Journal of Alzheimer's Disease - Volume 60, issue 2

Authors: Javidnia, Monica | Hebron, Michaeline L. | Xin, Yue | Kinney, Nikolas G. | Moussa, Charbel E-H.

Article Type: Research Article

Abstract: Hyperphosphorylation and aggregation of tau protein is a critical factor in many neurodegenerative diseases. These diseases are increasing in prevalence, and there are currently no cures. Previous work from our group and others has shown that tyrosine kinase inhibitors (TKIs) can stimulate autophagy, decrease pathological proteins, and improve symptoms in models of neurodegeneration. Here we examined the role of pazopanib in mouse models that express either human mutant P301L tau (TauP301L) or triple mutant amyloid precursor protein (3x-AβPP). The TauP301L mouse expresses P301L tau under the control of a prion promoter in both neurons and astrocytes, reminiscent of some human …tauopathies. Pazopanib crosses the blood-brain barrier with no detectable peripheral off-side effects, and decreases p-tau in TauP301L mice. Pazopanib reaches a brain concentration sufficient for inhibition of several tyrosine kinases, including vascular endothelial growth factor receptors (VEGFRs). Further, pazopanib does not affect microglia but reduces astrocyte levels toward nontransgenic controls in TauP301L mice. Pazopanib does not alter amyloid beta levels or astrocytes in 3x-AβPP mice but modulates a number of inflammatory markers (IP-10, MIP-1α, MIP-1β, and RANTES). These data suggest that pazopanib may be involved in p-tau clearance and modulation of astrocytic activity in models of tauopathies. Show more

Keywords: Alzheimer’s disease, amyloid-β, pazopanib, tau, tauopathies

DOI: 10.3233/JAD-170429

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 461-481, 2017

Authors: Poulin, Stéphane P. | Bergeron, David | Dickerson, Bradford C. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: An integrative model of neuropsychiatric symptoms (NPS) in Alzheimer’s disease (AD) is lacking. Objective: In this study, we investigated the risk factors, anatomy, biology, and outcomes of NPS in AD. Methods: 181 subjects were included from the Alzheimer’s Disease Neuroimaging Study (ADNI). NPS were assessed with the Neuropsychiatric Inventory Questionnaire at baseline and 6 months. NPI >3 was used as a threshold for NPS positivity. Three NPS courses were characterized: 1) minimal/absent (negative at 0 and 6 months, n  = 77); 2) fluctuating (positive only at one time point, n  = 53); 3) persistent (positive at both time …points, n  = 51). We examined the association between NPS course and family history of dementia, personal history of psychiatric disorders, cerebrospinal fluid biomarkers, atrophy patterns, as well as longitudinal cognitive and functional measures at 12 and 24 months (MMSE, CDR-SOB, FAQ). Results: AD subjects with absent, fluctuating, or persistent NPS had similar CSF amyloid-β and tau levels. AD subjects with minimal/absent NPS had less personal history of psychiatric disorders (35%) than those with fluctuating (57%; p  = 0.015) or persistent NPS (47%, not significant). At 24 months, AD subjects with persistent NPS had worse cognitive (MMSE; p  = 0.05) and functional (CDR-SOB; p  = 0.016) outcomes. Dorsolateral prefrontal atrophy was seen in persistent NPS, but not in fluctuating NPS. Conclusions: Our results suggest that individuals with personal history of psychiatric disorders might be more vulnerable to develop NPS throughout the course of AD. The worst cognitive and functional outcomes associated with NPS in AD underscores the importance of monitoring NPS early in the disease course. Show more

Keywords: Alzheimer’s disease, Alzheimer’s Disease Neuroimaging Initiative, apathy, depression, neuropsychiatric inventory, neuropsychiatric symptoms, psychosis

DOI: 10.3233/JAD-160767

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 483-493, 2017

Authors: Giil, Lasse Melvaer | Midttun, Øivind | Refsum, Helga | Ulvik, Arve | Advani, Rajiv | Smith, A. David | Ueland, Per Magne

Article Type: Research Article

Abstract: Background: Metabolites of tryptophan, produced via the kynurenine pathway (kynurenines), have been linked to Alzheimer’s disease (AD) in small cohorts with conflicting results. Objective: To compare differences in plasma kynurenine levels between AD and controls and identify potential associations with cognition. Methods: The study included 65 histopathologically-confirmed AD patients and 65 cognitively-screened controls from the Oxford Project to Investigate Memory and Ageing (OPTIMA) cohort. Cognition was assessed using the Cambridge Cognitive Examination (CamCog). Tryptophan, kynurenines, neopterin, and vitamin B6 forms were measured in plasma by liquid chromatography-tandem mass spectrometry. Non-parametric statistics, logistic regression and standardized robust …regressions were applied with a false discovery rate of 0.05. Results: Tryptophan, xanthurenic acid, 3-hydroxyanthranilic acid, and quinolinic acid were lower in AD (Odds ratios (ORs) 0.24 –0.47; p -values <0.001 –0.01). Pyridoxal 5’phosphate did not differ between AD and controls. Kynurenine, anthranilic acid, quinolinic acid, and markers of immune activation (neopterin, kynurenine/tryptophan ratio, and the PAr index (Pyridoxic acid/(Pyridoxal 5’phosphate + Pyridoxal)) increased with age (β 0.31 –0.51; p -values <0.001 –0.006). Xanthurenic acid decreased with age (β: –0.42, p  < 0.001). Elderly AD patients with high quinolinic acid performed worse on the CamCog test, indicated by a significant age*quinolinic acid interaction (β 0.21, p  < 0.001). Conclusion: Plasma concentrations of several kynurenines were lower in patients with AD compared to controls. Low xanthurenic acid occurred in both AD and with aging. Inflammation-related markers were associated with age, but not AD. However, elevated QA was associated with poor cognition in older AD patients. Show more

