Journal of Alzheimer's Disease - Volume 71, issue 4

Authors: Hashimoto, Masakazu | Yamazaki, Akira | Ohno, Atsushi | Kimura, Toru | Winblad, Bengt | Tjernberg, Lars O.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disease without a cure. The pathological process starts decades before clinical onset, and thus clinical trials of drugs aimed at treating AD should start at a presymptomatic stage. Therefore, it is critical to diagnose AD at an early stage. Tau, phosphorylated tau, and amyloid-β peptide (Aβ) in cerebrospinal fluid (CSF), and positron emission tomography (PET) imaging of Aβ or tau accumulation are supportive biomarkers for AD diagnosis, but there is no reliable presymptomatic diagnostic marker. Since CSF sampling is invasive, and PET imaging is expensive and available only at specialized centers, a reliable …blood biomarker has long been sought for. Here we describe a novel extramembrane fragment from solute carrier family 38 member 10 (SLC38A10, S38AA) that we found to be decreased in pyramidal neurons in AD cases by proteomics and immunohistochemical analysis. We detected a S38AA fragment in CSF and found the levels to correlate with severity of AD and APOE genotype. Importantly, the plasma levels of the fragment also showed a significant correlation with Mini-Mental State Examination scores in AD. Moreover, plasma from other neurodegenerative disease was analyzed and the fragment was found to be increased specifically in AD. Interestingly, the fragment is detected in mouse, rat, and monkey, and increases in amyloid precursor protein transgenic mice as the AD-like pathology progresses. We propose that the S38AA fragment in plasma could be a novel quantitative diagnostic marker for AD and potentially a marker of disease progression in AD. Show more

Keywords: Alzheimer’s disease, APOE, cerebrospinal fluid, diagnosis, mouse, neurodegenerative disease, plasma

DOI: 10.3233/JAD-190700

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1163-1174, 2019

Authors: Guo, Zongjun | Peng, Xing | Li, Hui-Yun | Wang, Yunlai | Qian, Ying | Wang, Zhihong | Ye, Dongqing | Ji, Xiaoyun | Wang, Zhixin | Wang, Yanjiang | Chen, Dongwan | Lei, Hongxing

Article Type: Research Article

Abstract: Immune dysregulation has been observed in the brain and blood of patients with Alzheimer’s disease (AD). However, a convenient assay to evaluate peripheral immune dysregulation in AD has not been developed, partly due to the inconsistent observations from different studies. We hypothesized that peripheral immune dysregulation may only exist in a subpopulation of AD patients; therefore it may be valuable to identify this subpopulation with a convenient assay. Along this line, we selected 14 candidate genes based on our analysis of microarray data on peripheral blood of AD and other diseases. We used RT-qPCR to examine the expression of these …14 genes in a cohort of 288 subjects, including 74 patients with AD, 64 patients with mild cognitive impairment (MCI), 51 patients with vascular dementia (VaD), and 99 elderly controls with no cognitive dysfunction/impairment. Seven of these 14 genes displayed significant difference in group comparison. Switching from group comparison to individualized evaluation revealed more in-depth information. First, there existed a wide dynamic range for the expression of these immune genes in peripheral blood even within the control group. Second, for the vast majority of the patients (AD, VaD, and MCI patients), the expression of these genes fell within the dynamic range of the control group. Third, a small portion of outliers were observed in the patient groups, more so in the VaD group than that in the AD or MCI groups. This is our first attempt to conduct personalized evaluation of peripheral immune dysregulation in AD and VaD. These findings may be applicable to the identification of peripheral immune dysregulation in AD and VaD patients which may lead to tailored treatment toward those patients. Show more

Keywords: Alzheimer’s disease, immune dysregulation, peripheral blood, precision medicine, vascular dementia

DOI: 10.3233/JAD-190666

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1175-1186, 2019

Authors: Yokoyama, Shunichi | Yoshinaga, Takuma | Matsuzaki, Juntaro | Suzuki, Hidekazu

