Journal of Alzheimer's Disease - Volume 61, issue 1

Authors: Frederiksen, Kristian Steen | Gjerum, Le | Waldemar, Gunhild | Hasselbalch, Steen Gregers

Article Type: Research Article

Abstract: Physical exercise may be an important adjunct to pharmacological treatment of Alzheimer's disease (AD). Animal studies indicate that exercise may be disease modifying through several mechanisms including reduction of AD pathology. We carried out a systematic review of intervention studies of physical exercise with hippocampal volume (on MRI), amyloid-β, total tau, phosphorylated tau in cerebrospinal fluid (CSF), 18 F-FDG-PET or amyloid PET as outcome measures in healthy subjects, patients with subjective memory complaints, mild cognitive impairment, or AD. We identified a total of 8 studies of which 6 investigated the effects of exercise on hippocampal volume in healthy subjects and …1 on CSF biomarkers and 1 on hippocampal volume in AD, and none investigating the remaining outcome measures or patient groups. Methodological quality of identified studies was generally low. One study found a detrimental effect on hippocampal volume and one found a positive effect, whereas the remaining studies did not find an effect of exercise on outcome measures. The present systematic study identified a relatively small number of studies, which did not support an effect of exercise on hippocampal volume. Methodological issues such small to moderate sample sizes and inadequate ramdomization procedures further limits conclusions. Our findings highlight the difficulties in conducting high quality studies of exercise and further studies are needed before definite conclusions may be reached. Show more

Keywords: Alzheimer’s disease, amyloid-β, dementia, 18F-FDG-PET, hippocampus, magnetic resonance imaging, phosphorylated tau, physical activity, physical exercise, total tau

DOI: 10.3233/JAD-170567

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 359-372, 2018

Authors: Lange, Catharina | Suppa, Per | Pietrzyk, Uwe | Makowski, Marcus R. | Spies, Lothar | Peters, Oliver | Buchert, Ralph | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: The aim of this study was to evaluate the incremental benefit of biomarkers for prediction of Alzheimer’s disease dementia (ADD) in patients with mild cognitive impairment (MCI) when added stepwise in the order of their collection in clinical routine. The model started with cognitive status characterized by the ADAS-13 score. Hippocampus volume (HV), cerebrospinal fluid (CSF) phospho-tau (pTau), and the FDG t-sum score in an AD meta-region-of-interest were compared as neurodegeneration markers. CSF-Aβ1-42 was used as amyloidosis marker. The incremental prognostic benefit from these markers was assessed by stepwise Kaplan-Meier survival analysis in 402 ADNI MCI subjects. Predefined cutoffs …were used to dichotomize patients as ‘negative’ or ‘positive’ for AD characteristic alteration with respect to each marker. Among the neurodegeneration markers, CSF-pTau provided the best incremental risk stratification when added to ADAS-13. FDG PET outperformed HV only in MCI subjects with relatively preserved cognition. Adding CSF-Aβ provided further risk stratification in pTau-positive subjects, independent of their cognitive status. Stepwise integration of biomarkers allows stepwise refinement of risk estimates for MCI-to-ADD progression. Incremental benefit strongly depends on the patient’s status according to the preceding diagnostic steps. The stepwise Kaplan-Meier curves might be useful to optimize diagnostic workflow in individual patients. Show more

Keywords: Alzheimer’s disease, biomarker, cerebrospinal fluid, FDG, magnetic resonance imaging, mild cognitive impairment, neuropsychological testing, positron emission tomography, prediction, white matter hyperintensities

DOI: 10.3233/JAD-170705

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 373-388, 2018

Authors: Beggiato, Sarah | Borelli, Andrea Celeste | Ferraro, Luca | Tanganelli, Sergio | Antonelli, Tiziana | Tomasini, Maria Cristina

Article Type: Research Article

Abstract: Background: Based on the pivotal role of astrocytes in brain homeostasis and the strong metabolic cooperation existing between neurons and astrocytes, it has been suggested that astrocytic dysfunctions might cause and/or contribute to neuroinflammation and neurodegenerative processes. Therapeutic approaches aimed at both neuroprotection and neuroinflammation reduction may prove particularly effective in slowing the progression of these diseases. The endogenous lipid mediator palmitoylethanolamide (PEA) displayed neuroprotective and anti(neuro)inflammatory properties, and demonstrated interesting potential as a novel treatment for Alzheimer’s disease. Objective and Methods: We firstly evaluated whether astrocytes could participate in regulating the Aβ42 -induced neuronal damage, by using …primary mouse astrocytes cell cultures and mixed astrocytes-neurons cultures. Furthermore, the possible protective effects of PEA against Aβ42 -induced neuronal toxicity have also been investigated by evaluating neuronal viability, apoptosis, and morphometric parameters. Results: The presence of astrocytes pre-exposed to Aβ42 (0.5μM; 24 h) induced a reduction of neuronal viability in primary mouse astrocytes-neurons co-cultures. Furthermore, under these experimental conditions, an increase in the number of neuronal apoptotic nuclei and a decrease in the number of MAP-2 positive neurons were observed. Finally, astrocytic Aβ42 pre-exposure induced an increase in the number of neurite aggregations/100μm as compared to control (i.e., untreated) astrocytes-neurons co-cultures. These effects were not observed in neurons cultured in the presence of astrocytes pre-exposed to PEA (0.1μM), applied 1 h before and maintained during Aβ42 treatment. Conclusion: Astrocytes contribute to Aβ42 -induced neurotoxicity and PEA, by blunting Aβ42 -induced astrocyte activation, improved neuronal survival in mouse astrocyte-neuron co-cultures. Show more