Keywords: Alzheimer’s disease, aging, cognition, dementia, kynurenine pathway, quinolinic acid, vitamin B6, xanthurenic acid

DOI: 10.3233/JAD-170485

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 495-504, 2017

Authors: Jacob, Louis | Adam-Schnepf, Leonie | Kostev, Karel

Article Type: Research Article

Abstract: Background: Hypertension, a chronic disease resulting from aging and its related physiopathological dysregulations, is often associated with dementia. Objective: The goal was to analyze the persistence with antihypertensive drugs in patients affected by both hypertension and dementia in Germany. Methods: This study included hypertension patients who were initially treated with antihypertensive drugs in 1,262 general practices in Germany between January 2013 and December 2015 (index date). Patients with hypertension and comorbid dementia were matched (1 : 1) to patients without dementia by age, gender, type of residence (nursing home versus home-care setting), physician, and initial antihypertensive therapy, using …a propensity score method. The primary outcome was the rate of patients without treatment discontinuation with antihypertensive drugs in cases and controls in the 12 months following the index date. Cox regressions were used to determine the impact of dementia on persistence with antihypertensive treatment. Results: This study included 2,191 patients with hypertension and comorbid dementia and 2,191 patients with hypertension but without dementia. The mean age was 79.3 years (SD = 10.3 years) in both groups. Twelve months after initiation of antihypertensive therapy, 73.5% of cases and 69.5% of controls were persistent (p  < 0.001). Dementia was associated with a significant decrease in the risk of non-persistence with antihypertensive drugs in the entire population (HR = 0.86, 95% CI: 0.79–0.93). This finding was corroborated in five different subgroups (age ≤60 years, age 61–70 years, men, women, and patients living in home-care settings). Conclusions: Dementia was found to be a protective factor for persistence with antihypertensive drugs in Germany. Show more

Keywords: Antihypertensive drugs, dementia, Germany, hypertension, persistence

DOI: 10.3233/JAD-170452

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 505-510, 2017

Authors: Willén, Katarina | Sroka, Agnieszka | Takahashi, Reisuke H. | Gouras, Gunnar K.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is increasingly viewed as a disease of synapses. Loss of synapses correlates better with cognitive decline than amyloid plaques and neurofibrillary tangles, the hallmark neuropathological lesions of AD. Soluble forms of amyloid-β (Aβ) have emerged as mediators of synapse dysfunction. Aβ binds to, accumulates, and aggregates in synapses. However, the anatomical and neurotransmitter specificity of Aβ and the amyloid-β protein precursor (AβPP) in AD remain poorly understood. In addition, the relative roles of Aβ and AβPP in the development of AD, at pre- versus post-synaptic compartments and axons versus dendrites, respectively, remain unclear. Here we use immunogold …electron microscopy and confocal microscopy to provide evidence for heterogeneity in the localization of Aβ/AβPP. We demonstrate that Aβ binds to a subset of synapses in cultured neurons, with preferential binding to glutamatergic compared to GABAergic neurons. We also highlight the challenge of defining pre- versus post-synaptic localization of this binding by confocal microscopy. Further, endogenous Aβ42 accumulates in both glutamatergic and GABAergic AβPP/PS1 transgenic primary neurons, but at varying levels. Moreover, upon knock-out of presenilin 1 or inhibition of γ -secretase AβPP C-terminal fragments accumulate both pre- and post-synaptically; however earlier pre-synaptically, consistent with a higher rate of AβPP processing in axons. A better understanding of the synaptic and anatomical selectivity of Aβ/AβPP in AD can be important for the development of more effective new therapies for this major disease of aging. Show more

Keywords: Alzheimer’s disease, amyloid-beta, gamma-secretase, synapse

DOI: 10.3233/JAD-170262

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 511-524, 2017

Authors: Amorim, João A. | Canas, Paula M. | Tomé, Angelo R. | Rolo, Anabela P. | Agostinho, Paula | Palmeira, Carlos M. | Cunha, Rodrigo A.

Article Type: Research Article

Abstract: Mitochondrial dysfunction is proposed to trigger memory deficits and synaptic damage at the onset of Alzheimer’s disease (AD). However, it is unknown how mitochondria dysfunction might trigger synaptotoxicity and if a differential susceptibility of mitochondria located in synapses underlies the greater glutamatergic than GABAergic synaptotoxicity in early AD. Hippocampal synaptosomes (purified synapses) of a rat model of early AD, typified by selective memory deficits two weeks after intracerebroventricular injection of amyloid-β peptides (Aβ1–42 , 2 nmol), simultaneously displayed three mitochondria-associated deleterious alterations: 1) hampered metabolism (decreased MTT reduction); 2) increased oxygen radical production (increased hydrogen peroxide production); 3) increased caspase-3 activity. …The direct exposure of hippocampal synaptosomes to Aβ1–42 (500 nM) similarly decreased mitochondrial membrane potential (TMRM+ fluorescence) and increased mitochondria-derived oxygen radicals (MitoTraker® red-CM-H2Xros fluorescence) in individual glutamatergic (vesicular glutamate transporter-immunopositive) and GABAergic (vesicular GABA transporter-immunopositive) synaptosomes. However, significantly more glutamatergic than GABAergic synaptosomes were endowed with mitochondria (Tom20-immunopositive). These results indicate that dysfunctional mitochondria located in synapses can trigger synaptotoxicity through multifaceted mechanisms and that it is not the susceptibility of mitochondria to Aβ but more likely a different impact of dysfunctional mitochondria that underlies the greater sensitivity to synaptotoxicity of glutamatergic than GABA synapses in early AD. Show more

Keywords: Alzheimer’s disease, caspase 3, GABA, glutamate, hippocampus, metabolism, mitochondria, oxygen radicals, synapse, synaptosomes

DOI: 10.3233/JAD-170356

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 525-536, 2017

Authors: Gerstenecker, Adam | Hoagey, David A. | Marson, Daniel C. | Kennedy, Kristen M.