Article Type: Research Article

Abstract: Background: Teprenone (geranylgeranylacetone), an anti-ulcer agent, has been reported to inhibit amyloid-β increase, senile plaque formation, and neuronal degeneration, and improve memory in mouse models of Alzheimer’s disease (AD). Objective: We conducted a randomized, double-blind, placebo-controlled study to ascertain teprenone’s therapeutic ability for AD. Methods: Patients with mild to moderate AD, with a Mini-Mental State Examination (MMSE) score of 13 to 26, were randomly allocated into two groups depending on the administered drug: donepezil +  placebo (placebo group) and donepezil + teprenone (teprenone group). The primary and secondary endpoints included changes in scores of the Japanese version of …the AD Assessment Scale-cognitive subscale (ADAS-J cog) and other evaluations, respectively, including MMSE scores, during a 12-month period after the first administration. Results: Forty-two and thirty-seven patients were allocated to the teprenone and placebo groups, respectively. ADAS-J cog score changes were not different between groups (placebo, 0.6±0.8; teprenone, 0.4±0.8; p  = 0.861). However, MMSE scores significantly improved in the teprenone group (placebo, – 1.2±0.5; teprenone, 0.2±0.5; p  = 0.044). Subgroup analysis considering the severity of medial temporal area atrophy revealed that this improvement by teprenone was significant in patients with mild (p  = 0.013) but not with severe atrophy (p  = 0.611). Adverse events were observed in 17.8 and 10.4% of patients in the placebo and teprenone group, respectively. Conclusion: Teprenone may be effective for AD when administered before atrophy progression in the medial temporal areas. Trial Registration: UMIN ID: UMIN000016843 Show more

Keywords: Alzheimer’s disease, dementia, donepezil, drug repositioning, geranylgeranylacetone

DOI: 10.3233/JAD-190305

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1187-1199, 2019

Authors: Iliadou, Paraskevi | Kladi, Anastasia | Frantzidis, Christos A. | Gilou, Sotiria | Tepelena, Ioanna | Gialaouzidis, Moses | Papaliagkas, Vasileios | Nigdelis, Vasilis | Nday, Christiane M. | Kiosseoglou, Grigorios | Papantoniou, Georgia | Bamidis, Panagiotis D. | Tsolaki, Magda | Moraitou, Despina

Article Type: Research Article

Abstract: Leading theories of affect development and empirical studies suggest that emotion can enhance memory in older adults. Destination memory which is defined as the ability to remember to whom we told a piece of information is being found to be compromised in aging. In the present study, we sought to assess destination memory using emotional stimuli (Emotional Destination Memory, EDM) in 16 older adults with mild cognitive impairment (MCI) and 16 healthy controls and shed light onto its potential neurophysiological aspects. We measured Mu suppression in frontal and temporal regions via EEG in real time while participants performed the task …of EDM. Results showed no group differences in task performance but significant differences in fronto-temporal activations, specifically in electrodes F7 and F8. Differential Mu rhythm pattern was observed between healthy controls and MCI with the first exhibiting Mu suppression and the last Mu enhancement. Furthermore, Mu enhancement in temporal electrodes within the MCI group was associated with lower scores on EDM. The absence of group differences in the task can be explained by the fact that even if there are underlying structural or functional deficits in the MCI group, these deficits are manifested only at neurophysiological level and not at a behavioral level, which is a common pattern in the process of cognitive decline in its initial phases. The overall findings reveal that, even if there are not any behavioral decrements in MCI patients, they show reduced activations in fronto-temporal regions and this can be attributed to general impairment in emotional destination memory due to possible mirror neuron deficiency. Show more

Keywords: Emotional destination memory, fronto-temporal, mild cognitive impairment, mirror neurons, Mu suppression

DOI: 10.3233/JAD-190311

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1201-1215, 2019

Authors: Patra, Kalicharan | Giannisis, Andreas | Edlund, Anna K. | Sando, Sigrid Botne | Lauridsen, Camilla | Berge, Guro | Grøntvedt, Gøril Rolfseng | Bråthen, Geir | White, Linda R. | Nielsen, Henrietta M.

