cognitive function, NHANES, normal weight obesity

DOI: 10.3233/JAD-180264

Citation: Journal of Alzheimer's Disease, vol. 65, no. 1, pp. 125-135, 2018

Authors: Sobol, Nanna A. | Dall, Christian Have | Høgh, Peter | Hoffmann, Kristine | Frederiksen, Kristian Steen | Vogel, Asmus | Siersma, Volkert | Waldemar, Gunhild | Hasselbalch, Steen G. | Beyer, Nina

Article Type: Research Article

Abstract: Background: Physical activity has the potential to improve physical function in patients with Alzheimer’s disease (AD) and may contribute to modify disease processes and cognitive function. Objective: The aim of this study was to investigate 1) the effect of moderate-high-intensity aerobic exercise on cardiorespiratory fitness, i.e., peak oxygen uptake (VO2peak ) determined by direct breath-by-breath cardiopulmonary exercise test, and 2) the association between changes in VO2peak and changes in cognition and neuropsychiatric symptoms in patients with mild AD. Methods: The study is based on secondary outcome analyses from the large single-blinded multi-center study ADEX (Preserving …Cognition, Quality of Life, Physical Health and Functional Ability in Alzheimer’s Disease: The Effect of Physical Exercise). A preselected sub-group of 55 participants (age 52–83 years), 29 from the intervention group (IG) and 26 from the control group (CG), was included. IG performed 16 weeks of supervised moderate-to-high intensity aerobic exercise. Assessments of VO2peak , mental speed and attention (Symbol Digit Modalities Test, SDMT), and neuropsychiatric symptoms (Neuropsychiatric Inventory, NPI) were performed at baseline and at 16 weeks. Result: VO2peak increased 13% in the IG and a between-group difference in mean change (3.92 ml/kg/min, 95% CI 6.34–1.51, p = 0.003) was present in favor of the IG. Combined data from IG and CG showed positive associations between changes in VO2peak and changes in NPI (Rho = – 0.41, p = 0.042) and changes in SDMT (Rho = 0.36, p = 0.010), respectively. Conclusion: Aerobic exercise improves VO2peak in community-dwelling patients with mild AD. Furthermore, changes in VO2peak appear to be associated to changes in cognition and neuropsychiatric symptoms. Show more

Keywords: Alzheimer’s disease, aerobic exercise, cardiorespiratory fitness, cognitive function, neuropsychiatric symptoms

DOI: 10.3233/JAD-180253

Citation: Journal of Alzheimer's Disease, vol. 65, no. 1, pp. 137-145, 2018

Authors: Sellami, Leila | Bocchetta, Martina | Masellis, Mario | Cash, David M. | Dick, Katrina M. | van Swieten, John | Borroni, Barbara | Galimberti, Daniela | Tartaglia, Maria Carmela | Rowe, James B. | Graff, Caroline | Tagliavini, Fabrizio | Frisoni, Giovanni | Finger, Elizabeth | de Mendonça, Alexandre | Sorbi, Sandro | Warren, Jason D. | Rohrer, Jonathan D. | Laforce Jr., Robert | on behalf of the Genetic FTD Initiative, GENFI

Collaborators: Andersson, Christin | Archetti, Silvana | Benussi, Luisa | Binetti, Giuliano | Black, Sandra | Cosseddu, Maura | Fallström, Marie | Ferreira, Carlos | Fox, Nick C | Freedman, Morris | Gazzina, Stefano | Ghidoni, Roberta | Grisoli, Marina | Jelic, Vesna | Jiskoot, Lize | Keren, Ron | Lombardi, Gemma | Maruta, Carolina | Mead, Simon | Meeter, Lieke | van Minkelen, Rick | Nacmias, Benedetta | öijerstedt, Linn | Ourselin, Sebastien | Padovani, Alessandro | Panman, Jessica | Pievani, Michela | Polito, Cristina | Premi, Enrico | Prioni, Sara | Rademakers, Rosa | Redaelli, Veronica | Rogaeva, Ekaterina | Rossi, Giacomina | Rossor , Martin N | Tang-Wai, David | Thomas, David L | Thonberg, Hakan | Tiraboschi, Pietro | Verdelho, Ana | Warren, Jason D

