Journal of Alzheimer's Disease - Volume 64, issue 2

Authors: Akhter, Hasina | Huang, Wen-Tan | van Groen, Thomas | Kuo, Hui-Chien | Miyata, Toshio | Liu, Rui-Ming

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a major cause of dementia in the elderly with no effective treatment. Accumulation of amyloid-β peptide (Aβ) in the brain is a pathological hallmark of AD and is believed to be a central disease-causing and disease-promoting event. In a previous study, we showed that deletion of plasminogen activator inhibitor 1 (PAI-1), a primary inhibitor of tissue type and urokinase type plasminogen activators (tPA and uPA), significantly reduced brain Aβ load in APP/PS1 mice, an animal model of familial AD. In this study, we further show that oral administration of TM5275, a small molecule inhibitor of PAI-1, …for a period of 6 weeks, inhibits the activity of PAI-1 and increases the activities of tPA and uPA as well as plasmin, which is associated with a reduction of Aβ load in the hippocampus and cortex and improvement of learning/memory function in APP/PS1 mice. Protein abundance of low density lipoprotein related protein-1 (LRP-1), a multi ligand endocytotic receptor involved in transporting Aβ out of the brain, as well as plasma Aβ42 are increased, whereas the expression and processing of full-length amyloid-β protein precursor is not affected by TM5275 treatment in APP/PS1 mice. In vitro studies further show that PAI-1 increases, whereas TM5275 reduces, Aβ40 level in the culture medium of SHSY5Y-APP neuroblastoma cells. Collectively, our data suggest that TM5275 improves memory function of APP/PS1 mice, probably by reducing brain Aβ accumulation through increasing plasmin-mediated degradation and LRP-1-mediated efflux of Aβ in the brain. Show more

Keywords: Alzheimer’s disease, amyloid-β accumulation, memory, PAI-1 inhibitor

DOI: 10.3233/JAD-180241

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 447-457, 2018

Authors: Korthauer, Laura E. | Awe, Elizabeth | Frahmand, Marijam | Driscoll, Ira

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is characterized by memory loss and executive dysfunction, which correspond to structural changes to the medial temporal lobes (MTL) and prefrontal cortex (PFC), respectively. Given the overlap in cognitive deficits between healthy aging and the earliest stages of AD, early detection of AD remains a challenge. The goal of the present study was to study MTL- and PFC-dependent cognitive functioning in middle-aged individuals at genetic risk for AD or cognitive impairment who do not currently manifest any clinical symptoms. Participants (N = 150; aged 40–60 years) underwent genotyping of 47 single nucleotide polymorphisms (SNPs) in six genes …previously associated with memory or executive functioning: APOE, SORL1, BDNF, TOMM40, KIBRA, and COMT. They completed two MTL-dependent tasks, the virtual Morris Water Task (vMWT) and transverse patterning discriminations task (TPDT), and the PFC-dependent reversal learning task. Although age was associated with poorer performance on the vMWT and TPDT within this middle-aged sample, there were no genotype-associated differences in cognitive performance. Although the vMWT and TPDT may be sensitive to age-related changes in cognition, carriers of APOE, SORL1, BDNF, TOMM40, KIBRA, and COMT risk alleles do not exhibit alteration in MTL- and PFC-dependent functioning in middle age compared to non-carriers. Show more

Keywords: Aging, Alzheimer’s disease, apolipoproteins E, brain-derived neurotrophic factor, cognition, hippocampus, prefrontal cortex, middle age

DOI: 10.3233/JAD-171043

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 459-471, 2018

Authors: Martínez-Sánchez, Francisco | Meilán, Juan José G. | Carro, Juan | Ivanova, Olga

Article Type: Research Article

Abstract: Background: Speech variations enable us to map the performance of cognitive processes of syntactic, semantic, phonological, and articulatory planning and execution. Speaking is one of the first functions to be affected by neurodegenerative complaints such as Alzheimer’s disease (AD), which makes the speech a highly promising biomarker for detecting the illness before the first preclinical symptoms appear. Objective: This paper has sought to develop and validate a technological prototype that adopts an automated approach to speech analysis among older people. Methods: It uses a mathematical algorithm based on certain discriminatory variables to estimate the probability of …developing AD. Results and Conclusion: This device may be used at a preclinical stage by non-expert health professionals to determine the likelihood of the onset of AD. Show more

Keywords: Alzheimer’s disease, diagnosis, prototype, voice

DOI: 10.3233/JAD-180037

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 473-481, 2018

Authors: Robinson, Andrew C. | Davidson, Yvonne S. | Horan, Michael A. | Pendleton, Neil | Mann, David M.A.

