Journal of Alzheimer's Disease - Volume 64, issue 1

Authors: Llorente-Ovejero, Alberto | Manuel, Iván | Lombardero, Laura | Giralt, Maria Teresa | Ledent, Catherine | Giménez-Llort, Lydia | Rodríguez-Puertas, Rafael

Article Type: Research Article

Abstract: The endocannabinoid system, which modulates emotional learning and memory through CB1 receptors, has been found to be deregulated in Alzheimer’s disease (AD). AD is characterized by a progressive decline in memory associated with selective impairment of cholinergic neurotransmission. The functional interplay of endocannabinoid and muscarinic signaling was analyzed in seven-month-old 3xTg-AD mice following the evaluation of learning and memory of an aversive stimulus. Neurochemical correlates were simultaneously studied with both receptor and functional autoradiography for CB1 and muscarinic receptors, and regulations at the cellular level were depicted by immunofluorescence. 3xTg-AD mice exhibited increased acquisition latencies and impaired memory …retention compared to age-matched non-transgenic mice. Neurochemical analyses showed changes in CB1 receptor density and functional coupling of CB1 and muscarinic receptors to Gi/o proteins in several brain areas, highlighting that observed in the basolateral amygdala. The subchronic (seven days) stimulation of the endocannabinoid system following repeated WIN55,212-2 (1 mg/kg) or JZL184 (8 mg/kg) administration induced a CB1 receptor downregulation and CB1 -mediated signaling desensitization, normalizing acquisition latencies to control levels. However, the observed modulation of cholinergic neurotransmission in limbic areas did not modify learning and memory outcomes. A CB1 receptor-mediated decrease of GABAergic tone in the basolateral amygdala may be controlling the limbic component of learning and memory in 3xTg-AD mice. CB1 receptor desensitization may be a plausible strategy to improve behavior alterations associated with genetic risk factors for developing AD. Show more

Keywords: 3xTg-AD, Alzheimer’s disease, autoradiography, basolateral amygdala, cholinergic, endocannabinoid, learning and memory

DOI: 10.3233/JAD-180137

Citation: Journal of Alzheimer's Disease, vol. 64, no. 1, pp. 117-136, 2018

Authors: Akushevich, Igor | Yashkin, Arseniy P. | Kravchenko, Julia | Ukraintseva, Svetlana | Stallard, Eric | Yashin, Anatoliy I.

Article Type: Research Article

Abstract: Background: Trends in the prevalence of cognitive impairment (CI) based on cognitive assessment instruments are often inconsistent with those of neurocognitive disorders (ND) based on Medicare claims records. Objective: We hypothesized that improved ascertainment and resulting decrease in disease severity at the time of diagnosis are responsible for this phenomenon. Methods: Using Medicare data linked to the Health and Retirement Study (1992–2012), we performed a joint analysis of trends in CI and ND to test our hypothesis. Results: We identified two major contributors to the divergent directions in CI and ND trends: reductions in …disease severity explained more than 60% of the differences between CI and ND prevalence over the study period; the remaining 40% was explained by a decrease in the fraction of undiagnosed individuals. Discussion: Improvements in the diagnoses of ND diseases were a major contributor to reported trends in ND and CI. Recent forecasts of CI and ND trends in the U.S. may be overly pessimistic. Show more

Keywords: Alzheimer’s disease, Ascertainment, cognitive impairment, disease prevalence, Health and Retirement Study (HRS), Medicare, neurocognitive disorders, severity, Telephone Interview for Cognitive Status (TICS), time trends, underdiagnosis

DOI: 10.3233/JAD-180060

Citation: Journal of Alzheimer's Disease, vol. 64, no. 1, pp. 137-148, 2018

Authors: Wang, Qi | Guo, Lei | Thompson, Paul M. | Jack Jr., Clifford R. | Dodge, Hiroko | Zhan, Liang | Zhou, Jiayu | for the Alzheimer’s Disease Neuroimaging Initiative and National Alzheimer’s Coordinating Center