Article Type: Research Article

Abstract: Financial capacity (FC) is a cognitively complex activity of daily living that declines in mild cognitive impairment (MCI) and Alzheimer’s disease (AD), limiting an individual’s ability to manage one’s finances and function independently. The neural underpinnings of this decline in function are poorly understood but likely involve age-related and disease-related degradation across structural networks. The purpose of the current study was to determine if altered white matter integrity is associated with declining FC in persons with MCI and AD compared to older controls. Individuals with MCI due to AD (n  = 31), mild dementia (n  = 39), and cognitively healthy older adults …(n  = 60) were administered a neuropsychological battery including the FC Instrument, a performance-based measure of FC. All 130 participants also underwent diffusion tensor imaging (DTI) upon which tract-based spatial statistics were performed. Both FC and white matter integrity decreased in accordance with disease severity with little to no effect in healthy elderly, significant effects in MCI, and greater effects in AD. Regional white matter degradation (increased diffusivities and decreased fractional anisotropy) was associated with reduced FC in both MCI and AD groups even after controlling for age, education, and gender. Specifically, in MCI, decreased fractional anisotropy, but not increased diffusivities, was associated with poorer FC in widespread cingulo-parietal-frontal and temporo-occipital areas. In AD, rather than anisotropy, increased mean and axial diffusivities in anterior cingulate, callosum, and frontal areas associated with poorer FC. These findings suggest a severity gradient of white matter degradation across DTI metrics and AD stages that predict declining financial skill and knowledge. Show more

Keywords: Aging, financial management, Alzheimer’s disease, brain, diffusion tensor imaging, magnetic resonance imaging, mild cognitive impairment, white matter connectivity

DOI: 10.3233/JAD-170341

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 537-547, 2017

Authors: Portbury, Stuart D. | Hare, Dominic J. | Sgambelloni, Charlotte | Perronnes, Kali | Portbury, Ashley J. | Finkelstein, David I. | Adlard, Paul A.

Article Type: Research Article

Abstract: This study assessed the therapeutic utility of the autophagy enhancing stable disaccharide trehalose in the Tg2576 transgenic mouse model of Alzheimer’s disease (AD) via an oral gavage of a 2% trehalose solution for 31 days. Furthermore, as AD is a neurodegenerative condition in which the transition metals, iron, copper, and zinc, are understood to be intricately involved in the cellular cascades leading to the defining pathologies of the disease, we sought to determine any parallel impact of trehalose treatment on metal levels. Trehalose treatment significantly improved performance in the Morris water maze, consistent with enhanced learning and memory. The improvement …was not associated with significant modulation of full length amyloid-β protein precursor or other amyloid-β fragments. Trehalose had no effect on autophagy as assessed by western blot of the LC3-1 to LC3-2 protein ratio, and no alteration in biometals that might account for the improved cognition was observed. Biochemical analysis revealed a significant increase in the hippocampus of both synaptophysin, a synaptic vesicle protein and surrogate marker of synapses, and doublecortin, a reliable marker of neurogenesis. The growth factor progranulin was also significantly increased in the hippocampus and cortex with trehalose treatment. This study suggests that trehalose might invoke a suite of neuroprotective mechanisms that can contribute to improved cognitive performance in AD that are independent of more classical trehalose-mediated pathways, such as Aβ reduction and activation of autophagy. Thus, trehalose may have utility as a potential AD therapeutic, with conceivable implications for the treatment of other neurodegenerative disorders. Show more

Keywords: Alzheimer’s disease, progranulin, synaptophysin, Tg2576, trehalose

DOI: 10.3233/JAD-170322

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 549-560, 2017

Authors: Niemantsverdriet, Ellis | Ottoy, Julie | Somers, Charisse | De Roeck, Ellen | Struyfs, Hanne | Soetewey, Femke | Verhaeghe, Jeroen | Van den Bossche, Tobi | Van Mossevelde, Sara | Goeman, Johan | De Deyn, Peter Paul | Mariën, Peter | Versijpt, Jan | Sleegers, Kristel | Van Broeckhoven, Christine | Wyffels, Leonie | Albert, Adrien | Ceyssens, Sarah | Stroobants, Sigrid | Staelens, Steven | Bjerke, Maria | Engelborghs, Sebastiaan

Article Type: Research Article

Abstract: Background: Evidence suggests that the concordance between amyloid-PET and cerebrospinal fluid (CSF) amyloid-β (Aβ) increases when the CSF Aβ1–42 /Aβ1–40 ratio is used as compared to CSF Aβ1–42 levels alone. Objective: In order to test this hypothesis, we set up a prospective longitudinal study comparing the concordance between different amyloid biomarkers for Alzheimer’s disease (AD) in a clinical setting. Methods: Seventy-eight subjects (AD dementia (n  = 17), mild cognitive impairment (MCI, n  = 48), and cognitively healthy controls (n  = 13)) underwent a [18 F]Florbetapir ([18 F]AV45) PET scan, [18 F]FDG PET scan, MRI scan, and an …extensive neuropsychological examination. In a large subset (n  = 67), a lumbar puncture was performed and AD biomarkers were analyzed (Aβ1–42 , Aβ1–40 , T-tau, P-tau181 ). Results: We detected an increased concordance in the visual and quantitative (standardized uptake value ratio (SUVR) and total volume of distribution (VT )) [18 F]AV45 PET measures when the CSF Aβ1–42 /Aβ1–40 was applied compared to Aβ1–42 alone. CSF biomarkers were stronger associated to [18 F]AV45 PET for SUVR values when considering the total brain white matter as reference region instead of cerebellar grey matter Conclusions: The concordance between CSF Aβ and [18 F]AV45 PET increases when the CSF Aβ1–42 /Aβ1–40 ratio is applied. This finding is of most importance for the biomarker-based diagnosis of AD as well as for selection of subjects for clinical trials with potential disease-modifying therapies for AD. Show more