Article Type: Research Article

Abstract: The neuropathological changes responsible for cognitive impairment and dementia remain incompletely understood. Longitudinal studies with a brain donation end point allow the opportunity to examine relationships between cognitive status and neuropathology. We report on the first 97 participants coming to autopsy with sufficient clinical information from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age. This study began in 1983 and recruited 6,542 healthy individuals between 1983 and 1994, 312 of whom consented to brain donation. Alzheimer-type pathology was common throughout the cohort and generally correlated well with cognitive status. However, there was some overlap between …cognitive status and measures of Alzheimer pathology with 26% of cognitively intact participants reaching either CERAD B or C, 11% reaching Thal phase 4 or 5, and 29% reaching Braak stage III– VI. Cerebral amyloid angiopathy(CAA), α -synuclein, and TDP-43 pathology was less common, but when present correlated well with cognitive status. Possession of APOE ɛ 4 allele(s) was associated with more severe Alzheimer-type and CAA pathology and earlier death, whereas possession of APOE ɛ 2 allele(s) had no effect on pathology but was more common in cognitively intact individuals. The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age cohort is pathologically representative when compared with similar studies. Cognitive impairment in life correlates strongly with all pathologies examined and the APOE status of an individual can affect pathology severity and longevity. Show more

Keywords: Alpha-synuclein, Alzheimer’s disease, APOE , cognitive dysfunction, cohort studies, dementia, longitudinal studies, neuropathology

DOI: 10.3233/JAD-180171

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 483-496, 2018

Authors: Bocchetta, Martina | Iglesias, Juan Eugenio | Scelsi, Marzia A. | Cash, David M. | Cardoso, M. Jorge | Modat, Marc | Altmann, Andre | Ourselin, Sebastien | Warren, Jason D. | Rohrer, Jonathan D.

Article Type: Research Article

Abstract: Background: Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder, with a strong genetic component. Previous research has shown that medial temporal lobe atrophy is a common feature of FTD. However, no study has so far investigated the differential vulnerability of the hippocampal subfields in FTD. Objectives: We aimed to investigate hippocampal subfield volumes in genetic FTD. Methods: We in6/2/2018vestigated hippocampal subfield volumes in a cohort of 75 patients with genetic FTD (age: mean (standard deviation) 59.3 (7.7) years; disease duration: 5.1 (3.4) years; 29 with MAPT , 28 with C9orf72 , and 18 with GRN …mutations) compared with 97 age-matched controls (age: 62.1 (11.1) years). We performed a segmentation of their volumetric T1-weighted MRI scans to extract hippocampal subfields volumes. Left and right volumes were summed and corrected for total intracranial volumes. Results: All three groups had smaller hippocampi than controls. The MAPT group had the most atrophic hippocampi, with the subfields showing the largest difference from controls being CA1-4 (24–27%, p < 0.0005). For C9orf72 , the CA4, CA1, and dentate gyrus regions (8–11%, p < 0.0005), and for GRN the presubiculum and subiculum (10–14%, p < 0.0005) showed the largest differences from controls. Conclusions: The hippocampus was affected in all mutation types but a different pattern of subfield involvement was found in the three genetic groups, consistent with differential cortical-subcortical network vulnerability. Show more

Keywords: Genetic frontotemporal dementia, hippocampal subfields, magnetic resonance imaging, volumetry

DOI: 10.3233/JAD-180195

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 497-504, 2018

Authors: Morenas-Rodríguez, Estrella | Sala, Isabel | Subirana, Andrea | Pascual-Goñi, Elba | Sánchez-Saudinós, Ma Belén | Alcolea, Daniel | Illán-Gala, Ignacio | Carmona-Iragui, María | Ribosa-Nogué, Roser | Camacho, Valle | Blesa, Rafael | Fortea, Juan | Lleó, Alberto