Article Type: Research Article

Abstract: T1-weighted MRI has been extensively used to extract imaging biomarkers and build classification models for differentiating Alzheimer’s disease (AD) patients from healthy controls, but only recently have brain connectome networks derived from diffusion-weighted MRI been used to model AD progression and various stages of disease such as mild cognitive impairment (MCI). MCI, as a possible prodromal stage of AD, has gained intense interest recently, since it may be used to assess risk factors for AD. Little work has been done to combine information from both white matter and gray matter, and it is unknown how much classification power the diffusion-weighted …MRI-derived structural connectome could provide beyond information available from T1-weighted MRI. In this paper, we focused on investigating whether diffusion-weighted MRI-derived structural connectome can improve differentiating healthy controls subjects from those with MCI. Specifically, we proposed a novel feature-ranking method to build classification models using the most highly ranked feature variables to classify MCI with healthy controls. We verified our method on two independent cohorts including the second stage of Alzheimer’s Disease Neuroimaging Initiative (ADNI2) database and the National Alzheimer’s Coordinating Center (NACC) database. Our results indicated that 1) diffusion-weighted MRI-derived structural connectome can complement T1-weighted MRI in the classification task; 2) the feature-rank method is effective because of the identified consistent T1-weighted MRI and network feature variables on ADNI2 and NACC. Furthermore, by comparing the top-ranked feature variables from ADNI2, NACC, and combined dataset, we concluded that cross-validation using independent cohorts is necessary and highly recommended. Show more

Keywords: Alzheimer’s disease, brain network, diffusion MRI, feature extraction, mild cognitive impairment, multiple cohorts

DOI: 10.3233/JAD-171048

Citation: Journal of Alzheimer's Disease, vol. 64, no. 1, pp. 149-169, 2018

Authors: Leinonen, Ville | Rauramaa, Tuomas | Johansson, Jarkko | Bottelbergs, Astrid | Tesseur, Ina | van der Ark, Peter | Pemberton, Darrel | Koivisto, Anne M. | Jääskeläinen, Juha E. | Hiltunen, Mikko | Herukka, Sanna-Kaisa | Blennow, Kaj | Zetterberg, Henrik | Jokinen, Pekka | Rokka, Johanna | Helin, Semi | Haaparanta-Solin, Merja | Solin, Olof | Okamura, Nobuyuki | Kolb, Hartmuth C. | Rinne, Juha O.

Article Type: Research Article

Abstract: Background: Detection of pathological tau aggregates could facilitate clinical diagnosis of Alzheimer’s disease (AD) and monitor drug effects in clinical trials. S -[18 F]THK-5117 could be a potential tracer to detect pathological tau deposits in brain. However, no previous study have correlated S -[18 F]THK-5117 uptake in PET with brain biopsy verified tau pathology in vivo . Objective: Here we aim to evaluate the association between cerebrospinal fluid (CSF) AD biomarkers, S -[18 F]THK-5117, and [11 C]PIB PET against tau and amyloid lesions in brain biopsy. Methods: Fourteen patients with idiopathic normal pressure hydrocephalus (iNPH) with …previous shunt surgery including right frontal cortical brain biopsy and CSF Aβ1 - 42 , total tau, and P-tau181 measures, underwent brain MRI, [11 C]PIB PET, and S -[18 F]THK-5117 PET imaging. Results: Seven patients had amyloid-β (Aβ, 4G8) plaques, two both Aβ and phosphorylated tau (Pτ , AT8) and one only Pτ in biopsy. As expected, increased brain biopsy Aβ was well associated with higher [11 C]PIB uptake in PET. However, S -[18 F]THK-5117 uptake did not show any statistically significant correlation with either brain biopsy Pτ or CSF P-tau181 or total tau. Conclusions: S -[18 F]THK-5117 lacked clear association with neuropathologically verified tau pathology in brain biopsy probably, at least partially, due to off-target binding. Further studies with larger samples of patients with different tau tracers are urgently needed. The detection of simultaneous Aβ and tau pathology in iNPH is important since that may indicate poorer and especially shorter response for CSF shunt surgery compared with no pathology. Show more