Article Type: Research Article

Abstract: Background: The overlap between frontotemporal dementia (FTD) and primary psychiatric disorders has been brought to light by reports of prominent neuropsychiatric symptoms (NPS) in FTD-related genetic mutations, particularly among C9orf72 and GRN carriers. It has been recently demonstrated that early neuroanatomical changes in genetic FTD may be different across the major disease-causing mutations. Objective: We aimed to identify whether NPS could be driven by distinct structural correlates. Methods: One hundred and sixty-seven mutation carriers (75 GRN , 60 C9orf72 , and 32 MAPT ) were included from the Genetic FTD Initiative (GENFI) study, a …large international cohort of genetic FTD. Neuropsychiatric symptoms including delusions, hallucinations (visual, auditory, and tactile), depression, and anxiety were investigated using a structured interview. Voxel-based morphometry was performed to identify neuroanatomical correlates of NPS. Results: Psychotic symptoms correlated mainly with grey matter (GM) atrophy in the anterior insula, left thalamus, cerebellum, and cortical regions including frontal, parietal, and occipital lobes in GRN mutations carriers. GM atrophy in posterior structures of the default-mode network was associated with anxiety in the GRN group. Delusions in C9orf72 expansion carriers were mainly associated with left frontal cortical atrophy. Cerebellar atrophy was found to be correlated only with anxiety in C9orf72 carriers. NPS in the MAPT group were mainly associated with volume loss in the temporal lobe. Conclusion: Neuroanatomical correlates of NPS appear to be distinct across the main forms of genetic FTD. Overall, our findings support overlapping brain structural changes between FTD and primary psychiatric disorders. Show more

Keywords: Frontotemporal dementia, genetics, magnetic resonance imaging, neuropsychiatry

DOI: 10.3233/JAD-180053

Citation: Journal of Alzheimer's Disease, vol. 65, no. 1, pp. 147-163, 2018

Authors: Plucińska, Kaja | Crouch, Barry | Yeap, Jie M. | Stoppelkamp, Sandra | Riedel, Gernot | Platt, Bettina

Article Type: Research Article

Abstract: Gene mutations within amyloid precursor protein (APP or AβPP ) and/or presenilin 1 (PS1 ) genes are determinants of familial Alzheimer’s disease (fAD) and remain fundamental for experimental models. Here, we generated a neuronal knock-in mouse (PLB2APP ) with mutated human APPSwe /Lon and investigated histopathology and behavioral phenotypes. Additionally, PLB2APP mice were cross-bred with a presenilin (PS1 A246E ) line to assess the impact of this gene combination. Immunohistochemistry determined amyloid-β (Aβ) pathology, astrogliosis (via GFAP labelling), and neuronal densities in hippocampal and cortical brain regions. One-year old PLB2APP mice showed higher levels …of intracellular Aβ in CA1, dentate gyrus, and cortical regions compared to PLBWT controls. Co-expression of PS1 reduced hippocampal but elevated cortical Aβ build-up. Amyloid plaques were sparse in aged PLB2APP mice, and co-expression of PS1 promoted plaque formation. Heightened GFAP expression followed the region-specific pattern of Aβ in PLB2APP and PLB2APP/PS1 mice. Behaviorally, habituation to a novel environment was delayed in 6-month-old PLB2APP mice, and overall home-cage activity was reduced in both lines at 6 and 12 months, particularly during the dark phase. Spatial learning in the water maze was impaired in PLB2APP mice independent of PS1 expression and associated with reduced spatial navigation strategies. Memory retrieval was compromised in PLB2APP mice only. Our data demonstrate that low expression of APP is sufficient to drive histopathological and cognitive changes in mice without overexpression or excessive plaque deposition. AD-like phenotypes were altered by co-expression of PS1 , including a shift from hippocampal to cortical Aβ pathology, alongside reduced deficits in spatial learning. Show more

Keywords: Amyloid, cognition, habituation, inflammation, search strategies, spatial learning

DOI: 10.3233/JAD-180336

Citation: Journal of Alzheimer's Disease, vol. 65, no. 1, pp. 165-180, 2018

Authors: Sánchez-Benavides, Gonzalo | Grau-Rivera, Oriol | Cacciaglia, Raffaele | Suárez-Calvet, Marc | Falcon, Carles | Minguillon, Carolina | Gramunt, Nina | Sala-Vila, Aleix | Gispert, Juan Domingo | Molinuevo, José Luis