Keywords: Aβ1–42/Aβ1–40 ratio, amyloid, amyloid imaging, biomarkers, cerebrospinal fluid, [18F]Florbetapir ([18F]AV45), magnetic resonance imaging

DOI: 10.3233/JAD-170327

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 561-576, 2017

Authors: Levy Nogueira, Marcel | Samri, Dalila | Epelbaum, Stéphane | Lista, Simone | Suppa, Per | Spies, Lothar | Hampel, Harald | Dubois, Bruno | Teichmann, Marc

Article Type: Research Article

Abstract: The International Working Group recently provided revised criteria of Alzheimer’s disease (AD) proposing that the diagnosis of typical amnesic AD should be established by a clinical-biological signature, defined by the phenotype of an “amnesic syndrome of the hippocampal type” (ASHT) combined with positive in vivo evidence of AD pathophysiology in the cerebrospinal fluid (CSF) or on amyloid PET imaging. The application and clinical value of this refined diagnostic algorithm, initially intended for research purposes, is explored in three memory clinic cases presenting with different cognitive profiles including an ASHT, hippocampal atrophy, and CSF AD-biomarker data. The case reports highlight …that the isolated occurrence of one of the two proposed AD criteria, ASHT or positive pathophysiological markers, does not provide a reliable diagnosis of typical AD. It is proposed that the twofold diagnostic IWG algorithm can be applied and operationalized in memory clinic settings to improve the diagnostic accuracy of typical amnesic AD in clinical practice. Show more

Keywords: Alzheimer’s disease, amnesic syndrome, biomarkers, cerebrospinal fluid, diagnosis, magnetic resonance imaging

DOI: 10.3233/JAD-170574

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 577-583, 2017

Authors: Kuate-Tegueu, Callixte | Avila-Funes, José-Alberto | Simo, Nadine | Le Goff, Mélanie | Amiéva, Hélène | Dartigues, Jean-François | Tabue-Teguo, Maturin

Article Type: Research Article

Abstract: Background: Gait speed (GS) and psychomotor speed (PS) could be considered as two different dimensions of age-related slowness and both measures are associated with higher risk of adverse health-related outcomes among elderly people. Objective: To determine the association between GS, PS, and incident dementia among community-dwelling older adults. Methods: Twelve-year longitudinal study of 1,265 participants in the Bordeaux Three-City Study, a French prospective cohort designed to determine the risk of dementia and cognitive impairment attributable to cardiovascular risk factors. Participants completed a battery of cognitive tests, including time to complete the Trail Making Test A, and …a walking speed test. The incidence of dementia was determined over the 12-year follow-up period. Cox proportional hazards models with delayed entry were used to estimate the cumulative risk of dementia and were adjusted for sex, education, and ApoE4 genotype. Results: Mean age of participants was 74.0 years (SD 4.8). Over the 12-year follow-up, 203 participants developed dementia. GS and PS were both independent predictors of incident all-cause dementia after 12 years of follow-up. For a one SD increase of either GS or PS, the hazard ratio (HR) for Alzheimer’s disease was 1.2 (95% CI = 1.02–1.32) and 1.4 (95% CI = 1.2–1.61), respectively; whereas for incident vascular dementia, the HR was 1.3 (95% CI = 1.05–1.71) and 1.5 (95% CI = 1.16–2.08), respectively. No significant interaction between GS and PS was observed. Conclusions: In older French people aged 65+, our findings showed that both low GS and PS were independently associated with risk of incident Alzheimer’s disease and vascular dementia. Show more

Keywords: Dementia, elderly, epidemiology, gait speed, psychomotor speed, vascular process

DOI: 10.3233/JAD-170267

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 585-592, 2017

Authors: Mavroeidi, Panagiota | Mavrofrydi, Olga | Pappa, Elpiniki | Panopoulou, Myrto | Papazafiri, Panagiota | Haralambous, Sylva | Efthimiopoulos, Spiros

Article Type: Research Article

Abstract: Alterations in tau synaptic distribution are considered to underlie synaptic dysfunction observed in Alzheimer’s disease (AD). In the present study, brain blood hypoperfusion was simulated in mouse brain slices, and tau levels and phosphorylation were investigated in total extracts, as well as in postsynaptic density fractions (PSDs) and non-PSDs obtained through differential extraction and centrifugation. Oxygen deprivation (OD) resulted in tau dephosphorylation at several AD-related residues and activation of GSK3β and phosphatase PP2A. On the contrary, glucose deprivation (GD) did not affect total levels of cellular tau or its phosphorylation despite inactivation of GSK3β. However, tau distribution in PSD and …non-PSD fractions and the pattern of tau phosphorylation in these compartments is highly complex. In PSDs, tau was increased under GD conditions and decreased under OD conditions. GD resulted in tau dephosphorylation at Ser199, Ser262, and Ser396 while OD resulted in tau hyperphosphorylation at Ser199 and Ser404. In the non-PSD fraction, GD or OD resulted in lower levels of tau, but the phosphorylation status of tau was differentially affected. In GD conditions, tau was found dephosphorylated at Ser199, Thr205, and Ser404 and hyperphosphorylated at Ser262. However, in OD conditions tau was found hyperphosphorylated at Thr205, SerSer356, Ser396, and Ser404. Combined OD and GD resulted in degradation of cellular tau and dephosphorylation of PSD tau at Ser396 and Ser404. These results indicate that oxygen deprivation causes dephosphorylation of tau, while GD and OD differentially affect distribution of total tau and tau phosphorylation variants in neuronal compartments by activating different mechanisms. Show more

