Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Lamartinière, Yordenca | Boucau, Marie-Christine | Dehouck, Lucie | Krohn, Markus | Pahnke, Jens | Candela, Pietra | Gosselet, Fabien | Fenart, Laurence

Article Type: Research Article

Abstract: The role of ABCA7 in brain homeostasis and Alzheimer’s disease (AD) is currently under intense scrutiny, since it has been reported that polymorphisms in the Abca7 gene and a loss of function of the protein are closely linked to excessive accumulation of amyloid peptides and disturbed cholesterol homeostasis. The blood-brain barrier (BBB), which isolates the brain from the blood compartment, is involved in both of these processes. We therefore hypothesized that ABCA7 downregulation might affect cholesterol and amyloid exchanges at the BBB. Using siRNA and primary cultures of mouse endothelial cells purified from brain microvessels and seeded on Transwell …® inserts, we investigated the role of ABCA7 in cholesterol and amyloid exchanges across the BBB. Our results showed that a decrease in ABCA7 expression at the BBB provokes in vitro a reduction in ABCA1 and a decrease in APOE secretion. In vitro , these decreases reduce cholesterol exchange across the BBB, particularly for high-density lipoproteins and ApoA-I particles. When ABCA7 was absent, we observed a reduction in Aβ peptide basolateral-to-apical transport in the presence of ApoA-I, with non-significant changes in the expression levels of Rage , Lrp1 , Abcb1 , Abcc1 , and Abcg2 . Our study in murine BBB model highlighted a putative new role for ABCA7 in AD via the protein’s involvement in cholesterol metabolism and amyloid clearance at the BBB. Show more

Keywords: ABCA7, Aβ peptides, Alzheimer’s disease, blood-brain barrier, cholesterol metabolism

DOI: 10.3233/JAD-170883

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 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. Pre-press, no. Pre-press, pp. 1-11, 2018

Authors: Smailagic, Nadja | Lafortune, Louise | Kelly, Sarah | Hyde, Chris | Brayne, Carol

Article Type: Research Article

Abstract: Background: A previous Cochrane systematic review concluded there is insufficient evidence to support the routine use of 18 F-FDG PET in clinical practice in people with mild cognitive impairment (MCI). Objectives: To update the evidence and reassess the accuracy of 18 F-FDG-PET for detecting people with MCI at baseline who would clinically convert to Alzheimer’s disease (AD) dementia at follow-up. Methods: A systematic review including comprehensive search of electronic databases from January 2013 to July 2017, to update original searches (1999 to 2013). All key review steps, including quality assessment using QUADAS 2, were performed independently …and blindly by two review authors. Meta-analysis could not be conducted due to heterogeneity across studies. Results: When all included studies were examined across all semi-quantitative and quantitative metrics, exploratory analysis for conversion of MCI to AD dementia (n = 24) showed highly variable accuracy; half the studies failed to meet four or more of the seven sets of QUADAS 2 criteria. Variable accuracy for all metrics was also found across eleven newly included studies published in the last 5 years (range: sensitivity 56–100%, specificity 24–100%). The most consistently high sensitivity and specificity values (approximately ≥80%) were reported for the sc-SPM (single case statistical parametric mapping) metric in 6 out of 8 studies. Conclusion: Systematic and comprehensive assessment of studies of 18 FDG-PET for prediction of conversion from MCI to AD dementia reveals many studies have methodological limitations according to the Cochrane diagnostic test accuracy gold standards, and shows accuracy remains highly variable, including in the most recent studies. There is some evidence, however, of higher and more consistent accuracy in studies using computer aided metrics, such as sc-SPM, in specialized clinical settings. Robust, methodologically sound prospective longitudinal cohort studies with long (≥5 years) follow-up, larger consecutive samples, and defined baseline threshold(s) are needed to test these promising results. Further evidence of the clinical validity and utility of 18 F-FDG PET in people with MCI is needed. Show more

Keywords: Accuracy, Alzheimer’s disease dementia, conversion, 18F-FDG PET, mild cognitive impairment, test predictive value