Article Type: Research Article

Abstract: Background: Dementia with Lewy bodies (DLB) is a heterogeneous disease in which clinical presentation, symptoms, and evolution widely varies between patients. Objective: To investigate the existence of clinical subtypes in DLB based on the initial clinical presentation. Methods: 81 patients with a clinical diagnosis of probable DLB were consecutively included. All patients underwent a neurological evaluation including a structured questionnaire about neuropsychiatric symptoms and sleep, an assessment of motor impairment (Unified Parkinson Disease Rating Scale subscale III), and a formal neuropsychological evaluation. Onset of core symptoms (hallucinations, parkinsonism, and fluctuations) and dementia were systematically reviewed from …medical records. We applied a K-means clustering method based on the initial clinical presentation. Results: Cluster analysis yielded three different groups. Patients in cluster I (cognitive-predominant, n = 46) presented more frequently with cognitive symptoms (95.7%, n = 44, p < 0.001), and showed a longer duration from onset to DLB diagnosis (p < 0.001) than the other clusters. Patients in cluster II (neuropsychiatric-predominant, n = 22) were older at disease onset (78.1±5 versus 73.6±6.1 and 73.6±4.2 in clusters I and III, respectively, both p < 0.01), presented more frequently with psychotic symptoms (77.3%, n = 17), and had a shorter duration until the onset of hallucinations (p < 0.001). Patients in cluster III (parkinsonism-predominant, n = 13) showed a shorter time from onset to presence of parkinsonism (p < 0.001) and dementia (0.008). Conclusions: Three clinical subtypes of DLB can be defined when considering the differential initial presentations. The proposed subtypes have distinct clinical profiles and progression patterns. Show more

Keywords: Clinical subtypes, cluster analyses, dementia with Lewy bodies, Lewy bodies

DOI: 10.3233/JAD-180167

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 505-513, 2018

Authors: Nakanishi, Miharu | Hirooka, Kayo | Imai, Yasuaki | Inoue, Shintaro | Yukari, Yukio | Katayama, Chie | Miyamoto, Yuki | Shindo, Yumi | Ueno, Hideki | Toya, Junichiro | Takano, Yosuke | Nishida, Atsushi

Article Type: Research Article

Abstract: Background: We developed a psychosocial dementia care program to help care managers and professional caregivers manage challenging behavior in home-dwelling persons with dementia in Japan. The program consists of a web-based tool for ongoing monitoring and assessment for challenging behavior, and multi-agency discussion meetings. Results of a cluster-randomized controlled trial indicate a reduction in challenging behavior through this program. Objectives: The present study aimed to identify a key component of the developed program that is associated with a reduction in challenging behavior. Methods: We used consecutive data of the intervention and examined the association between challenging …behavior in home-dwelling persons with dementia, professionals’ competence, and the frequency of revision of action plans. Challenging behavior was assessed using the total score of the Neuropsychiatric Inventory. A baseline and follow-up questionnaire was completed by care professionals using a Japanese version of the Sense of Competence in Dementia Care Staff scale. Results: A total of 86 care professionals completed a 6-month intervention with 219 persons with dementia. The 86 care professionals significantly improved in their dementia care competence. Challenging behavior was significantly reduced among the 219 persons with dementia at follow-up regardless of the level of professionals’ competence or the frequency of revision of action plans. Less pain was significantly related to the lower levels of challenging behavior. Conclusion: The ongoing multi-agency discussion meetings, with a focus on challenging behavior, may have been the key component in the psychosocial dementia care program. Pain management should be emphasized in action plans for challenging behavior. Show more

Keywords: Challenging behavior, dementia, home-dwelling, palliative care, professional competence

DOI: 10.3233/JAD-171077

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 515-523, 2018

Authors: Schirinzi, Tommaso | Di Lorenzo, Francesco | Sancesario, Giulia Maria | Di Lazzaro, Giulia | Ponzo, Viviana | Pisani, Antonio | Mercuri, Nicola Biagio | Koch, Giacomo | Martorana, Alessandro

