Journal of Alzheimer's Disease - Volume 56, issue 4

Authors: Chang, Ki Jung | Hong, Chang Hyung | Lee, Kang Soo | Kang, Dae Ryong | Lee, Jeong Dong | Choi, Seong Hye | Kim, Seong Yoon | Na, Duk L. | Seo, Sang Won | Kim, Do-Kwan | Lee, Yunhwan | Chung, Young Ki | Lim, Ki Young | Noh, Jai Sung | Park, Jungsik | Son, Sang Joon

Article Type: Research Article

Abstract: Background/Objective: We aimed to compare the risk of mortality in patients with early-onset Alzheimer’s disease (EOAD) versus those with late-onset AD (LOAD) using a large number of study subjects. We applied propensity score matching (PSM) to minimize confounding biases in the comparison between EOAD and LOAD. Methods: We obtained data from elderly Korean subjects with AD (n  = 3,611) at baseline from the CREDOS cohort study, which was conducted from November 2005 to July 2013. We conducted PSM to reduce the bias due to confounding variables related to survival in patients with AD. The risks of mortality associated …with EOAD and LOAD were evaluated by Cox proportional hazard analyses, controlling for relevant covariates. Results: After propensity score matching, 312 subjects with EOAD and 624 subjects with LOAD were selected for further analysis. The Cox proportional hazard analysis showed that patients with EOAD are at a greater risk for mortality compared to those with LOAD (Hazard Ratio: 2.01, 95% CI: 1.01–4.00, p -value: 0.04) when controlling for the direct effect of aging on mortality. The results did not change after adjusting for age at diagnosis, general cognitive function, nutritional factor related to body mass index, and physical disability using activities of daily living. The results support the assumption that EOAD takes a more malignant course than LOAD. Conclusions: Our results provide support for the idea that EOAD takes a clinical course that is distinct from that of LOAD, especially as pertains to the risk of mortality. Show more

Keywords: Early-onset Alzheimer’s disease, late-onset Alzheimer’s disease, mortality, propensity score matching

DOI: 10.3233/JAD-161181

Citation: Journal of Alzheimer's Disease, vol. 56, no. 4, pp. 1341-1348, 2017

Authors: Kallio, Eeva-Liisa | Öhman, Hanna | Kautiainen, Hannu | Hietanen, Marja | Pitkälä, Kaisu

Article Type: Research Article

Abstract: Background: Cognitive training (CT) refers to guided cognitive exercises designed to improve specific cognitive functions, as well as enhance performance in untrained cognitive tasks. Positive effects of CT on cognitive functions in healthy elderly people and persons with mild cognitive impairment have been reported, but data regarding the effects of CT in patients with dementia is unclear. Objective: We systematically reviewed the current evidence from randomized controlled trials (RCTs) to find out if CT improves or stabilizes cognition and/or everyday functioning in patients with mild and moderate Alzheimer’s disease. Results: Altogether, 31 RCTs with CT …as either the primary intervention or part of a broader cognitive or multi-component intervention were found. A positive effect was reported in 24 trials, mainly on global cognition and training-specific tasks, particularly when more intensive or more specific CT programs were used. Little evidence of improved everyday functioning was found. Conclusions: Despite some positive findings, the inaccurate definitions of CT, inadequate sample sizes, unclear randomization methods, incomplete datasets at follow-up and multiple testing may have inflated the results in many trials. Future high quality RCTs with appropriate classification and specification of cognitive interventions are necessary to confirm CT as an effective treatment option in Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, cognition, cognitive training, dementia, systematic review

DOI: 10.3233/JAD-160810

Citation: Journal of Alzheimer's Disease, vol. 56, no. 4, pp. 1349-1372, 2017

Authors: McKinnon, Andrew C. | Duffy, Shantel L. | Cross, Nathan E. | Terpening, Zoe | Grunstein, Ron R. | Lagopoulos, Jim | Batchelor, Jennifer | Hickie, Ian B. | Lewis, Simon J.G. | Shine, James M. | Naismith, Sharon L.