Keywords: Alzheimer’s disease, amyloid-beta, idiopathic normal pressure hydrocephalus, neuropathology, PIB, positron emission tomography, PTHK-5117, tau, contstartabstract

DOI: 10.3233/JAD-180071

Citation: Journal of Alzheimer's Disease, vol. 64, no. 1, pp. 171-179, 2018

Authors: Kuźma, Elżbieta | Hannon, Eilis | Zhou, Ang | Lourida, Ilianna | Bethel, Alison | Levine, Deborah A. | Lunnon, Katie | Thompson-Coon, Jo | Hyppönen, Elina | Llewellyn, David J.

Article Type: Research Article

Abstract: Background: Numerous risk factors for dementia are well established, though the causal nature of these associations remains unclear. Objective: To systematically review Mendelian randomization (MR) studies investigating causal relationships between risk factors and global cognitive function or dementia. Methods: We searched five databases from inception to February 2017 and conducted citation searches including MR studies investigating the association between any risk factor and global cognitive function, all-cause dementia or dementia subtypes. Two reviewers independently assessed titles and abstracts, full-texts, and study quality. Results: We included 18 MR studies investigating education, lifestyle factors, cardiovascular factors …and related biomarkers, diabetes related and other endocrine factors, and telomere length. Studies were of predominantly good quality, however eight received low ratings for sample size and statistical power. The most convincing causal evidence was found for an association of shorter telomeres with increased risk of Alzheimer’s disease (AD). Causal evidence was weaker for smoking quantity, vitamin D, homocysteine, systolic blood pressure, fasting glucose, insulin sensitivity, and high-density lipoprotein cholesterol. Well-replicated associations were not present for most exposures and we cannot fully discount survival and diagnostic bias, or the potential for pleiotropic effects. Conclusions: Genetic evidence supported a causal association between telomere length and AD, whereas limited evidence for other risk factors was largely inconclusive with tentative evidence for smoking quantity, vitamin D, homocysteine, and selected metabolic markers. The lack of stronger evidence for other risk factors may reflect insufficient statistical power. Larger well-designed MR studies would therefore help establish the causal status of these dementia risk factors. Show more

Keywords: Alzheimer’s disease, cognition, dementia, instrumental variable, Mendelian randomization, risk factor

DOI: 10.3233/JAD-180013

Citation: Journal of Alzheimer's Disease, vol. 64, no. 1, pp. 181-193, 2018

Authors: Thomas, Kelsey R. | Edmonds, Emily C. | Eppig, Joel | Salmon, David P. | Bondi, Mark W. | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: We previously operationally-defined subtle cognitive decline (SCD) in preclinical Alzheimer’s disease (AD) using total scores on neuropsychological (NP) tests. NP process scores (i.e., provide information about how a total NP score was achieved) may be a useful tool for identifying early cognitive inefficiencies prior to objective impairment seen in mild cognitive impairment (MCI) and dementia. Objective: We aimed to integrate process scores into the SCD definition to identify stages of SCD and improve early detection of those at risk for decline. Methods: Cognitively “normal” participants from the Alzheimer’s Disease Neuroimaging Initiative were classified as …“early” SCD (E-SCD; >1 SD below norm-adjusted mean on 2 process scores or on 1 process score plus 1 NP total score), “late” SCD (L-SCD; existing SCD criteria of >1 SD below norm-adjusted mean on 2 NP total scores in different domains), or “no SCD” (NC). Process scores considered in the SCD criteria were word-list intrusion errors, retroactive interference, and learning slope. Cerebrospinal fluid AD biomarkers were used to examine pathologic burden across groups. Results: E-SCD and L-SCD progressed to MCI 2.5–3.4 times faster than the NC group. Survival curves for E-SCD and L-SCD converged at 7-8 years after baseline. The combined (E-SCD+L-SCD) group had improved sensitivity to detect progression to MCI relative to L-SCD only. AD biomarker positivity increased across NC, SCD, and MCI groups. Conclusions: Process scores can be integrated into the SCD criteria to allow for increased sensitivity and earlier identification of cognitively normal older adults at risk for decline prior to frank impairment on NP total scores. Show more