Article Type: Research Article

Abstract: Background: Although motor disturbances parallel the course of dementia, worsening both quality of life and social costs, the pathogenesis remains still unclear. Objective: Through the combination of cerebrospinal fluid (CSF) biomarkers assessment and transcranial magnetic stimulation (TMS) protocols, here we provided a cross-sectional study to understand pathogenic mechanisms of Alzheimer’s disease (AD)-related early motor disturbances. Methods: The motor phenotype, as defined with Unified Parkinson’s Disease Rating Scale (UPDRS) part 2-3, Rating Scale for Gait Evaluation in Cognitive Deterioration (RSEGCD) and Tinetti scale, together with CSF profile of amyloid-β 42 (Aβ 42 ), total-tau, and phosphorylated-tau …were determined in 37 AD patients and compared to 18 patients with vascular dementia (VaD). A TMS protocol of short afferent inhibition (SAI) was further applied on a subset of AD patients. Clinical, biochemical, and neurophysiological data were then compared and correlated in order to find significant associations. Results: AD patients exhibited subtle locomotor impairment and slight extrapyramidal signs. Main motor features (UPDRS part 3, RSGECD, and Tinetti scale scores) correlate with Aβ 42 levels but not with t-tau and p-tau. AD patients also presented SAI impairment directly related to UPDRS part 3 score and Aβ 42 levels. Motor disturbances of VaD group did not differ statistically from AD and did not correlate with CSF biomarkers. Conclusions: The association of motor disturbances with low Aβ 42 CSF levels and individual SAI suggests that amyloid-mediated degeneration of cholinergic system may account for early AD-related motor impairment, providing interesting insights either for frailty stratification of patients or personalized therapies. Show more

Keywords: Alzheimer’s disease, amyloid, cholinergic, frailty, gait, locomotor, vascular dementia

DOI: 10.3233/JAD-171166

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 525-532, 2018

Authors: Payton, Nicola M. | Kalpouzos, Grégoria | Rizzuto, Debora | Fratiglioni, Laura | Kivipelto, Miia | Bäckman, Lars | Laukka, Erika J.

Article Type: Research Article

Abstract: Background: Cognitive and biological markers have shown varying degrees of success in identifying persons who will develop dementia. Objective: To evaluate different combinations of cognitive and biological markers and identify prediction models with the highest accuracy for identifying persons with increased dementia risk. Methods: Neuropsychological assessment, genetic testing (apolipoprotein E –APOE ), and structural magnetic resonance imaging (MRI) were performed for 418 older individuals without dementia (60–97 years) from a population-based study (SNAC-K). Participants were followed for six years. Results: Cognitive, genetic, and MRI markers were systematically combined to create prediction models for dementia at …six years. The most predictive individual markers were perceptual speed or carrying at least one APOE ɛ 4 allele (AUC = 0.875). The most predictive model (AUC = 0.924) included variables from all three modalities (category fluency, general knowledge, any ɛ 4 allele, hippocampal volume, white matter-hyperintensity volume). Conclusion: This study shows that combining markers within and between modalities leads to increased predictivity for future dementia. However, minor increases in predictive value should be weighed against the cost of additional tests in larger-scale screening. Show more

Keywords: Biomarkers, cognition, neuroimaging, preclinical dementia, prediction

DOI: 10.3233/JAD-180199

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 533-542, 2018

Authors: Ruiz, Maria | Arias, Alfonso | Sánchez-Llanos, Ernesto | Gil, Maria Pilar | López-Ortega, Ricard | Dakterzada, Faridé | Purroy, Francisco | Piñol-Ripoll, Gerard

Article Type: Research Article

Abstract: Background: Hallucinations may have a broad spectrum and include so-called minor hallucinations (MHs). MHs include passage hallucinations (PHs), visual illusions, and presence hallucinations (PrHs). Objective: To determine the prevalence and characteristics of MHs in Alzheimer’s disease (AD) and amnestic mild cognitive impairment (aMCI) patients, and to describe their potential relationship with cognition, behavioral symptoms, and use of psychoactive drugs. Methods: We have recruited prospectively and consecutively 268 subjects (90 AD mild-moderate drug-naïve patients, 78 aMCI, and 100 controls). All patients responded to a semi-structured questionnaire in order to rate psychotic phenomena. Clinical, neuropsychological, and demographic data …of patients with and without MH were compared with those of age, sex, and education-matched controls. Results: The prevalence of MHs was 21.1% (19) in AD, 12.8% (10) in aMCI, and 3% (3) in controls (p < 0.01). The most frequent MH was PrH (9.3%), followed by PH (4.9%) and illusion (0.7%). Eight (27.8%) patients had more than one MH. After adjusting for age and gender, there was a negative correlation between the presence of MHs and MMSE score (r = –0.261; p < 0.01) and a positive correlation between MHs and Neuropsychiatric Inventory score (r = 0.237; p < 0.01). We did not observe a significant relationship between presence of MHs and the consumption of psychoactive drugs (p > 0.05). Conclusion: We have shown that the presence of MHs in patients with newly diagnosed, untreated AD and aMCI is more than controls. MHs were correlated with other behavioral symptoms and a worse cognitive performance. We suggest the specific interrogation for MHs as a clinical feature for this population. Show more