Article Type: Research Article

Abstract: Background: Sleep disturbance is prevalent in MCI, and is a risk factor for cognitive deterioration. Objective: To identify functional connectivity deficits in the default mode network (DMN) in patients with mild cognitive impairment (MCI) and sleep disturbance, relative to MCIs with intact sleep. Methods: Participants comprised 47 adults aged 55 years and over, recruited from the Healthy Brain Ageing Clinic at the Brain and Mind Centre, Sydney, Australia. This sample contained 15 controls and 32 participants meeting criteria for MCI. Participants underwent resting-state fMRI and actigraphy, along with comprehensive neuropsychological, medical and psychiatric assessment. MCIs …were split into two groups according to average wake after sleep onset (WASO) per night. WASO equal to or greater than 1 standard deviation (SD) above the control mean was deemed to reflect disturbed sleep. There were 11 patients in the MCI sleep-disturbed group, and 21 in the MCI sleep-intact group. Results: Relative to controls, MCIs demonstrated significant connectivity reductions between parietal and temporoparietal regions, and between temporal regions. Relative to MCIs with intact sleep, MCIs with sleep disturbance demonstrated reductions in functional connectivity between temporal and parietal regions, and between temporal and temporoparietal regions. Conclusions: MCIs with nocturnal awakenings demonstrate reductions in DMN connectivity. These reductions comprise brain regions that are crucially involved in sleep and memory processes. These results strengthen our previous findings, which found reduced connectivity in MCIs with self-reported sleep disturbances. Future studies may build on these findings through incorporating complementary neuroimaging techniques and experimental manipulations of sleep. Show more

Keywords: Actigraphy, default mode network, memory, mild cognitive impairment, sleep

DOI: 10.3233/JAD-160922

Citation: Journal of Alzheimer's Disease, vol. 56, no. 4, pp. 1373-1384, 2017

Authors: Baazaoui, Narjes | Flory, Michael | Iqbal, Khalid

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a slow, progressive neurodegenerative disease in which cognitive decline takes place over a period of several years with a very variable period of mild cognitive impairment (MCI) and, in some cases, relatively long period before progression to dementia. The cognitive deficit during MCI is probably due to neuronal loss, an intermediate level of amyloid-β (Aβ) plaques and neurofibrillary tangles (NFT) and synaptosis, which is interrupted with a transient compensatory increase. We found impairment in reference memory accompanied by a decrease in the expression of synaptophysin, β-III tubulin, and MAP2 and a trend for GluR1, at 12 …weeks of age in 3xTg-AD mice (hAPPSwe , P301L tau, PS1 [M146V] knock-in), a widely used transgenic model of AD. Past 12 weeks, the cross-sectional analysis of different age groups showed a compensatory increase in synaptic markers relative to that in wild type animals in a topographic and time-dependent manner. When studied across time we found that in 3xTg-AD mice, the compensatory phenomenon occurred in parallel in different regions of the brain. However, this attempt of the brain to repair itself was able to only partially rescue cognitive impairment. These findings for the first time raise the intriguing possibility that AD causing mutated transgenes may initially cause an increase in synaptic and dendritic markers as a compensatory mechanism for synaptic deficit, and this phenomenon, though transient, could be the biological basis of the period of MCI seen in AD. Show more

Keywords: Alzheimer’s disease, cognitive impairment, neuronal plasticity, synaptic compensation, 3xTg-AD transgenic mouse model

DOI: 10.3233/JAD-160845

Citation: Journal of Alzheimer's Disease, vol. 56, no. 4, pp. 1385-1401, 2017

Authors: Li, Lin | Xu, Shaofeng | Liu, Lifei | Feng, Rentian | Gong, Yongxiang | Zhao, Xuyang | Li, Jiang | Cai, Jie | Feng, Nan | Wang, Ling | Wang, Xiaoliang | Peng, Ying