Keywords: Alzheimer’s disease, glucose deprivation, oxygen deprivation, postsynaptic density, tau distribution, tau phosphorylation

DOI: 10.3233/JAD-170157

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 593-604, 2017

Authors: Amen, Daniel G. | Trujillo, Manuel | Keator, David | Taylor, Derek V. | Willeumier, Kristen | Meysami, Somayeh | Raji, Cyrus A.

Article Type: Research Article

Abstract: Background: Studies have reported that females have widespread increases in regional cerebral blood flow, but the studies were relatively small and inconsistent. Objective: Here we analyzed a healthy and a very large clinical psychiatric population to determine the effect of gender, using single photon emission computed tomography (SPECT). Methods: Whole brain and region of interest (ROI) gender differences were analyzed in a total of 46,034 SPECT scans at baseline and concentration. The sample included 119 healthy subjects and 26,683 patients (60.4% male, 39.6% female); a subset of 11,587 patients had complete diagnostic information. A total of …128 regions were analyzed according to the AAL Atlas, using ROI Extract and SPSS statistical software programs, controlling for age, diagnoses, and correcting for multiple comparisons. Results: Compared to males, healthy females showed significant whole brain (p  < 0.01) and ROI increases in 65 baseline and 48 concentration regions (p  < 0.01 corrected). Healthy males showed non-significant increases in 9 and 22 regions, respectively. In the clinical group, there were widespread significant increases in females, especially in the prefrontal and limbic regions, and specific increases in males in the inferior occipital lobes, inferior temporal lobes, and lobule 7 and Crus 2 of the cerebellum. These findings were replicated in the subset of 11,587 patients with the effect of diagnoses removed. Conclusions: Our results demonstrated significant gender differences in a healthy and clinical population. Understanding these differences is crucial in evaluating functional neuroimaging and may be useful in understanding the epidemiological gender differences among psychiatric disorders. Show more

Keywords: Brain, gender, regions of interest, SPECT

DOI: 10.3233/JAD-170432

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 605-614, 2017

Authors: Pantoni, Leonardo | Poggesi, Anna | Diciotti, Stefano | Valenti, Raffaella | Orsolini, Stefano | Della Rocca, Eleonora | Inzitari, Domenico | Mascalchi, Mario | Salvadori, Emilia

Article Type: Research Article

Abstract: Background and Objective: Mild cognitive impairment (MCI) patients with small vessel disease (SVD) are at high dementia risk. We tested the effects of cognitive rehabilitation in these patients using the Attention Process Training-II (APT-II) program in a single-blinded, randomized clinical trial. Methods: Patients were randomized to APT-II or standard care and evaluated at baseline, 6, and 12 months with functional, quality of life, cognitive tests, and resting state functional MRI (rsfMRI). Results: Forty-six patients were enrolled and 43 (mean±SD age 75.1±6.8) completed the study. No change was seen in functionality and quality of life between treated …and non-treated patients. However, the Rey Auditory-Verbal Learning Test immediate recall showed a significant improvement in treated compared to non-treated group (change score 6 versus 12 months: 1.8±4.9 and –1.4±3.8, p  = 0.021; baseline versus 12 months: 3.8±6.1 and 0.2±4.4, p  = 0.032). A higher proportion of treated patients had stable/better evaluation compared to non-treated group on Visual search test (6 versus 12 months: 95% versus 71%, p  = 0.038) and Rey–Osterrieth Complex Figure copy (6 versus 12 months: 95% versus 67%, p  = 0.027). RsfMRI, performed in a subsample, showed that the difference between follow-up and baseline in synchronization of activity in cerebellar areas was significantly greater in treated than in non-treated patients. Conclusion: We were unable to show a significant effect in quality of life or functional status in treated patients with MCI and SVD. However, APT-II produces some beneficial effects in focused attention and working memory and seems to increase activity in brain circuits involved in cognitive processes. Show more

Keywords: Cerebrovascular disorders, clinical trial, cognitive dysfunction, functional magnetic resonance imaging, rehabilitation

DOI: 10.3233/JAD-170428

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 615-624, 2017

Authors: Chung, Chih-Ping | Lee, Hsiang-Ying | Lin, Po-Chen | Wang, Pei-Ning

Article Type: Research Article

Abstract: The concept that excess pulsation in cerebral arteries might be involved at the early stage of dementia is based on the results of studies on aorta stiffness. In these studies, aorta stiffness is cross-sectionally associated with cognitive impairment and longitudinally related to cognitive decline in non-demented subjects. However, a direct measure of cerebral artery pulsatility is absent in the literature. We aimed to investigate the associations between cerebral artery pulsatility and (1) different cognitive-domains and (2) conversion to dementia in non-demented individuals at the prodromal-stage of Alzheimer’s disease (AD). Non-demented individuals with subjective memory decline or mild cognitive impairment were …included. Neuropsychological tests at baseline and cognitive status at 6 years were evaluated. Cerebral pulsatility was assessed in the middle cerebral artery (MCA) and posterior cerebral artery by transcranial color-coded sonography. Multivariate-analyses of 79 subjects with robust acoustic windows showed that increased pulsatility in cerebral arteries was significantly associated with impairment in corresponding cognitive domains. Analyses in 54 subjects who completed 6-year follow up revealed that high left MCA pulsation (pulsatility index≥1.1) independently predicted conversion to AD with an odds-ratio of 11.2. Our results demonstrate the spatio-temporal relationship between increased cerebral artery pulsation and cognitive impairment and suggest that increased cerebrovascular pulsation might be involved in the early pathogenesis of AD. Cerebrovascular pulsation may be a therapeutic target to prevent/delay AD onset. Future studies with other AD biomarkers and animal/cell models of increased vascular-pulsation are needed to elucidate the mechanisms by which cerebrovascular pulsatile injury initiates or precipitates neurodegeneration in AD. Show more