Keywords: Alzheimer’s disease, dementia, drug-naïve, illusion, mild cognitive impairment, minor hallucination, passage hallucination, presence hallucination

DOI: 10.3233/JAD-180234

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 543-549, 2018

Authors: Croteau, Etienne | Castellano, Christian-Alexandre | Richard, Marie Anne | Fortier, Mélanie | Nugent, Scott | Lepage, Martin | Duchesne, Simon | Whittingstall, Kevin | Turcotte, Éric E. | Bocti, Christian | Fülöp, Tamàs | Cunnane, Stephen C.

Article Type: Research Article

Abstract: Background : In Alzheimer’s disease (AD), it is unknown whether the brain can utilize additional ketones as fuel when they are derived from a medium chain triglyceride (MCT) supplement. Objective : To assess whether brain ketone uptake in AD increases in response to MCT as it would in young healthy adults. Methods : Mild-moderate AD patients sequentially consumed 30 g/d of two different MCT supplements, both for one month: a mixture of caprylic (55%) and capric acids (35%) (n = 11), followed by a wash-out and then tricaprylin (95%; n = 6). Brain ketone …(11 C-acetoacetate) and glucose (FDG) uptake were quantified by PET before and after each MCT intervention. Results : Brain ketone consumption doubled on both types of MCT supplement. The slope of the relationship between plasma ketones and brain ketone uptake was the same as in healthy young adults. Both types of MCT increased total brain energy metabolism by increasing ketone supply without affecting brain glucose utilization. Conclusion : Ketones from MCT compensate for the brain glucose deficit in AD in direct proportion to the level of plasma ketones achieved. Show more

Keywords: Acetoacetate, Alzheimer’s disease, beta-hydroxybutyrate, brain energy metabolism, [11C]-acetoacetate, cerebral blood flow, [18F]-fluorodeoxyglucose, ketones, medium chain triglycerides

DOI: 10.3233/JAD-180202

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 551-561, 2018

Authors: Kawanishi, Shohei | Takata, Kazuyuki | Itezono, Shouma | Nagayama, Hiroko | Konoya, Sayaka | Chisaki, Yugo | Toda, Yuki | Nakata, Susumu | Yano, Yoshitaka | Kitamura, Yoshihisa | Ashihara, Eishi

Article Type: Research Article

Abstract: Microglia, the primary immune cells in the brain, sense pathogens and tissue damage, stimulate cytokine production, and phagocytosis to maintain homeostasis. Accumulation of amyloid-β peptides (Aβ) in the brain triggers the onset of Alzheimer’s disease (AD). Accordingly, promotion of Aβ clearance represents a promising strategy for AD therapy. We previously demonstrated that primary-cultured rat microglia phagocytose Aβ, and that transplantation of these cells ameliorates the Aβ burden in brains of Aβ-injected rats. In this study, we demonstrate that stimulation with colony-stimulating factor-1 efficiently differentiates mouse bone marrow cells into bone marrow-derived microglia-like (BMDML) cells that express markers for microglia, including …the recently identified transmembrane protein 119. BMDML cells effectively phagocytose Aβ in vitro , with effects comparable to primary-cultured mouse microglia and greater than peritoneal macrophages. RT-qPCR analysis for cytokine mRNA levels revealed that BMDML cells polarize to a relatively anti-inflammatory state under non-stimulated and inflammatory conditions but exert a pro-inflammatory reaction after lipopolysaccharide treatment. Moreover, BMDML cells hippocampally injected into a mouse model of AD are morphologically similar to the ramified and amoeboid types of residential microglia. Comparisons with simulations assuming a uniform distribution of cells suggest that BMDML cells migrate directionally toward Aβ plaques. We also detected Aβ phagocytosis by BMDML cells, concomitant with a reduction in the number and area of Aβ plaques. Finally, we observed amelioration of cognitive impairment in a mouse model of AD after hippocampal injection of BMDML cells. Our results suggest that BMDML cells have potential as a cell-based disease-modifying therapy against AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, bone-marrow-derived cells, microglia

DOI: 10.3233/JAD-170994

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 563-585, 2018

Authors: Haapala, Eero A. | Paananen, Jussi | Hiltunen, Mikko | Lakka, Timo A.