Article Type: Research Article

Abstract: The APOE ɛ 4 gene variant is the strongest genetic risk factor for Alzheimer’s disease (AD), whereas APOE ɛ 3 conventionally is considered as ‘risk neutral’ although APOE ɛ 3-carriers also develop AD. Previous studies have shown that the apolipoprotein E3 (apoE3) isoform occurs as monomers, homodimers and heterodimers with apolipoprotein A-II in human body fluids and brain tissue, but the relevance of a plasma apoE3 monomer/dimer profile to AD is unknown. Here we assessed the distribution of monomers, homodimers and heterodimers in plasma from control subjects and patients with mild cognitive impairment (MCI) and AD with …either a homozygous APOE ɛ 3 (n  = 31 control subjects, and n  = 14 MCI versus n  = 5 AD patients) or APOE ɛ 4 genotype (n  = 1 control subject, n  = 21 MCI and n  = 7 AD patients). Total plasma apoE levels were lower in APOE ɛ 4-carriers and overall correlated significantly to CSF Aβ42 , p(Thr181)-tau and t-tau levels. Apolipoprotein E dimers were only observed in the APOE ɛ 3-carriers and associated with total plasma apoE levels, negatively correlated to apoE monomers, but were unrelated to plasma homocysteine levels. Importantly, the APOE ɛ 3-carrying AD patients versus controls exhibited a significant decrease in apoE homodimers (17.8±9.6% versus 26.7±6.3%, p  = 0.025) paralleled by an increase in apoE monomers (67.8±18.3% versus 48.5±11.2%, p  = 0.008). In the controls, apoE monomers and heterodimers were significantly associated with plasma triglycerides; the apoE heterodimers were also associated with levels of high-density lipoprotein cholesterol. The physiological relevance of apoE dimer formation needs to be further investigated, though the distribution of apoE in monomers and dimers appears to be of relevance to AD in APOE ɛ 3 subjects. Show more

Keywords: Alzheimer’s disease, apolipoprotein A-II, apolipoprotein E, biomarkers, dementia, dimers

DOI: 10.3233/JAD-190175

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1217-1231, 2019

Authors: Luikku, Antti J. | Hall, Anette | Nerg, Ossi | Koivisto, Anne M. | Hiltunen, Mikko | Helisalmi, Seppo | Herukka, Sanna-Kaisa | Junkkari, Antti | Sutela, Anna | Kojoukhova, Maria | Korhonen, Ville | Mattila, Jussi | Lötjönen, Jyrki | Rummukainen, Jaana | Alafuzoff, Irina | Jääskeläinen, Juha E. | Remes, Anne M. | Solomon, Alina | Kivipelto, Miia | Soininen, Hilkka | Rauramaa, Tuomas | Leinonen, Ville

Article Type: Research Article

Abstract: Background: Idiopathic normal pressure hydrocephalus (iNPH) patients often develop Alzheimer’s disease (AD) related brain pathology. Disease State Index (DSI) is a method to combine data from various sources for differential diagnosis and progression of neurodegenerative disorders. Objective: To apply DSI to predict clinical AD in shunted iNPH-patients in a defined population. Methods: 335 shunted iNPH-patients (median 74 years) were followed until death (n  = 185) or 6/2015 (n  = 150). DSI model (including symptom profile, onset age of NPH symptoms, atrophy of medial temporal lobe in CT/MRI, cortical brain biopsy finding, and APOE genotype) was applied. Performance …of DSI model was evaluated with receiver operating characteristic (ROC) curve analysis. Results: A total of 70 (21%) patients developed clinical AD during median follow-up of 5.3 years. DSI-model predicted clinical AD with moderate effectiveness (AUC = 0.75). Significant factors were cortical biopsy (0.69), clinical symptoms (0.66), and medial temporal lobe atrophy (0.66). Conclusion: We found increased occurrence of clinical AD in previously shunted iNPH patients as compared with general population. DSI supported the prediction of AD. Cortical biopsy during shunt insertion seems indicated for earlier diagnosis of comorbid AD. Show more