Article Type: Research Article

Abstract: Background: Subtle cognitive decline preceding cognitive impairment can be self-perceived, referred to as subjective cognitive decline (SCD), or go unrecognized. Objective: To study the clinical, cognitive, and structural neuroimaging characteristics of psychometrically normal subjects without self-awareness of cognitive decline (unaware decliners, UD) and to compare them with SCD participants and controls. Methods: 2,640 participants from the ALFA cohort, 1,899 controls, 173 UD (decline reported by the informant only), and 568 SCD underwent clinical and cognitive explorations. A subset of 530 underwent structural MRI (379 Controls; 43 UD; 108 SCD). Linear models adjusting for confounders (age, sex, …education, and mood state) were used to assess group differences on cognition and voxel-wise grey matter (GM) volumes. Results: 6.6% were UD while 21.5% SCD. No differences in anxiety and depression were observed between controls and UD, while SCD did (p < 0.01). UD showed lower performance in the Memory Binding Test free recall (p < 0.005) than controls, but no differences compared to SCD. Right medial frontal and insular increments of GM volumes were observed in UD with respect to controls. Informant report of decline in UD and SCD was associated with lower left hippocampal GM volume but related to memory performance only in UD (rho = 0.46, p = 0.002). Conclusions: UD had worse memory performance than controls which correlated with hippocampal GM volume and presented brain volume increments in self-appraisal areas (medial frontal and insula). Individuals unaware of cognitive decline may represent a distinct group at risk for cognitive impairment and support the usefulness of informant-reported cognitive decline. Show more

Keywords: Anosognosia, cognition, subjective cognitive decline, unaware decliners, voxel-based morphometry

DOI: 10.3233/JAD-180378

Citation: Journal of Alzheimer's Disease, vol. 65, no. 1, pp. 181-191, 2018

Authors: Cruz-Rivera, Yazeli E. | Perez-Morales, Jaileene | Santiago, Yaritza M. | Gonzalez, Valerie M. | Morales, Luisa | Cabrera-Rios, Mauricio | Isaza, Clara E.

Article Type: Research Article

Abstract: In 2017, approximately 5 million Americans were living with Alzheimer’s disease (AD), and it is estimated that by 2050 this number could increase to 16 million. In this study, we apply mathematical optimization to approach microarray analysis to detect differentially expressed genes and determine the most correlated structure among their expression changes. The analysis of GSE4757 microarray dataset, which compares expression between AD neurons without neurofibrillary tangles (controls) and with neurofibrillary tangles (cases), was casted as a multiple criteria optimization (MCO) problem. Through the analysis it was possible to determine a series of Pareto efficient frontiers to find the most …differentially expressed genes, which are here proposed as potential AD biomarkers. The Traveling Sales Problem (TSP) model was used to find the cyclical path of maximal correlation between the expression changes among the genes deemed important from the previous stage. This leads to a structure capable of guiding biological exploration with enhanced precision and repeatability. Ten genes were selected (FTL, GFAP, HNRNPA3, COX1, ND2, ND3, ND4, NUCKS1, RPL41, and RPS10) and their most correlated cyclic structure was found in our analyses. The biological functions of their products were found to be linked to inflammation and neurodegenerative diseases and some of them had not been reported for AD before. The TSP path connects genes coding for mitochondrial electron transfer proteins. Some of these proteins are closely related to other electron transport proteins already reported as important for AD. Show more

Keywords: Alzheimer’s disease, correlation, optimization, traveling salesman problem

DOI: 10.3233/JAD-170799

Citation: Journal of Alzheimer's Disease, vol. 65, no. 1, pp. 193-205, 2018

Authors: Gámez-Valero, Ana | Canet-Pons, Julia | Urbizu, Aintzane | Anillo, Ana | Santos, Cristina | Ariza, Aurelio | Beyer, Katrin

Article Type: Research Article

Abstract: Lewy body diseases (LBD) include Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) and together with Alzheimer’s disease (AD) they show an important neuropathological and clinical overlap. The human alpha- and beta-synuclein genes (SNCA and SNCB ) are key factors for the development of Lewy body diseases. Here, we aimed to analyze the genotype distribution of potentially functional SNPs in SNCA and SNCB , perform haplotype analysis for SNCB , and to identify functional insertion and deletion (INDEL) variations within the regulatory region of SNCB which might be responsible for the drastically diminished beta-synuclein levels reported …for pure DLB. Thus, we genotyped brain samples from AD, DLB, PD, and healthy controls for two SNCA and four SNCB SNPs. We also analyzed INDEL variations upstream of SNCB , determined SNCB expression levels, and correlated INDEL lengths with expression levels. Applying Fisher’s exact, chi-square, ANOVA tests, and the Δ Δ Ct method, we found disease-specific genotype distribution of SNCA and SNCB SNPs. Additionally, we identified three INDEL variations upstream of SNCB and showed that the INDEL allele lengths were associated with SNCB expression levels. INDEL alleles associated with low SNCB expression were accumulated in pure DLB. Finally, one major and four minor DLB specific SNCB haplotypes were identified with Haploview and Arlequin. In summary, our study showed that different SNCA and SNCB genotypes are associated with the development of either PD or DLB, and that the frequencies of genotypes associated with low SNCB expression are elevated in DLB. Show more