Article Type: Research Article

Abstract: We investigated the associations of genetic risk score (GRS) for Alzheimer’s disease and apolipoprotein E (APOE ) ɛ variant with cardiometabolic risk factors during 2-year follow-up in children and whether body fat percentage (BF%) modify these associations. A population-based sample of 469 children (246 boys, 223 girls) at baseline and 398 children (201 boys, 197 girls) at 2-year follow-up participated in the study. Genotyping was performed using the Illumina Custom Infinium CardioMetabo BeadChip and the Illumina Infinium HumanCoreExome BeadChip. The GRS was calculated using information on nine independent gene variants available in our genomic data. We assessed BF%, waist …circumference, insulin, glucose, triglycerides, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, and systolic and diastolic blood pressure. We computed a cardiometabolic risk score and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). In boys, the GRS was not associated with cardiometabolic risk factors. In girls, GRS was directly associated with LDL cholesterol (β = 0.133, 95% CI = 0.002 to 0.262) at baseline and with a higher cardiometabolic risk score (β = 0.154, 95% CI = 0.015 to 0.294), glucose (β = 0.143, 95% CI = 0.003 to 0.284), and HOMA-IR (β = 0.141, 95% CI = 0.004 to 0.278) at 2-year follow-up. GRS was directly associated with a cardiometabolic risk score at baseline and 2-year follow-up among girls in the highest third of BF% at baseline, but not in other girls (p < 0.05 for interaction). Children with the APOE ɛ 3/3 genotype had higher LDL cholesterol at and 2-year follow-up than those with the APOE ɛ 2/3 genotype. In conclusion, GRS was associated with increased cardiometabolic risk in girls and especially those with higher BF%. Show more

Keywords: Alzheimer’s disease, child, genetics, insulin resistance, metabolic syndrome

DOI: 10.3233/JAD-180216

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 587-595, 2018

Authors: Leoutsakos, Jeannie-Marie S. | Yan, Haijuan | Anderson, William S. | Asaad, Wael F. | Baltuch, Gordon | Burke, Anna | Chakravarty, M. Mallar | Drake, Kristen E. | Foote, Kelly D. | Fosdick, Lisa | Giacobbe, Peter | Mari, Zoltan | McAndrews, Mary Pat | Munro, Cynthia A. | Oh, Esther S. | Okun, Michael S. | Pendergrass, Jo Cara | Ponce, Francisco A. | Rosenberg, Paul B. | Sabbagh, Marwan N. | Salloway, Stephen | Tang-Wai, David F. | Targum, Steven D. | Wolk, David | Lozano, Andres M. | Smith, Gwenn S. | Lyketsos, Constantine G.

Article Type: Research Article

Abstract: Background: Given recent challenges in developing new treatments for Alzheimer dementia (AD), it is vital to explore alternate treatment targets, such as neuromodulation for circuit dysfunction. We previously reported an exploratory Phase IIb double-blind trial of deep brain stimulation targeting the fornix (DBS-f) in mild AD (the ADvance trial). We reported safety but no clinical benefits of DBS-f versus the delayed-on (sham) treatment in 42 participants after one year. However, secondary post hoc analyses of the one-year data suggested a possible DBS-f benefit for participants≥65 years. Objective: To examine the long-term safety and clinical effects of sustained …and delayed-on DBS-f treatment of mild AD after two years. Methods: 42 participants underwent implantation of DBS-f electrodes, with half randomized to active DBS-f stimulation (early on) for two years and half to delayed-on (sham) stimulation after 1 year to provide 1 year of active DBS-f stimulation (delayed on). We evaluated safety and clinical outcomes over the two years of the trial. Results: DBS-f had a favorable safety profile with similar rates of adverse events across both trial phases (years 1 and 2) and between treatment arms. There were no differences between treatment arms on any primary clinical outcomes. However, post-hoc age group analyses suggested a possible benefit among older (>65) participants. Conclusion: DBS-f was safe. Additional study of mechanisms of action and methods for titrating stimulation parameters will be needed to determine if DBS has potential as an AD treatment. Future efficacy studies should focus on patients over age 65. Show more

Keywords: Alzheimer’s disease, deep brain stimulation, dementia, delayed start, fornix, treatment