Keywords: Alzheimer’s disease, computer-assisted diagnosis, normal pressure hydrocephalus, Data and results has been partly presented as an abstract at Hydrocephalus 2017, Kobe, Japan

DOI: 10.3233/JAD-190334

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1233-1243, 2019

Authors: Ledreux, Aurélie | Håkansson, Krister | Carlsson, Roger | Kidane, Mhretab | Columbo, Laura | Terjestam, Yvonne | Ryan, Eliza | Tusch, Erich | Winblad, Bengt | Daffner, Kirk | Granholm, Ann-Charlotte | Mohammed, Abdul Kadir H.

Article Type: Research Article

Abstract: Previous studies have indicated that an active lifestyle is associated with better brain health and a longer life, compared to a more sedentary lifestyle. These studies, both on human and animal subjects, have typically focused on a single activity, usually physical exercise, but other activities have received an increasing interest. One proposed mechanism is that physical exercise increases levels of brain-derived neurotrophic factor (BDNF) in the brain. For the first time, the long-term effects on serum BDNF levels were compared in persons who engaged in either physical exercise training, cognitive training, or mindfulness practice during 5 weeks, and compared with …an active control group. Two cohorts of healthy older individuals, one from the Boston area in the US and one from the Växjö area in Sweden, participated. A total of 146 participants were randomly assigned to one of the four groups. All interventions were structurally similar, using interactive, computer-based software that directed participants to carry out specified activities for 35 minutes/day, 5 days per week for 5 weeks. Blood samples were obtained at baseline and soon after the completion of the 5-week long intervention program, and serum BDNF levels were measured using a commercially available ELISA. Only the group that underwent cognitive training increased their serum BDNF levels after 5 weeks of training (F1,74  = 4.22, p  = 0.044, partial η 2  = 0.054), corresponding to an average 10% increase. These results strongly suggest that cognitive training can exert beneficial effects on brain health in an older adult population. Show more

Keywords: Aging, brain-derived neurotrophic factor, cognitive training, mindfulness, physical exercise

DOI: 10.3233/JAD-190756

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1245-1261, 2019

Authors: Chanteloup, Gäetan | Cordonnier, Marine | Moreno-Ramos, Teresa | Pytel, Vanesa | Matías-Guiu, Jorge | Gobbo, Jessica | Cabrera-Martín, María Nieves | Gómez-Pinedo, Ulises | Garrido, Carmen | Matías-Guiu, Jordi A.

Article Type: Research Article

Abstract: We aimed to study the expression of circulating heat-shock protein HSP70 and exosomes in plasma of a cohort of patients with Alzheimer’s disease (AD) and frontotemporal dementia (FTD) at different stages. We performed correlations with clinical scales and FDG-PET. HSP70 levels were higher within exosomes than free in plasma. Moderate correlations were found between exosomal HSP70 and CDR, FTLD-CDR, and extension of hypometabolism. Our results suggest modifications in the level of exosomal HSP70 during the course of neurodegeneration, regardless of AD or FTD, and therefore HSP70 could have a potential role in the follow-up of these disorders.

Keywords: Alzheimer’s disease, biomarkers, exosomes, frontotemporal dementia, PET

DOI: 10.3233/JAD-190545

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1263-1269, 2019

Authors: Lamar, Melissa | León, Adeline | Romo, Karina | Durazo-Arvizu, Ramon A. | Sachdeva, Shruti | Lipton, Richard B. | Perreira, Krista M. | Gallo, Linda C. | Cai, Jianwen | Khambaty, Tasneem | Carrasco, Jessica | Llabre, Maria M. | Eyler, Lisa T. | Daviglus, Martha L. | González, Hector M.