Article Type: Research Article

Abstract: The dyshomeostasis of transition metal ions, accumulation of amyloid-β (Aβ) senile plaques and neuroinflammatory response found in the brain of patients with Alzheimer’s disease (AD) have been suggested to be involved in AD pathogenesis. Novel compounds capable of targeting metal-Aβ species and neuroinflammation would be valuable. AD-35 is such a patented small-molecule compound derived from innovative modification of the chemical structure of donepezil. This compound could moderately inhibit acetylcholinesterase and metal-induced Aβ aggregation in vitro and showed disassembly of Aβ aggregates. The effects of AD-35 on cognitive impairments and neuroinflammatory changes caused by intracerebroventricular injection of Aβ25–35 were …studied in rats. Compared to sham group, Aβ25–35 injection significantly led to learning and memory deficits, astrocyte activation, and pro-inflammatory cytokines releases (TNF-α and IL-1β). Further studies indicated that the phosphorylation of extracellular signal-regulated kinase was involved in astrocyte activation and pro-inflammatory cytokines production. Oral administration of AD-35 could markedly attenuate Aβ25–35 injection-induced astrocyte activation, pro-inflammatory cytokines TNF-α and IL-1β release, and memory deficits. On the contrary, donepezil only showed inhibition of IL-1β production, but failed to block astrocyte activation and TNF-α production. These results showed that AD-35 would be a novel multi-mechanism drug for the prevention and/or treatment of AD. Show more

Keywords: AD-35, Alzheimer’s disease, amyloid-β, cognitive impairment, metal ions, neuroinflammatory response

DOI: 10.3233/JAD-160587

Citation: Journal of Alzheimer's Disease, vol. 56, no. 4, pp. 1403-1417, 2017

Authors: Granholm, Eric L. | Panizzon, Matthew S. | Elman, Jeremy A. | Jak, Amy J. | Hauger, Richard L. | Bondi, Mark W. | Lyons, Michael J. | Franz, Carol E. | Kremen, William S.

Article Type: Research Article

Abstract: Task-evoked pupillary responses may be a psychophysiological biomarker of early risk for mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Pupil dilation during cognitive tasks reflects cognitive effort until compensatory capacity is surpassed and performance declines are manifest, and reflects activation in the locus coeruleus, where degenerative changes have been found in the earliest stages of AD. We recorded pupillary responses during digit span recall in 918 participants ages 56–66. Despite normal performance, amnestic single-domain MCI (S-MCI) participants showed greater pupil dilation than non-amnestic S-MCI and cognitively normal (CN) participants at lower cognitive loads. Multi-domain MCI (M-MCI) participants failed to …modulate effort across cognitive loads and showed poorer performance. Pupillary responses differentiated MCI and CN groups. Amnestic S-MCI participants required compensatory effort to maintain performance, consistent with increased risk for decline. Greater effort in CN individuals might indicate risk for MCI. Results are consistent with dysfunction in locus coeruleus-linked brain systems. This brief task shows promise as a biomarker for early MCI and AD risk prediction. Show more

Keywords: Alzheimer’s disease, compensatory cognitive effort, mild cognitive impairment, pupillometry, pupillary responses

DOI: 10.3233/JAD-161078

Citation: Journal of Alzheimer's Disease, vol. 56, no. 4, pp. 1419-1428, 2017

Authors: Thygesen, Lau Caspar | Gimsing, Louise NØrreslet | Bautz, Andrea | Hvidt, Niels Christian | Johansen, Christoffer