DOI: 10.3233/JAD-180121

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 597-606, 2018

Authors: Bae, Jong Bin | Han, Ji Won | Kwak, Kyung Phil | Kim, Bong Jo | Kim, Shin Gyeom | Kim, Jeong Lan | Kim, Tae Hui | Ryu, Seung-Ho | Moon, Seok Woo | Park, Joon Hyuk | Youn, Jong Chul | Lee, Dong Young | Lee, Dong Woo | Lee, Seok Bum | Lee, Jung Jae | Jhoo, Jin Hyeong | Kim, Ki Woong

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI) is a cognitive state that lies on the continuum between normal aging and dementia, and the prevalence of MCI is higher than dementia. However, the risk for mortality of people with MCI has been far less studied than that of people with dementia, and the population attributable risk percent (PAR%) of death attributable to MCI has not been estimated yet. Objective: To investigate the impact of MCI on mortality and the cause of death in the elderly, and to estimate the PAR% of deaths attributable to MCI. Methods: Data came from …7,315 elderly subjects aged ≥60 years without dementia from two cohort studies with diagnostic assessments of MCI at baseline. Deaths among participants were confirmed through the nationwide mortality database of Statistics Korea. Results: MCI increased the risk of mortality in a multivariate Cox proportional model adjusting for age, sex, education, smoking, alcohol drinking, chronic illness, depression, vascular components, and cohort (hazard ratio = 1.59, 95% confidence interval 1.30, 1.94). PAR% of death attributable to MCI was 10.7% for age 65–74 years, 16.0% for age 75–84 years, and 24.2% for age ≥85 years. In the elderly with MCI, mortality risks from cerebrovascular disease, respiratory disease, and external causes were higher than in the cognitively normal elderly. Conclusions: Our results suggest that the mortality risk of MCI in Asian countries may be comparable to that in Western countries, and MCI can contribute to the death of the elderly as much as dementia. Show more

Keywords: Cause of death, cognitive dysfunction, death, epidemiology, neurocognitive disorders, mortality

DOI: 10.3233/JAD-171182

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 607-616, 2018

Authors: Craven, Kristen M. | Kochen, William R. | Hernandez, Carlos M. | Flinn, Jane M.

Article Type: Research Article

Abstract: Hyperphosphorylated tau protein is a key pathology in Alzheimer’s disease (AD), frontotemporal dementia, chronic traumatic encephalopathy, and Parkinson’s disease. The essential trace element zinc exacerbates tauopathy in vitro as well as in a Drosophila model of AD. However, the interaction has never been assessed behaviorally or biochemically in mammals. Zinc supplementation is prevalent in society, finding use as a treatment for macular degeneration and cataracts, and is also taken as an immune system booster with high levels appearing in multivitamins marketed toward the elderly. Using a transgenic mouse model that contains the human gene for tau protein (P301L), …we assessed the effects of excess chronic zinc supplementation on tau pathology. Behavioral tests included nest building, circadian rhythm, Morris Water Maze, fear conditioning, and open field. Biochemically, total tau and Ser396 phosphorylation were assessed using western blot. Number of tangles were assessed by Thioflavin-S and free zinc levels were assessed by Zinpyr-1. Tau mice demonstrated behavioral deficits compared to control mice. Zinc supplementation exacerbated tauopathic deficits in circadian rhythm, nesting behavior, and Morris Water Maze. Biochemically, zinc-supplemented tau mice showed increased phosphorylation at pSer396. Zinc supplementation in tau mice also increased tangle numbers in the hippocampus while decreasing free-zinc levels, demonstrating that tangles were sequestering zinc. These results show that zinc intensified the deficits in behavior and biochemistry caused by tau. Show more

Keywords: Circadian rhythm, spatial memory, tau proteins, tauopathies, western blotting, zinc

DOI: 10.3233/JAD-180151

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 617-630, 2018

Authors: Barnes, Josephine | Bartlett, Jonathan W. | Wolk, David A. | van der Flier, Wiesje M. | Frost, Chris

Article Type: Research Article

Abstract: Health-care professionals, patients, and families seek as much information as possible about prognosis for patients with Alzheimer’s disease (AD); however, we do not yet have a robust understanding of how demographic factors predict prognosis. We evaluated associations between age at presentation, age of onset, and symptom length with cognitive decline as measured using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating sum-of-boxes (CDR-SOB) in a large dataset of AD patients. Age at presentation was associated with post-presentation decline in MMSE (p < 0.001), with younger patients showing faster decline. There was little evidence of an association with change …in CDR-SOB. Symptom length, rather than age, was the strongest predictor of MMSE and CDR-SOB at presentation, with increasing symptom length associated with worse outcomes. The evidence that younger AD patients have a more aggressive disease course implies that early diagnosis is essential. Show more