Article Type: Research Article

Abstract: Sixty percent of Hispanics/Latinos are bilingual which research suggests may confer certain cognitive advantages. Female sex confers cognitive advantages in verbal learning and memory compared to male sex, regardless of race or ethnicity. Understanding the independent and interactive associations of bilingualism and sex with cognition may aid in predicting cognitive aging in Hispanics/Latinos. We examined baseline (2008–2011) data from the Hispanic Community Health Study/Study of Latinos, a multicenter, prospective community-based study. Our analyses included 6,110 males and females ≥45 years old who self-reported birth and parents’ origin outside of the continental US, Spanish as their first language, and were evaluated …in Spanish. Bilingualism was assessed along a Likert scale (1 = only Spanish to 4 = English>Spanish) for language proficiency (reading/spoken) and patterns of use (thinking/socializing). Cognitive testing included verbal learning, memory, fluency, and Digit Symbol Substitution (DSS). Linear regression models adjusted for relevant confounders, the complex survey design, and sampling weights. Participants’ self-reported language proficiency was Spanish better than English, while patterns of use suggested more Spanish than English. Higher language proficiency was associated with higher performance on all cognitive indices while higher patterns of use associated with higher fluency and DSS scores (p -values < 0.01). Female sex was associated with higher performance on all cognitive indices (p -values < 0.05). There were no significant interactions with bilingualism (regardless of metric) by sex on cognition. For Hispanics/Latinos residing in the continental US and reporting birth and parents’ origin elsewhere, bilingualism and female sex have independent cognitive benefits that are important to consider when evaluating cognitive performance. Show more

Keywords: Bilingualism, cognition, Hispanics/Latinos, memory, serial learning, sex differences

DOI: 10.3233/JAD-190019

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1271-1283, 2019

Authors: Suarez-Gonzalez, Aida | Ocal, Dilek | Pavisic, Ivanna | Peacock, Ashley | Naessens, Michelle | Ahmed, Samrah | Butler, Christopher R. | Leff, Alexander P. | Yong, Keir X.X. | Crutch, Sebastian J.

Article Type: Research Article

Abstract: Background: Progressive reading impairment is an early and debilitating symptom of posterior cortical atrophy (PCA) arising from the progressive deterioration of visual processing skills. Objective: The goal of this study was to test the effectiveness of a purpose-built reading app (ReadClear) co-produced with people living with PCA and designed to reduce the reading difficulties experienced by this population (e.g., getting lost in the page and missing words when reading). Methods: Twenty subjects with PCA were included in a cross-over design home-based study aimed at determining whether ReadClear could 1) enhance the subjective reading experience (reading pleasantness) …and 2) improve reading accuracy (reducing the number of reading errors) compared with a sham condition (a standard e-reader). Results: Reading using ReadClear provided a better subjective reading experience than sham (p  = 0.018, d = 0.5) and significantly reduced the percentage of reading errors (p  < 0.0001, r  = 0.82), particularly errors due to omissions (p  = 0.01, r  = 0.50), repeated words (p  = 0.002, r  = 0.69), and regressions in the text (p  = 0.003, r  = 0.69). We found that different kinds of reading errors were related to specific neuropsychological profiles. Conclusion: ReadClear can assist reading in people living with PCA by reducing the number of reading errors and improving the subjective reading experience of users. Show more

Keywords: Assistive technology, dyslexia, posterior cortical atrophy, reading

DOI: 10.3233/JAD-190335

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1285-1295, 2019

Authors: Linna, Miika | Vuoti, Sauli | Silander, Katariina | Hörhammer, Iiris | Halminen, Olli | Mikkola, Teija | Koivuranta-Vaara, Päivi | Virta, Lauri J. | Koivusalo, Mirkka | Ylisaukko-oja, Tero