Keywords: Alzheimer’s disease, cerebral artery, cognitive function, pulsatility index

DOI: 10.3233/JAD-170349

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 625-632, 2017

Authors: Cid-Fernández, Susana | Lindín, Mónica | Díaz, Fernando

Article Type: Research Article

Abstract: Early identification of amnestic mild cognitive impairment (aMCI) subtypes is important for early diagnosis and prognosis of Alzheimer’s disease. Healthy, single-domain (sdaMCI) and multiple-domain aMCI (mdaMCI) participants performed an auditory-visual distraction-attention task. Event-related brain potentials (ERPs) were recorded while the participants performed the task to evaluate Go/NoGo N2 and P3 ERP components. The results showed the expected behavioral and cognitive decline in mdaMCI participants relative to controls (fewer hits, longer reaction times [RTs], slightly smaller Go-N2 and NoGo-N2 amplitudes), while sdaMCI participants showed some decline (slightly longer RTs, smaller Go- and NoGo-N2 amplitudes) along with some unexpected results (a late …positive slow wave, PSW) and good levels of execution. In addition, some of these parameters proved to be useful markers. Thus, the number of hits was the best marker for diagnosing mdaMCI participants (distinguishing them from controls, from sdaMCI participants, and from both groups together), while the PSW amplitude was the best marker for diagnosing sdaMCI participants (distinguishing them from controls, and from control & mdaMCI participants). Show more

Keywords: Biomarkers, electroencephalogram, event-related potentials, mild cognitive impairment, slow wave

DOI: 10.3233/JAD-170369

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 633-649, 2017

Authors: Antón-Fernández, Alejandro | Merchán-Rubira, Jesús | Avila, Jesús | Hernández, Félix | DeFelipe, Javier | Muñoz, Alberto

Article Type: Research Article

Abstract: The Golgi apparatus (GA) is a highly dynamic organelle involved in the processing and sorting of cellular proteins. In Alzheimer’s disease (AD), it has been shown to decrease in size and become fragmented in neocortical and hippocampal neuronal subpopulations. This fragmentation and decrease in size of the GA in AD has been related to the accumulation of hyperphosphorylated tau. However, the involvement of other pathological factors associated with the course of the disease, such as the extracellular accumulation of amyloid-β (Aβ) aggregates, cannot be ruled out, since both pathologies are present in AD patients. Here we use the P301S tauopathy …mouse model to examine possible alterations of the GA in neurons that overexpress human tau (P301S mutated gene) in neocortical and hippocampal neurons, using double immunofluorescence techniques and confocal microscopy. Quantitative analysis revealed that neurofibrillary tangle (NFT)-bearing neurons had important morphological alterations and reductions in the surface area and volume of the GA compared with NFT-free neurons. Since in this mouse model there are no Aβ aggregates typical of AD, the present findings support the idea that the progressive accumulation of phospho-tau is associated with structural alterations of the GA, and that these changes may occur in the absence of Aβ pathology. Show more

Keywords: Golgi apparatus, hippocampus, neocortex, neurofibrillary tangles, tauopathies

DOI: 10.3233/JAD-170332

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 651-661, 2017

Authors: Pongan, Elodie | Tillmann, Barbara | Leveque, Yohana | Trombert, Béatrice | Getenet, Jean Claude | Auguste, Nicolas | Dauphinot, Virginie | El Haouari, Hanane | Navez, Malou | Dorey, Jean-Michel | Krolak-Salmon, Pierre | The LACMé Group | Laurent, Bernard | Rouch, Isabelle

Collaborators: Auguste, Nicolas | Bachelet, Romain | Brunon, Laurence | Dayot, Jenny | Dorey, Jean-Michel | El Haouari, Hanane | Fatisson, Marion | Ferrer, Marion | Gaillat, Charlotte | Gentil, Claire | Getenet, Jean Claude | Goldet, Karine | Krolak-Salmon, Pierre | Laurent, Bernard | Leroyer, Marie | Leveque, Yohana | Michon, Agnès | Mortreux, Angélique | Navez, Malou | Neagu, Anca | Perrot, Catherine | Pongan, Elodie | Rouch, Isabelle | Solimeo, Mathilde | Tillmann, Barbara | Touzet du Vigier, Anaïs | Vulliez, Elodie