Keywords: Alzheimer’s disease, dementia, early detection, mild cognitive impairment, neuropsychology, subtle cognitive decline

DOI: 10.3233/JAD-180229

Citation: Journal of Alzheimer's Disease, vol. 64, no. 1, pp. 195-204, 2018

Authors: Li, Chuanzhou | Götz, Jürgen

Article Type: Research Article

Abstract: The protein tyrosine kinase Pyk2 is encoded by PTK2B , a novel Alzheimer’s disease (AD) susceptibility variant, with the PTK2B risk allele being associated with increased mRNA levels, suggestive of increased Pyk2 levels. However, the role of Pyk2, a member of the focal adhesion kinase (FAK) family, in AD pathology and its regulation are largely unknown. To address this, we generated mice with neuronal expression of human Pyk2. Because we had previously reported an association of Pyk2 and hyperphosphorylated tau (a hallmark feature of AD) in human tau transgenic pR5 mice, we also generated Pyk2/tau double-transgenic mice, which exhibit …increased tyrosine phosphorylation and accumulation of tau. We further demonstrated that Pyk2 colocalizes, interacts with, and phosphorylates tau in vivo and in vitro . Importantly, although Pyk2 interacts with the established tyrosine-directed tau kinase Fyn, we identified an increased Pyk2 activity in mice which constitutively overexpress Fyn (FynCA), and a decreased activity in mice lacking Fyn (FynKO). Together, our study reveals a novel role for Pyk2 as a direct tyrosine kinase of tau that is active downstream of Fyn. Our analysis may enhance the understanding of how the PTK2B risk allele contributes to tauopathy. Show more

Keywords: Alzheimer’s disease, Fyn, Pyk2, tau, tau phosphorylation, tyrosine kinase

DOI: 10.3233/JAD-180054

Citation: Journal of Alzheimer's Disease, vol. 64, no. 1, pp. 205-221, 2018

Authors: Hoffman, Alexander | Taleski, Goce | Qian, Helena | Wasek, Brandi | Arning, Erland | Bottiglieri, Teodoro | Sontag, Jean-Marie | Sontag, Estelle

Article Type: Research Article

Abstract: Deregulation of the amyloid-β protein precursor (AβPP) plays a critical role in the neurodegenerative cascade of Alzheimer’s disease (AD). Significantly, common functional polymorphisms in the 5,10-methylenetetrahydrofolate reductase (MTHFR ) gene are a risk factor for the development of late-onset AD. Reduced MTHFR activity is associated with alterations in folate and homocysteine metabolism. Here, we first show that in young MTHFR knockout mice, mild and severe MTHFR deficiency markedly increase cortical and hippocampal AβPP phosphorylation at the regulatory Thr668 site. However, the hippocampus is especially vulnerable to the effects of aging and mild MTHFR deficiency. Notably, the effects of severe …MTHFR deficiency in young mice are recapitulated by prolonged dietary folate deficiency in old mice, which leads to regional brain accumulation of cystathionine due to impaired methylation of homocysteine. The incremental AβPP phosphorylation at Thr668 mediated by severe genetic-or diet-induced impairment of the folate cycle correlates with enhanced accumulation of demethylated protein phosphatase 2A (PP2A), and activation of glycogen synthase kinase-3β (GSK-3β). Lastly, we show that severe disturbances in folate metabolism can also affect AβPP expression levels in a brain region specific manner. Together our findings identify a novel link between genetic MTHFR deficiency, activation of GSK-3β, demethylation of PP2A, and enhanced phosphorylation of AβPP at Thr668, which is known to critically influence neuronal AβPP function and pathological amyloidogenic processing. Deregulation of AβPP provides a novel mechanism by which common human MTHFR polymorphisms may interact with dietary folate deficiency to alter neuronal homeostasis and increase the risk for sporadic AD. Show more

Keywords: Alzheimer’s disease, amyloid-β protein precursor, cystathionine, folate, glycogen synthase kinase 3β, methylation, MTHFR, phosphorylation, protein phosphatase 2A