DOI: 10.3233/JAD-171125

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2018

Authors: Brendel, Matthias | Sauerbeck, Julia | Greven, Sonja | Kotz, Sebastian | Scheiwein, Franziska | Blautzik, Janusch | Delker, Andreas | Pogarell, Oliver | Ishii, Kazunari | Bartenstein, Peter | Rominger, Axel | and for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Late-life depression, even when of subsyndromal severity, has shown strong associations with mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Preclinical studies have suggested that serotonin selective reuptake inhibitors (SSRIs) can attenuate amyloidogenesis. Therefore, we aimed to investigate the effect of SSRI medication on amyloidosis and grey matter volume in subsyndromal depressed subjects with MCI and AD during an interval of two years. 256 cognitively affected subjects (225 MCI/ 31 AD) undergoing [18 F]-AV45-PET and MRI at baseline and 2-year follow-up were selected from the ADNI database. Subjects with a positive depression item (DEP(+); n = 73) in the …Neuropsychiatric Inventory Questionnaire were subdivided to those receiving SSRI medication (SSRI(+); n = 24) and those without SSRI treatment (SSRI(−); n = 49). Longitudinal cognition (Δ-ADAS), amyloid deposition rate (standardized uptake value, using white matter as reference region (SUVRWM ), and changes in grey matter volume were compared using common covariates. Analyses were performed separately in all subjects and in the subgroup of amyloid-positive subjects. Cognitive performance in DEP(+)/SSRI(+) subjects (Δ-ADAS: –5.0%) showed less deterioration with 2-year follow-up when compared to DEP(+)/SSRI(−) subjects (Δ-ADAS: +18.6%, p < 0.05), independent of amyloid SUVRWM at baseline. With SSRI treatment, the progression of grey matter atrophy was reduced (−0.9% versus –2.7%, p < 0.05), notably in fronto-temporal cortex. A slight trend towards lower amyloid deposition rate was observed in DEP(+)/SSRI(+) subjects versus DEP(+)/SSRI(−). Despite the lack of effect to amyloid PET, SSRI medication distinctly rescued the declining cognitive performance in cognitively affected patients with depressive symptoms, and likewise attenuated grey matter atrophy. Show more

Keywords: Alzheimer’s disease, amyloid PET, depressive symptoms, grey matter volume, SSRI

DOI: 10.3233/JAD-170387

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2018

Authors: Qin, Yiren | Zhang, Yu | Tomic, Inge | Hao, Wenlin | Menger, Michael D. | Liu, Chunfeng | Fassbender, Klaus | Liu, Yang

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disease pathologically characterized by extracellular amyloid-β (Aβ ) deposits and intracellular neurofibrillary tangles (NFT) in many brain regions. NFT are primarily composed of hyperphosphorylated tau protein (p-Tau). Aβ and p-Tau are two major pathogenic molecules with tau acting downstream to Aβ to induce neuronal degeneration. In this study, we investigated whether Ginkgo biloba extract EGb 761 reduces cerebral p-Tau level and prevents AD pathogenesis. Human P301S tau mutant-transgenic mice were fed with EGb 761, added to the regular diet for 2 or 5 months. We observed that treatment with EGb …761 for 5 months significantly improved the cognitive function of mice, attenuated the loss of synaptophysin and recovered the phosphorylation of CREB in the mouse brain. Treatment with EGb 761 for 5 but not 2 months also decreased p-Tau protein amount and shifted microglial pro-inflammatory to anti-inflammatory activation in the brain. As potential therapeutic mechanisms, we demonstrated that treatment with EGb 761, especially the components of ginkgolide A, bilobalide, and flavonoids, but not with purified ginkgolide B or C, increased autophagic activity and degradation of p-Tau in lysosomes of neurons. Inhibiting ATG5 function or treating cells with Bafilomycin B1 abolished EGb 761-enhanced degradation of p-Tau in cultured neurons. Additionally, we observed that 5- instead of 2-month-treatment with EGb 761 inhibited the activity of p38-MAPK and GSK-3β . Therefore, long-term treatment with Ginkgo biloba extract EGb 761, a clinically available and well-tolerated herbal medication, ameliorates AD pathology through mechanisms against multiple AD pathogenic processes. Show more

Keywords: Alzheimer’s disease, autophagy, Ginkgo biloba extract, inflammation, tauopathies

DOI: 10.3233/JAD-180426

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-22, 2018

Authors: Liu, Ning | Yu, Zhanyang | Xun, Yu | Shu, Pan | Yue, Yiwei | Yuan, Shishan | Jiang, Yinghua | Huang, Zixuan | Yang, Xiaoping | Feng, Xing | Xiang, Shuanglin | Wang, Xiaoying

Article Type: Research Article

Abstract: Neuroglobin (Ngb) has been reported to be increased in early and moderately advanced Alzheimer’s disease (AD) stages but declined in the severe stage. However, its regulatory mechanisms and pathophysiological roles in the disease remain to be defined. In this study, we found that Ngb expression was significantly upregulated by low dose Aβ25–35 , the neurotoxic fragment of Aβ1 - 40 and Aβ1 - 42 , but was not further increased by a higher dose of Aβ25–35 . Mutation analysis and supershift assay demonstrated that transcription factor Nuclear Factor κ B (NFκ B), κ B2 and κ B3 sites located …in mouse Ngb promoter region were involved in dynamic regulation of Ngb expression in response to different doses of Aβ25–35 stimulation. In addition, we found that suppression of endogenous Ngb expression exacerbated Aβ25–35 -induced neuronal cell death and mitochondrial dysfunction. Our results indicate that endogenous Ngb expression may be upregulated by low dose Aβ25–35, which is responsible for protecting against Aβ25–35 -mediated neurotoxicity. These experimental findings suggest that upregulation of endogenous Ngb expression might be an effective intervention approach for AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, mitochondria, neuroglobin, neurotoxicity, NFκB