Article Type: Research Article

Abstract: Background: Among non-pharmacological therapies, musical intervention is often used for patients with Alzheimer’s disease (AD) and patients presenting chronic pain. However, their efficacy is still under debate. Objective: Our aim was to determine the efficacy of choral singing versus painting sessions on chronic pain, mood, quality of life, and cognition in AD patients. Methods: In this multicenter randomized controlled trial, 59 mild AD patients were randomized to a 12-week singing (SG; n  = 31) or painting group (PG; n  = 28). Chronic pain, anxiety, depression, and quality of life were assessed before, after, and 1 month after the …sessions. Cognitive abilities were assessed before and after interventions. The evolution of these different measures was assessed with mixed linear models. The primary data analysis was by intention-to-treat, and completed by a ‘per protocol’ approach. Results: Both singing and painting interventions led to significant pain reduction (Time effect: F = 4.71; p  = 0.01), reduced anxiety (Time effect: F = 10.74; p  < 0.0001), improved Quality of Life (Time effect: F = 6.79; p  = 0.002), improved digit span (F = 12.93; p  = 0.001), and inhibitory processes (Time effect: F = 4.93; p  = 0.03). Depression was reduced over time in PG only (Time x Group effect: F = 4.53; p  = 0.01). Verbal Memory performance remained stable over time in SG, but decreased in PG (Time x group effect: F = 9.29; p  = 0.004). Conclusion: Findings suggest that singing and painting interventions may reduce pain and improve mood, quality of life, and cognition in patients with mild AD, with differential effects of painting for depression and singing for memory performance. Show more

Keywords: Alzheimer’s disease, anxiety, cognitive impairment, depression, music, pain

DOI: 10.3233/JAD-170410

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 663-677, 2017

Authors: Tao, Wuhai | Li, Xin | Zhang, Junying | Chen, Yaojing | Ma, Chao | Liu, Zhen | Yang, Caishui | Wang, Wenxiao | Chen, Kewei | Wang, Jun | Zhang, Zhanjun

Article Type: Research Article

Abstract: The alteration of the default mode network (DMN) functional connectivity (FC) has been reported in patients with amnestic mild cognitive impairment (aMCI) as a predictor of Alzheimer’s disease (AD). However, no studies exist that examined stage-dependent DMN FC changes throughout the course of aMCI. The present study aims to characterize patterns of DMN FC over three aMCI stages as first defined. Utilizing the extreme groups approach on the performance of memory tasks, aMCI subjects were divided into mild, moderate, and severe stages. Independent component analysis was used to assess DMN for individual patients in each of the three cross-sectionally defined …stages. Instead of finding that continued monotonic decline was the case for the hippocampus volume, which we also investigated in this study, we observed an increase in DMN functional connectivity from mild aMCI to moderate aMCI and a decrease to severe aMCI, mainly in the left precuneus and superior parietal lobe. Moreover, the FC was significantly associated with cognitive performance. Though a longitudinal study is needed to confirm these results, our cross-sectional finding is that non-linear FC changes in DMN could be a characteristic of prodromal early disease development. Show more

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, default mode network, functional connectivity, non-monotomic trajectory

DOI: 10.3233/JAD-170252

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 679-690, 2017

Authors: Larsson, Susanna C. | Traylor, Matthew | Burgess, Stephen | Markus, Hugh S.

Article Type: Research Article

Abstract: Background: Observational studies have linked increased adult height with better cognitive performance and reduced risk of Alzheimer’s disease (AD). It is unclear whether the associations are due to shared biological processes that influence height and AD or due to confounding by early life exposures or environmental factors. Objective: To use a genetic approach to investigate the association between adult height and AD. Methods: We selected 682 single nucleotide polymorphisms (SNPs) associated with height at genome-wide significance (p  < 5×10–8 ) in the Genetic Investigation of ANthropometric Traits (GIANT) consortium. Summary statistics for each of these SNPs on …AD were obtained from the International Genomics of Alzheimer’s Project (IGAP) of 17,008 individuals with AD and 37,154 controls. The estimate of the association between genetically predicted height and AD was calculated using the inverse-variance weighted method. Results: The odds ratio of AD was 0.91 (95% confidence interval, 0.86–0.95; p  = 9.8×10–5 ) per one standard deviation increase (about 6.5 cm) in genetically predicted height based on 682 SNPs, which were clustered in 419 loci. In an analysis restricted to one SNP from each height-associated locus (n  = 419 SNPs), the corresponding OR was 0.92 (95% confidence interval, 0.86–0.97; p  = 4.8×10–3 ). Conclusions: This finding suggests that biological processes that influence adult height may have a role in the etiology of AD. Show more

Keywords: Alzheimer’s disease, anthropometry, genetics, polymorphism, single nucleotide

DOI: 10.3233/JAD-170528

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 691-698, 2017

Authors: Kueider, Alexandra M. | An, Yang | Tanaka, Toshiko | Kitner-Triolo, Melissa H. | Studenski, Stephanie | Ferrucci, Luigi | Thambisetty, Madhav

Article Type: Research Article

Abstract: Serum uric acid (SUA) is an abundant natural antioxidant capable of reducing cellular oxidation, a major cause of neurodegenerative disease. In line with this, SUA levels are lower in Alzheimer’s disease; however, the association between SUA and cognition remains unclear. Results from studies examining the effects of SUA on cognition may be difficult to interpret in the context of normal versus pathological aging. This study examined sex-specific associations of baseline SUA with cognition during aging. Data from dementia-free participants initially aged 26–99 (N  = 1,451) recruited for the Baltimore Longitudinal Study of Aging (BLSA), were used in the current analyses. SUA …was assessed using blood samples collected during research visits. Cognition was measured using five composite scores (verbal memory, attention, executive function, language, and visuospatial ability). At the first study visit, compared with women, men were older, more likely to be White, had more years of education, higher baseline SUA levels, and higher cardiovascular risk scores. Higher baseline SUA was associated with attenuated declines in attention (β= 0.006; p  = 0.03) and visuospatial abilities (β= 0.007; p  = 0.01) in men. There was a trend to suggest higher baseline SUA in men was associated with attenuated declines in language, but this finding did not reach statistical significance (p  = 0.09). There were no significant findings with SUA and cognition in women. In this sample of cognitively healthy, community-dwelling adults, we found that higher SUA levels at baseline were associated with attenuated declines in attention and visuospatial abilities in men. SUA was not associated with cognition or change in cognition over time in women. Show more

Keywords: Aging, cognitive function, older adults, uric acid

DOI: 10.3233/JAD-170287

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 699-706, 2017

Authors: Weissberger, Gali H. | Melrose, Rebecca J. | Fanale, Candace M. | Veliz, Joseph V. | Sultzer, David L.