Keywords: Age factors, age of onset, Alzheimer’s disease, cognition, cognitive decline

DOI: 10.3233/JAD-170841

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 631-642, 2018

Authors: Thomann, Alessandra E. | Goettel, Nicolai | Monsch, Raphael J. | Berres, Manfred | Jahn, Thomas | Steiner, Luzius A. | Monsch, Andreas U.

Article Type: Research Article

Abstract: Background: The Montreal Cognitive Assessment (MoCA) is used to evaluate multiple cognitive domains in elderly individuals. However, it is influenced by demographic characteristics that have yet to be adequately considered. Objective: The aim of our study was to investigate the effects of age, education, and sex on the MoCA total score and to provide demographically adjusted normative values for a German-speaking population. Methods: Subjects were recruited from a registry of healthy volunteers. Cognitive health was defined using the Mini-Mental State Examination (score ≥27/30 points) and the Consortium to Establish a Registry for Alzheimer’s Disease-Neuropsychological Assessment Battery …(total score ≥85.9 points). Participants were assessed with the German version of the MoCA. Normative values were developed based on regression analysis. Covariates were chosen using the Predicted Residual Sums of Squares approach. Results: The final sample consisted of 283 participants (155 women, 128 men; mean (SD) age = 73.8 (5.2) years; education = 13.6 (2.9) years). Thirty-one percent of participants scored below the original cut-off (<26/30 points). The MoCA total score was best predicted by a regression model with age, education, and sex as covariates. Older age, lower education, and male sex were associated with a lower MoCA total score (p  < 0.001). Conclusion: We developed a formula to provide demographically adjusted standard scores for the MoCA in a German-speaking population. A comparison with other MoCA normative studies revealed considerable differences with respect to selection of volunteers and methods used to establish normative data. Show more

Keywords: Elderly individuals, healthy participants, mild cognitive impairment, Montreal Cognitive Assessment, regression analysis

DOI: 10.3233/JAD-180080

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 643-655, 2018

Authors: Larsson, Susanna C. | Markus, Hugh S.

Article Type: Research Article

Abstract: Background: Epidemiological evidence has associated Alzheimer’s disease (AD) with vascular risk factors (VRFs), but whether treatment of VRFs reduces the incidence of dementia and AD is uncertain. Objective: To conduct a systematic review and meta-analysis to summarize available data on the impact of treatment of VRFs on dementia and AD incidence. Methods: Pertinent studies published until 1 January 2018 were identified from PubMed. Both randomized controlled trials (RCT) and prospective studies that investigated the impact of treatment of VRFs on dementia or AD incidence were included. Results: …Eight RCTs and 52 prospective studies were identified. Antihypertensive treatment was associated with a non-significant reduced risk of dementia in RCTs (n = 5; relative risk [RR], 0.84; 95% confidence interval [CI], 0.69–1.02) and prospective studies (n = 3; RR, 0.77; 95% CI, 0.58–1.01) and with reduced AD risk in prospective studies (n = 5; RR = 0.78; 95% CI, 0.66–0.91). In prospective studies, treatment of hyperlipidemia with statins, but not nonstatin lipid-lowering agents, was associated with reduced risk of dementia (n = 17; RR, 0.77; 95% CI, 0.63–0.95) and AD (n = 13; RR, 0.86; 95% CI, 0.80–0.92). The single RCT on statins and dementia incidence showed no association. Data from one RCT and six prospective studies did not support a beneficial impact of antidiabetic drugs or insulin therapy on dementia risk. Conclusion: Current evidence indicates that antihypertensives and statins might reduce the incidence of dementia and AD. Further trials to determine the effect of VRF on AD are needed. Show more

Keywords: Alzheimer’s disease, dementia, meta-analysis, prevention, prospective studies, randomized controlled trials, risk factors, systematic review

DOI: 10.3233/JAD-180288

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 657-668, 2018

Authors: Mandal, Pravat K. | Shukla, Deepika

Article Type: Correction

DOI: 10.3233/JAD-189005

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 669-670, 2018