DOI: 10.3233/JAD-180163

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 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 | B. Frisoni, Giovanni | 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. Pre-press, no. Pre-press, pp. 1-10, 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. | Laforcem Jr., Robert | on behalf of the Genetic FTD Initiative, GENF

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. Pre-press, no. Pre-press, pp. 1-16, 2018

Authors: Ni, Hua | Xu, Min | Zhan, Gui-Lai | Fan, Yu | Zhou, Hejiang | Jiang, Hong-Yan | Lu, Wei-Hong | Tan, Liwen | Zhang, Deng-Feng | Yao, Yong-Gang | Zhang, Chen

Article Type: Research Article

Abstract: Depression is one of the most frequent psychiatric symptoms observed in people during the development of Alzheimer’s disease (AD). We hypothesized that genetic factors conferring risk of depression might affect AD development. In this study, we screened 31 genes, which were located in 19 risk loci for major depressive disorder (MDD) identified by two recent large genome-wide association studies (GWAS), in AD patients at the genomic and transcriptomic levels. Association analysis of common variants was performed by using summary statistics of the International Genomics of Alzheimer’s Project (IGAP), and association analysis of rare variants was conducted by sequencing the entire …coding region of the 31 MDD risk genes in 107 Han Chinese patients with early-onset and/or familial AD. We also quantified the mRNA expression alterations of these MDD risk genes in brain tissues of AD patients and AD mouse models, followed by protein-protein interaction network prediction to show their potential effects in AD pathways. We found that common and rare variants of L3MBTL2 were significantly associated with AD. mRNA expression levels of 18 MDD risk genes, in particular SORCS3 and OAT , were differentially expressed in AD brain tissues. 13 MDD risk genes were predicted to physically interact with core AD genes. The involvement of HACE1 , NEGR1 , and SLC6A15 in AD was supported by convergent lines of evidence. Taken together, our results showed that MDD risk genes might play an active role in AD pathology and supported the notion that depression might be the “common cold” of psychiatry. Show more

Keywords: Alzheimer’s disease, depression, genome-wide association studies, genomics, transcriptomics

DOI: 10.3233/JAD-180276

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2018

Authors: Renard, Dimitri | Tatu, Lavinia | Collombier, Laurent | Wacongne, Anne | Ayrignac, Xavier | Charif, Mahmoud | Boukriche, Yassine | Chiper, Laura | Fourcade, Genevieve | Azakri, Souhayla | Gaillard, Nicolas | Mercier, Erick | Lehmann, Sylvain | Thouvenot, Eric

Article Type: Research Article

Abstract: Background: Cerebral amyloid angiopathy (CAA) can be associated with primary vasculitis of small/medium-sized leptomeningeal and cortical arteries, called CAA-related inflammation (CAA-ri). Objective: To compare hemorrhagic and diffusion-weighted imaging (DWI) MRI features in CAA and CAA-ri. Methods: We prospectively scored in a consecutive CAA and CAA-ri cohort: presence/number of chronic intracerebral hemorrhage (ICH), cerebral microbleeds (CMB), and cortical superficial siderosis (CSS) on initial T2*-weighted imaging, and DWI lesions on both initial and follow-up imaging. In a subgroup, ApoE, CSF, and FBB-PET were also analyzed. Results: In CAA-ri, CMB presence was more frequent (100% versus 40%, …p < 0.001) and CMB numbers higher (mean 137 versus 8, p < 0.001). No difference was observed for chronic ICH or CSS. DWI lesions were more frequent in acute compared to chronic CAA-ri (p = 0.025), whereas no such difference was observed between acute and chronic CAA (p = 0.18). Both ApoE4 (genotyping available in 22 CAA-ri and 48 CAA patients) carriers and homozygosity were more frequent in CAA-ri (48% versus 19% [p = 0.014] and 32% versus 2% [p < 0.001] respectively). CSF biomarker analyses (performed in 20 CAA-ri and 45 CAA patients) showed lower Aβ 42 levels in CAA-ri compared to CAA (median 312 versus 422 pg/mL, p = 0.0032). FBB-PET (performed in 11 CAA-ri and 20 CAA patients) showed higher standardized uptake value ratios in CAA-ri compared with CAA, only significant when the pons was used as reference (p = 0.037). Conclusion: Compared to CAA, CAA-ri was associated with higher CMB numbers, more frequent ApoE4 carriers and homozygotes, lower CSF Aβ 42 levels, and more severe amyloid load on FBB-PET. Show more

Keywords: Amyloid imaging, apolipoprotein E genotype, cerebral amyloid angiopathy, cerebral amyloid angiopathy-related inflammation, cerebral microbleeds, cerebrospinal fluid, florbetaben, intracerebral hemorrhage, positron emission tomography

DOI: 10.3233/JAD-180269

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2018