Article Type: Research Article

Abstract: Orientation to time, date, and place is commonly utilized in clinical settings to aid in diagnosis, staging, and monitoring of Alzheimer’s disease (AD). This study aimed to identify the cerebral metabolic correlates of orientation in patients with AD, and the degree to which regions associated with orientation overlap with memory-related structures. Eighty-five patients with a diagnosis of probable AD underwent fluorodeoxyglucose positron emission tomography (FDG-PET) and neuropsychological testing. Orientation items from the Dementia Rating Scale and recognition performance from the Consortium to Establish a Registry for AD (CERAD) Word List Learning test were correlated with cerebral glucose metabolism. Post-hoc …analyses examined neuropsychological predictors of orientation. Better orientation performance related to greater cerebral metabolism in the bilateral middle-inferior temporal lobes, bilateral middle-posterior cingulate, left angular gyrus, and left middle occipital gyrus. In comparison, higher CERAD recognition discriminability score was associated with greater metabolic activity in left medial temporal lobe regions including the hippocampal and parahippocampal gyri, and the left fusiform gyrus. Post-hoc behavioral analyses revealed multiple cognitive functions to be related to orientation, including list learning, recognition memory, visuospatial functioning, attention, and language. Findings from the present study suggest that disorientation in AD results from dysfunction of a network of structures and cognitive abilities commonly found to be implicated in AD. The study supports the notion that memory is necessary but not sufficient for successful orientation. Show more

Keywords: Alzheimer’s disease, fluorodeoxyglucose F18, memory, neuropsychology, orientation

DOI: 10.3233/JAD-170420

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 707-719, 2017

Authors: Karki, Reagon | Kodamullil, Alpha Tom | Hofmann-Apitius, Martin

Article Type: Research Article

Abstract: Background: Various studies suggest a comorbid association between Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM) indicating that there could be shared underlying pathophysiological mechanisms. Objective: This study aims to systematically model relevant knowledge at the molecular level to find a mechanistic rationale explaining the existing comorbid association between AD and T2DM. Method: We have used a knowledge-based modeling approach to build two network models for AD and T2DM using Biological Expression Language (BEL), which is capable of capturing and representing causal and correlative relationships at both molecular and clinical levels from various knowledge resources. …Results: Using comparative analysis, we have identified several putative “shared pathways”. We demonstrate, at a mechanistic level, how the insulin signaling pathway is related to other significant AD pathways such as the neurotrophin signaling pathway, PI3K/AKT signaling, MTOR signaling, and MAPK signaling and how these pathways do cross-talk with each other both in AD and T2DM. In addition, we present a mechanistic hypothesis that explains both favorable and adverse effects of the anti-diabetic drug metformin in AD. Conclusion: The two computable models introduced here provide a powerful framework to identify plausible mechanistic links shared between AD and T2DM and thereby identify targeted pathways for new therapeutics. Our approach can also be used to provide mechanistic answers to the question of why some T2DM treatments seem to increase the risk of AD. Show more

Keywords: Alzheimer’s disease, comorbidity, disease mechanisms, disease modeling, metformin, OpenBEL, type 2 diabetes mellitus

DOI: 10.3233/JAD-170440

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 721-731, 2017

Authors: Zhang, Li | Sun, Caixian | Jin, Yaxi | Gao, Kai | Shi, Xudong | Qiu, Wenying | Ma, Chao | Zhang, Lianfeng

Article Type: Research Article

Abstract: Dysfunctional Wnt signaling is associated with Alzheimer’s disease (AD), and activation of the Wnt signaling pathway inhibits AD development. Dickkopf 3 (Dkk3) is a modulator of the Wnt signaling pathway and is physiologically expressed in the brain. The role of Dkk3 in the pathogenesis of AD has not been evaluated. In the present study, we determined that Dkk3 expression was significantly decreased in brain tissue from AD patients and the AD transgenic mouse model APPswe/PS1dE9 (AD mice). Transgenic mice with brain tissue-specific Dkk3 expression were generated or crossed with AD mice to study the effects of Dkk3 on AD. In …AD mice, transgenic expression of Dkk3 improved abnormalities in learning, memory, and locomotor activity, reduced the accumulation of amyloid-β, and ameliorated glucose uptake deficits. Furthermore, we determined that Dkk3 downregulated GSK-3β, a central negative regulator in canonical Wnt signaling, and upregulated PKCβ1, a factor implicated in noncanonical Wnt signaling. This indicates that increased activation of GSK-3β and the inhibition of PKCβ1 in AD patients may be responsible for the dysfunctional Wnt signaling in AD. In summary, our data suggest that Dkk3 is an agonist of Wnt signaling, and the ability of transgenic expression of Dkk3 to compensate for the decrease in Dkk3 expression in AD mice, reverse dysfunctional Wnt signaling, and partially inhibit the pathological development of AD suggests that Dkk3 could serve as a therapeutic target for the treatment of AD. Show more

Keywords: Alzheimer’s disease, cognition, Dkk3, transgenic mice, Wnt signaling pathway

DOI: 10.3233/JAD-161254

Citation: Journal of Alzheimer's Disease, vol. 60, no. 2, pp. 733-746, 2017