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