DOI: 10.3233/JAD-180032

Citation: Journal of Alzheimer's Disease, vol. 64, no. 1, pp. 223-237, 2018

Authors: Lysen, Thom S. | Wolters, Frank J. | Luik, Annemarie I. | Ikram, M. Kamran | Tiemeier, Henning | Ikram, M. Arfan

Article Type: Research Article

Abstract: Background: Poor sleep is related to higher dementia risk, but this association is more equivocal for subjective sleep quality specifically. This study investigates the link between subjective sleep quality and dementia risk in the general population. Objective: To study the role of subjective sleep quality in the risk of dementia in the general population. Methods: In the prospective population-based Rotterdam Study, 4,835 persons (mean age 72 years, 58% women) underwent a home interview (2002– 2006) that included the validated Pittsburgh Sleep Quality Index (PSQI) to assess sleep quality. Participants were followed until 2015 for incident dementia, …through in-person screening and continuous monitoring of medical records. We used Cox regression models to associate sleep quality with dementia risk, adjusting for age, sex, education, smoking, employment, coffee consumption, alcohol consumption, activities of daily living, cardiovascular risk factors, anxiety, depressive symptoms, cognition, and snoring. Results: During 41,385 person-years (8.5 years mean), 420 participants developed dementia, of whom 320 Alzheimer’s disease (AD). Poorer subjective sleep quality was not associated with the risk of all-cause dementia (hazard ratio [HR] per SD increase in PSQI score: 0.91, 95% CI 0.82– 1.02) or AD (HR 0.92, 95% CI 0.81– 1.05). Similarly, individual components of the PSQI were also not associated with dementia. Several sensitivity analyses, i.e., excluding last years of the follow-up time duration or restricting to those with best MMSE scores at baseline, did not reveal subgroups with increased risks. Conclusion: In this study, we found no association of poor subjective sleep quality with higher risk of dementia. Show more

Keywords: Alzheimer’s disease, cognition, dementia, epidemiology, sleep

DOI: 10.3233/JAD-180055

Citation: Journal of Alzheimer's Disease, vol. 64, no. 1, pp. 239-247, 2018

Authors: Durani, Lina Wati | Hamezah, Hamizah Shahirah | Ibrahim, Nor Faeizah | Yanagisawa, Daijiro | Nasaruddin, Muhammad Luqman | Mori, Masaki | Azizan, Kamalrul Azlan | Damanhuri, Hanafi Ahmad | Makpol, Suzana | Wan Ngah, Wan Zurinah | Tooyama, Ikuo

Article Type: Research Article

Abstract: We have recently shown that the tocotrienol-rich fraction (TRF) of palm oil, a mixture of vitamin E analogs, improves amyloid pathology in vitro and in vivo . However, precise mechanisms remain unknown. In this study, we examined the effects of long-term (10 months) TRF treatment on behavioral impairments and brain metabolites in (15 months old) AβPP/PS1 double transgenic (Tg) Alzheimer’s disease (AD) mice. The open field test, Morris water maze, and novel object recognition tasks revealed improved exploratory activity, spatial learning, and recognition memory, respectively, in TRF-treated Tg mice. Brain metabolite profiling of wild-type and Tg mice treated with …and without TRF was performed using ultrahigh performance liquid chromatography (UHPLC) coupled to high-resolution accurate mass (HRAM)-orbitrap tandem mass spectrometry (MS/MS). Metabolic pathway analysis found perturbed metabolic pathways that linked to AD. TRF treatment partly ameliorated metabolic perturbations in Tg mouse hippocampus. The mechanism of this pre-emptive activity may occur via modulation of metabolic pathways dependent on Aβ interaction or independent of Aβ interaction. Show more

Keywords: Alzheimer’s disease, behavioral impairments, metabolomics, pre-emptive medicine, tocotrienol

DOI: 10.3233/JAD-170880

Citation: Journal of Alzheimer's Disease, vol. 64, no. 1, pp. 249-267, 2018