Keywords: Alzheimer’s disease, cell viability, Hoechst 33258, MAP-2 immunoreactivity

DOI: 10.3233/JAD-170699

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 389-399, 2018

Authors: Seddighi, Sahba | Varma, Vijay R. | An, Yang | Varma, Sudhir | Beason-Held, Lori L. | Tanaka, Toshiko | Kitner-Triolo, Melissa H. | Kraut, Michael A. | Davatzikos, Christos | Thambisetty, Madhav

Article Type: Research Article

Abstract: We recently reported that alpha-2 macroglobulin (A2M) is a biomarker of neuronal injury in Alzheimer’s disease (AD) and identified a network of nine genes co-expressed with A2M in the brain. This network includes the gene encoding SPARCL1, a protein implicated in synaptic maintenance. Here, we examine whether SPARCL1 is associated with longitudinal changes in brain structure and function in older individuals at risk for AD in the Baltimore Longitudinal Study of Aging. Using data from the Gene-Tissue Expression Project, we first identified two single nucleotide polymorphisms (SNPs), rs9998212 and rs7695558, associated with lower brain SPARCL1 gene expression. We …then analyzed longitudinal trajectories of cognitive performance in 591 participants who remained cognitively normal (average follow-up interval: 11.8 years) and 129 subjects who eventually developed MCI or AD (average follow-up interval: 9.4 years). Cognitively normal minor allele carriers of rs7695558 who developed incident AD showed accelerated memory loss prior to disease onset. Next, we compared longitudinal changes in brain volumes (MRI; n  = 120 participants; follow-up = 6.4 years; 826 scans) and resting-state cerebral blood flow (rCBF; 15 O-water PET; n  = 81 participants; follow-up = 7.7 years; 664 scans) in cognitively normal participants. Cognitively normal minor allele carriers of rs9998212 showed accelerated atrophy in several global, lobar, and regional brain volumes. Minor allele carriers of both SNPs showed longitudinal changes in rCBF in several brain regions, including those vulnerable to AD pathology. Our findings suggest that SPARCL1 accelerates AD pathogenesis and thus link neuroinflammation with widespread changes in brain structure and function during aging. Show more

Keywords: Alzheimer’s disease, magnetic resonance imaging, positron emission tomography, single nucleotidepolymorphism

DOI: 10.3233/JAD-170557

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 401-414, 2018

Authors: Su, Li | Hayes, Lawrence | Soteriades, Soteris | Williams, Guy | Brain, Susannah A.E. | Firbank, Michael J. | Longoni, Giulia | Arnold, Robert J. | Rowe, James B. | O’Brien, John T.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is associated with atrophy in entorhinal cortex (ERC), the hippocampus, and its subfields Cornu Ammonis 1 (CA1) and subiculum, which predict conversion from mild cognitive impairment (MCI) to clinical AD. The stratum radiatum, lacunosum, and moleculare (SRLM) are also important gateways involving ERC and CA1, which are affected by early AD pathology. Objective: To assess whether the SRLM is affected in MCI and AD. Methods: In this proof-of-concept study, 27 controls, 13 subjects with AD, and 22 with MCI underwent 3T MRI. T1 maps were used for whole-hippocampal volumetry, T2 maps were …segmented for hippocampal subfield areas, entorhinal cortex and subiculum thickness, and evaluated for SRLM integrity. Results: Significant CA1 atrophy and subiculum thinning were found in both AD and MCI compared to similarly aged controls. However, SRLM integrity was only significantly reduced in AD but not in MCI compared to controls. There were no significant differences in other hippocampal subfields (CA2, CA3/dentate gyrus) or ERC thickness between the groups. Finally, CA1 and CA3/DG areas and SRLM clarity were correlated with clinical and cognitive measurements of disease severity. Conclusion: Although this study was cross sectional, it suggests a progression of specific subfield changes from MCI to established AD that is associated with the reduced integrity of SRLM, which may reflect more widespread hippocampal involvement as the disease progresses and the relative preservation of SRLM in MCI. These results provide new MRI biomarkers for disease staging and understanding of the neurobiology in AD. Show more