Keywords: α-synuclein gene (SNCA), β-synuclein gene (SNCB), dementia with Lewy bodies, haplotypes, INDEL variations, Parkinson’s disease

DOI: 10.3233/JAD-180074

Citation: Journal of Alzheimer's Disease, vol. 65, no. 1, pp. 207-219, 2018

Authors: Padovani, Alessandro | Benussi, Alberto | Cantoni, Valentina | Dell’Era, Valentina | Cotelli, Maria Sofia | Caratozzolo, Salvatore | Turrone, Rosanna | Rozzini, Luca | Alberici, Antonella | Altomare, Daniele | Depari, Alessandro | Flammini, Alessandra | Frisoni, Giovanni B. | Borroni, Barbara

Article Type: Research Article

Abstract: Background: Considering the increasing evidence that disease-modifying treatments for Alzheimer’s disease (AD) must be administered early in the disease course, the development of diagnostic tools capable of accurately identifying AD at early disease stages has become a crucial target. In this view, transcranial magnetic stimulation (TMS) has become an effective tool to discriminate between different forms of neurodegenerative dementia. Objective: To determine whether a TMS multi-paradigm approach can be used to correctly identify mild cognitive impairment (MCI) due to AD (AD MCI). Methods: A sample of 69 subjects with MCI were included and classified as AD …MCI or MCI unlikely due to AD (non-AD MCI) based on 1) extensive neurological and neuropsychological evaluation, 2) MRI imaging, and 3) cerebrospinal fluid analysis or/and amyloid PET imaging. A paired-pulse TMS multi-paradigm approach assessing short interval intracortical inhibition-facilitation (SICI-ICF), dependent on GABAergic and glutamatergic intracortical circuits, respectively, and short latency afferent inhibition (SAI), dependent on cholinergic circuits, was performed. Results: We observed a significant impairment of SAI and unimpaired SICI and ICF in AD MCI as compared to non-AD MCI. According to ROC curve analysis, the SICI-ICF / SAI index differentiated AD MCI from non-AD MCI with a specificity of 87.9% and a sensitivity of 94.4%. Conclusions: The assessment of intracortical connectivity with TMS could aid in the characterization of MCI subtypes, correctly identifying AD pathophysiology. TMS can be proposed as an adjunctive, non-invasive, inexpensive, and time-saving screening tool in MCI differential diagnosis. Show more

Keywords: Alzheimer’s disease, dementia, mild cognitive impairment, short interval intracortical inhibition, short latency afferent inhibition, transcranial magnetic stimulation

DOI: 10.3233/JAD-180293

Citation: Journal of Alzheimer's Disease, vol. 65, no. 1, pp. 221-230, 2018

Authors: Douglass, Amanda | Walterfang, Mark | Velakoulis, Dennis | Abel, Larry

Article Type: Research Article

Abstract: Background: Saccadic paradigms display changes across a number of degenerative conditions reflecting changes in the oculomotor pathway which in some conditions have been linked to disease presentation. Objective: To examine a novel range of saccadic paradigms in behavioral variant frontotemporal dementia (bvFTD). Methods: Prosaccade, predictive, self-paced, memory-guided, and anti-saccade tasks were examined in bvFTD patients and controls. Results: A significant increase in latency for the bvFTD group was seen in all tasks. Self-paced saccades are reduced in number, memory-guided saccades display an increase in errors. Predictive saccades show an increased latency that does not …remain when prosaccade latency changes are accounted for. While changes were seen across a range of paradigms, no individual task completely separated bvFTD from control participants. Conclusion: bvFTD patients as a group display a number of changes on saccadic testing which may reflect the frontal lobe changes seen in this condition. Show more

Keywords: Dementia, eye movements, saccades

DOI: 10.3233/JAD-170797

Citation: Journal of Alzheimer's Disease, vol. 65, no. 1, pp. 231-242, 2018