Article Type: Research Article

Abstract: Background: The Finnish population offers many advantages for evaluating the impact of anti-dementia medication on mortality in Alzheimer’s disease (AD) due to broad range of individual-level data collected in national health and social care registries and the fact that Finland has one of the highest mortality rates for dementia globally. Objective: The aim of this study was to investigate the association of anti-dementia medication with 2-year risk of death and all-cause mortality in patients with AD. Methods: This was a retrospective, non-interventional registry study based on individual-level data using Finnish national health and social care registries. …An incident cohort of 9,204 AD patients (first AD diagnosis in 2012) was formed from a population of 316,470 individuals ≥74 years of age. The main outcome measure was overall 2-year risk of death. Statistical modelling was used to assess mortality (Kaplan-Meier) and adjusted hazard ratios (HR) (Cox proportional hazard model). Results: Early start of anti-dementia medication (treatment started ≤3 months from AD diagnosis) reduced significantly the risk of all-cause death compared to AD patients who had late medication initiation (defined as treatment started >3 months from AD diagnosis/no medication; HR, 0.51; 95% confidence interval (CI), 0.46–0.57). Dementia was the most common recorded cause of death in both groups. Conclusion: This study places importance on early diagnosis of AD and subsequent early initiation of drug treatment in decreasing 2-year risk of death. Show more

Keywords: Alzheimer’s disease, cause of death, cholinesterase inhibitors, dementia, Finland, memantine, registry study, risk of death

DOI: 10.3233/JAD-190288

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1297-1308, 2019

Authors: Gyanwali, Bibek | Shaik, Muhammad Amin | Venketasubramanian, Narayanaswamy | Chen, Christopher | Hilal, Saima

Article Type: Research Article

Abstract: Background: Cerebral microbleeds (CMBs) in the lobar and deep locations have been associated with two distinct pathologies namely cerebral amyloid angiopathy (CAA) and hypertensive arteriopathy. However, the role of mixed-location CMBs in cerebrovascular disease and cognitive impairment remain unexplored. Objective: The present study aims to investigate the association of strictly lobar, strictly deep and mixed-location CMBs with cognitive impairment and dementia as well as functional decline. Methods: A prospective case-control study, where 520 patients underwent 3T brain MRI to assess region and lobe-specific CMBs, and other cerebrovascular diseases (CeVD) markers such as cortical infarcts, lacunes, and …white matter hyperintensities. Patients were classified as no cognitive Impairment, cognitive impairment no dementia (CIND), and dementia [Alzheimer’s disease (AD) and vascular dementia (VaD)]. Severity of cognitive impairment was assessed using Clinical Dementia Rating scale. Results: Mixed-location CMBs were associated with dementia [Odds ratio (OR):1.23; 95% confidence interval (CI):1.04, 1.47]. When stratified by the presence of CeVD, mixed-location CMBs were associated with CIND [OR:1.20;95% CI:1.02, 1.42], AD [OR:1.22;95% CI:1.02, 1.46], and VaD [OR:1.33;95% CI:1.08, 1.62]. Furthermore, CMBs in frontal, parietal, and temporal regions were associated with CIND whereas those in parietal, temporal, and occipital regions were associated with AD. Mixed-location CMBs were also associated with increased severity of cognitive impairment [OR:1.02; 95% CI:1.00, 1.05]. Conclusion: Mixed-location CMBs are associated with cognitive impairment and dementia in the presence of CeVD. Furthermore mixed-location CMBs were linked with increased severity of cognitive impairment, suggesting severe parenchymal damage as well as microangiopathy to be common underlying mechanisms in the elderly. Show more

Keywords: Alzheimer’s disease, cerebral microbleeds, cerebrovascular disease, cognition, mixed-pathology

DOI: 10.3233/JAD-190540

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1309-1320, 2019

Authors: Gallucci, Maurizio | Pallucca, Claudia | Di Battista, Maria Elena | Fougère, Bertrand | Grossi, Enzo