Keywords: Alzheimer’s disease, CA1, dementia, hippocampal, magnetic resonance imaging, mild cognitive impairment, segmentation, SRLM, subfield, subiculum

DOI: 10.3233/JAD-170344

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 415-424, 2018

Authors: Fajardo, Val Andrew | Fajardo, Val Andrei | LeBlanc, Paul J. | MacPherson, Rebecca E.K.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) mortality rates have steadily increased over time. Lithium, the current gold standard treatment for bipolar disorder, can exert neuroprotective effects against AD. Objective: We examined the relationship between trace levels of lithium in drinking water and changes in AD mortality across several Texas counties. Methods: 6,180 water samples from public wells since 2007 were obtained and averaged for 234 of 254 Texas counties. Changes in AD mortality rates were calculated by subtracting aggregated age-adjusted mortality rates obtained between 2000–2006 from those obtained between 2009–2015. Using aggregated rates maximized the number of counties …with reliable mortality data. Correlational analyses between average lithium concentrations and changes in AD mortality were performed while also adjusting for gender, race, education, rural living, air pollution, physical inactivity, obesity, and type 2 diabetes. Results: Age-adjusted AD mortality rate was significantly increased over time (+27%, p  < 0.001). Changes in AD mortality were negatively correlated with trace lithium levels (p  = 0.01, r  = –0.20), and statistical significance was maintained after controlling for most risk factors except for physical inactivity, obesity, and type 2 diabetes. Furthermore, the prevalence of obesity and type 2 diabetes positively correlated with changes in AD mortality (p  = 0.01 and 0.03, respectively), but also negatively correlated with trace lithium in drinking water (p  = 0.05 and <0.0001, respectively). Conclusion: Trace lithium in water is negatively linked with changes in AD mortality, as well as obesity and type 2 diabetes, which are important risk factors for AD. Show more

Keywords: Dementia, GSK3, neuroprotection, obesity, type 2 diabetes

DOI: 10.3233/JAD-170744

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 425-434, 2018

Authors: Wilcock, Gordon K. | Gauthier, Serge | Frisoni, Giovanni B. | Jia, Jianping | Hardlund, Jiri H. | Moebius, Hans J. | Bentham, Peter | Kook, Karin A. | Schelter, Bjoern O. | Wischik, Damon J. | Davis, Charles S. | Staff, Roger T. | Vuksanovic, Vesna | Ahearn, Trevor | Bracoud, Luc | Shamsi, Kohkan | Marek, Ken | Seibyl, John | Riedel, Gernot | Storey, John M.D. | Harrington, Charles R. | Wischik, Claude M.

Article Type: Research Article

Abstract: Background: LMTM is being developed as a treatment for AD based on inhibition of tau aggregation. Objectives: To examine the efficacy of LMTM as monotherapy in non-randomized cohort analyses as modified primary outcomes in an 18-month Phase III trial in mild AD. Methods: Mild AD patients (n  = 800) were randomly assigned to 100 mg twice a day or 4 mg twice a day. Prior to unblinding, the Statistical Analysis Plan was revised to compare the 100 mg twice a day as monotherapy subgroup (n  = 79) versus 4 mg twice a day as randomized (n  = 396), and 4 mg twice a day …as monotherapy (n  = 76) versus 4 mg twice a day as add-on therapy (n  = 297), with strong control of family-wise type I error. Results: The revised analyses were statistically significant at the required threshold of p  < 0.025 in both comparisons for change in ADAS-cog, ADCS-ADL, MRI atrophy, and glucose uptake. The brain atrophy rate was initially typical of mild AD in both add-on and monotherapy groups, but after 9 months of treatment, the rate in monotherapy patients declined significantly to that reported for normal elderly controls. Differences in severity or diagnosis at baseline between monotherapy and add-on patients did not account for significant differences in favor of monotherapy. Conclusions: The results are consistent with earlier studies in supporting the hypothesis that LMTM might be effective as monotherapy and that 4 mg twice a day may serve as well as higher doses. A further suitably randomized trial is required to test this hypothesis. Show more

Keywords: ADAS-cog, Alzheimer’s disease, amyloid protein, clinical trial, cohort study, methylthioninium, tau protein, treatment

DOI: 10.3233/JAD-170560

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 435-457, 2018

Authors: Robinson, Morgan | Lee, Brenda Y. | Hanes, Francis T.

Article Type: Correction

DOI: 10.3233/JAD-179007

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 459-459, 2018

Authors: Talan, Jamie

Article Type: Correction

DOI: 10.3233/JAD-179009

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 461-461, 2018