Article Type: Research Article

Abstract: Background: Nutrition plays an important role in the aging process. Adherence to the Mediterranean diet (MedDiet) has been shown to be associated with lower rates of diseases. Cognitive status seems to be strongly interrelated with physical well-being, so that one influences the other. Physical performance measures are not only associated with clinical and subclinical age-related modifications, but are also able to predict disability, institutionalization, and mortality. Objective: To evaluate prospectively the associations between Mediterranean-Style Dietary Pattern Score (MSDPS), clinical characteristics, and cognition of the population sample of The TREVISO LONGEVA (TRELONG) Study, in Treviso, Italy. Methods: …Global cognition, physical performance measures, MSDPS, and other clinical features were detected in 2010 in 82 men and 108 women. These characteristics were evaluated in relation to the physical performance measures identified 3.8 years later in 2013 in the same subjects, using a semantic connectivity map, through Auto-CM system, to grasp further and non-linear associations between variables which might remain, otherwise, undetected. Results: The Auto-CM system’s map showed a close association between better levels of global cognition and MSDPS in 2010 and higher physical performance in 2013. On the other hand, worse levels of global cognition and MSDPS in 2010 were associated with lower physical performance in 2013. Conclusion: The prevention models for successful aging may benefit from integrated programs that include cognitive, physical, and dietary interventions, since these aspects are mutually interrelated. Show more

Keywords: Aging, hand grip, mediterranean-style dietary pattern score, mini-mental state examination, physical performance, short physical performance battery, TRELONG

DOI: 10.3233/JAD-190609

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1321-1330, 2019

Authors: Xu, Heng | Yue, Chengjin | Chen, Lin

Article Type: Research Article

Abstract: Many patients with Alzheimer’s disease suffer from severe neuropathic pain. Soluble guanylate cyclase (sGC) is a critical enzyme of the nitric oxide (NO) signaling pathway. Binding of NO to a group of prosthetic heme on sGC initiates the second messenger cGMP synthesis, resulting in increases in the mechanical threshold for neuropathic pain. Nevertheless, the regulation of sGC remains unclear. Here, we aimed to figure out a strategy to reduce sGC levels by microRNA (miRNA) intervention. Bioinformatical studies were then performed to predict sGC-targeting miRNAs; additionally, an assay of dual luciferase reporter was used for evaluating the functional binding of miRNAs …to sGC. Among all sGC-targeting miRNAs, in particularly we found that miR-142-5p markedly inhibited sGC protein translation by pairing to the 3’-UTR of the sGC mRNA. Orthotopic injection of adeno-associated virus carrying miR-142-5p significantly decreased sGC and sGMP levels, resulting in reduction of the neuropathic pain in rats with the left hind leg sciatic nerve injured in the tibia and peroneal branches. In summary, these data show that miR-142-5p induction in injured neurons may be an effective treatment for neuropathic pain and worthy of further investigation as a treatment for those patients with Alzheimer’s disease and neuropathic pain. Show more

Keywords: Alzheimer’s disease, miR-142-5p, neuropathic pain, nitric oxide, soluble guanylate cyclase

DOI: 10.3233/JAD-190743

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1331-1338, 2019

Authors: Frison, Eric | Dufouil, Carole | Helmer, Catherine | Berr, Claudine | Auriacombe, Sophie | Chêne, Geneviève

Article Type: Research Article

Abstract: Diabetes is associated with a higher dementia and mortality risk. However, few studies have accounted for death when estimating the association between diabetes and dementia. We estimated absolute and relative risks of all-cause dementia according to diabetes exposure status in older adults while accounting for competing risk of death using illness-death models. Effect modification by specific characteristics (age, gender, education, cardiovascular risk factors, body mass index, cardiovascular history, depressive symptomatology, impaired renal function, and APOE ɛ 4 genotype) was also investigated. We analyzed the Three-City study data, a French population-based cohort of adults aged 65 years and above who …were followed up for 12 years from 1999–2001. Among 8,328 participants selected in the analytical sample (median age, 73.3 years; 60.3% women), 809 (9.3%) presented with diabetes at baseline. Over a median follow-up period of 8.3 years, 836 participants developed incident dementia. Baseline diabetes was associated with a higher risk of dementia: hazard ratio, 1.79 [95% confidence interval, 1.46–2.19]. No effect modification was shown. Diabetes was associated with a higher 12-year absolute risk of dementia and a lower dementia-free life expectancy (e.g., 14.5% [11.2–18.1] versus 8.7% [7.6–10.2], and 13.4 [12.7–14.1] years versus 16.5 [16.0–17.1] years, respectively, for a 70-year-old woman with the highest level of education). These findings support the potential impact of preventing diabetes on reducing dementia risk in older adults, with a 2-3-year higher dementia-free life expectancy for individuals without diabetes, and inform the design of future interventional trials. Show more

Keywords: Cohort studies, death, dementia, type 2 diabetes mellitus

DOI: 10.3233/JAD-190427

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1339-1350, 2019

Authors: Ralbovsky, Nicole M. | Halámková, Lenka | Wall, Kathryn | Anderson-Hanley, Cay | Lednev, Igor K.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease and related dementias (ADRDs) are being diagnosed at epidemic rates, with incidence to triple from 35 to 115 million cases worldwide. Most ADRDs are characterized by progressive neurodegeneration, and Alzheimer’s disease (AD) is the sixth leading cause of death in the United States. The ideal moment for diagnosing ADRDs is during the earliest stages of its progression; however, current diagnostic methods are inefficient, expensive, and unsuccessful at making diagnoses during the earliest stages of the disease. Objective: The aim of this project was to utilize Raman hyperspectroscopy in combination with machine learning to develop a …novel method for the diagnosis of AD based on the analysis of saliva. Methods: Raman hyperspectroscopy was used to analyze saliva samples collected from normative, AD, and mild cognitive impairment (MCI) individuals. Genetic Algorithm and Artificial Neural Networks machine learning techniques were applied to the spectral dataset to build a diagnostic algorithm. Results: Internal cross-validation showed 99% accuracy for differentiating the three classes; blind external validation was conducted using an independent dataset to further verify the results, achieving 100% accuracy. Conclusion: Raman hyperspectroscopic analysis of saliva has a remarkable potential for use as a non-invasive, efficient, and accurate method for diagnosing AD. Show more

Keywords: Alzheimer’s disease, artificial neural networks, early diagnosis, genetic algorithm, machine learning, mild cognitive impairment, Raman spectroscopy, saliva

DOI: 10.3233/JAD-190675

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1351-1359, 2019

Authors: Rhea, Elizabeth M. | Nirkhe, Surabhi | Nguyen, Steven | Pemberton, Sarah | Bammler, Theo K. | Beyer, Richard | Niehoff, Michael L. | Morley, John E. | Farr, Susan A. | Banks, William A.

Article Type: Research Article

Abstract: Research on intranasal delivery of drugs, peptides, and proteins has grown over the past decade as an alternate way to deliver substrates to the brain. Recent work has shown intranasal (INL) delivery of insulin improves memory and cognition in healthy subjects as well as patients with Alzheimer’s disease (AD) and in AD mouse models. However, the molecular mechanism(s) for the beneficial effect of insulin on memory are still unclear. Using the SAMP8 mouse model of AD, we investigated the impact of INL insulin on protein and gene expression in brain regions including the olfactory bulb, hypothalamus, and hippocampus. We found …genes and proteins in the insulin receptor signaling pathway were not activated by the doses tested. However, we did find the expression of genes present in the hippocampus involved in other pathways, especially those related to inflammation, were altered due to age and with a dose of INL insulin previously shown to improve cognition. These alternate pathways could be targets of insulin when delivered via the INL route to aid in memory improvement. Show more

Keywords: Alzheimer’s disease, cognition, hippocampus, insulin, intranasal, RNA sequence analysis

DOI: 10.3233/JAD-190707

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1361-1373, 2019

Authors: Fanning, Laura | Ryan-Atwood, Taliesin E. | Bell, J. Simon | Meretoja, Atte | McNamara, Kevin P. | Dārziņš, Pēteris | Wong, Ian C.K. | Ilomäki, Jenni

Article Type: Correction

DOI: 10.3233/JAD-199005

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1375-1378, 2019

Article Type: Correction

DOI: 10.3233/JAD-199006

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1379-1380, 2019

Authors: Hvidsten, Lara | Engedal, Knut | Selbæk, Geir | Wyller, Torgeir Bruun | Benth, Jūratė Šaltytė | Kersten, Hege

Article Type: Correction

DOI: 10.3233/JAD-199007

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1381-1381, 2019