Article Type: Research Article

Abstract: Background: Limited knowledge of the influence of lifestyle risk factors and religious living on chronic neurological diseases exists. Seventh-day Adventists (SDA) do not consume tobacco, alcohol, or pork, and many adhere to lacto-ovo-vegetarian diet, and Baptists discourage excessive use of alcohol and tobacco. Objective: We investigated whether the incidence of four common chronic neurological illnesses: dementia, Alzheimer’s disease, Parkinson’s disease, and epilepsy in a large cohort of Danish Adventists and Baptists was different compared to the general Danish population. Three of the illnesses are neurodegenerative, whereas epilepsy can occur at any age. Methods: We compared …hospital admission rates for some major neurological diseases among members of the Danish Religious Societies Health Study comprising 6,532 SDA and 3,720 Baptists with the general Danish population. Standardized incidence ratios (SIR) stratified by sex, age, and calendar time were calculated. Results: SIR of dementia or Alzheimer’s disease was significantly decreased for members of both communities (SDA, 0.78; 95% CI, 0.67–#x2013;0.90 and Baptists, 0.59; 0.47–#x2013;0.73). The SIRs of Parkinson’s disease and epilepsy were not significantly different compared to the general population. Conclusions: We observe reduced incidence for dementia or Alzheimer’s disease in a large cohort of members of two religious communities characterized by lifestyle recommendations. More studies are needed to disentangle the interaction between such lifestyle and other components of the religious belief system. Show more

Keywords: Alzheimer’s disease, cohort study, cognitive disorders, epidemiology, epilepsy, Parkinson’s disease

DOI: 10.3233/JAD-160710

Citation: Journal of Alzheimer's Disease, vol. 56, no. 4, pp. 1429-1435, 2017

Authors: Timmers, Maarten | Barão, Soraia | Van Broeck, Bianca | Tesseur, Ina | Slemmon, John | De Waepenaert, Katja | Bogert, Jennifer | Shaw, Leslie M. | Engelborghs, Sebastiaan | Moechars, Dieder | Mercken, Marc | Van Nueten, Luc | Tritsmans, Luc | de Strooper, Bart | Streffer, Johannes Rolf

Article Type: Research Article

Abstract: The β-site amyloid-β protein precursor (AβPP) cleaving enzyme-1 (BACE1) is the rate limiting enzyme in the generation of amyloid-β peptide (Aβ) from AβPP, one of the major pathways in Alzheimer’s disease (AD) pathology. Increased BACE1 levels and activity have been reported in the brain of patients with sporadic AD. Therefore, changes of BACE1 levels in the cerebrospinal fluid (CSF) have also been investigated as a possible biomarker of the disease. We analyzed BACE1 levels in CSF of elderly healthy participants before and after chronic treatment with a BACE inhibitor (BACEi) and evaluated the correlation between BACE1 levels and downstream AD …markers. Overall, BACE1 CSF levels showed strong correlations to all downstream AD markers investigated. This is the first reported finding that shows BACE1 levels in CSF were well correlated to its end product Aβ1 - 42 . As previously described, BACE1 levels were strongly correlated to total-tau and phosphorylated tau levels in CSF. Generally, chronic BACE inhibition did not influence BACE1 CSF protein levels. Follow-up studies including early-stage AD pathophysiology and prodromal AD patients will help to understand the importance of measuring BACE1 routinely in daily clinical practice and AD clinical trials. Show more

Keywords: AD markers, Alzheimer’s disease, BACE-1, β-secretase enzyme, JNJ-54861911

DOI: 10.3233/JAD-160829

Citation: Journal of Alzheimer's Disease, vol. 56, no. 4, pp. 1437-1449, 2017

Authors: Stoccoro, Andrea | Tannorella, Pierpaola | Salluzzo, Maria Grazia | Ferri, Raffaele | Romano, Corrado | Nacmias, Benedetta | Siciliano, Gabriele | Migliore, Lucia | Coppedè, Fabio

Article Type: Research Article

Abstract: Background: A functional polymorphism in the methylenetetrahydrofolate reductase (MTHFR ) gene, namely C677T (rs1801133), results in increased Hcy levels and has been associated with risk of late-onset Alzheimer’s disease (LOAD). Many investigators reported association between rs1801133 and LOAD risk in Asian populations and in carriers of the apolipoprotein E (APOE ) ɛ 4 allele, but recent meta-analyses suggest a contribution also in other populations, including Caucasians and/or northern Africans. Objective: To further address this issue, we performed a relatively large case-control study, including 581 LOAD patients and 468 matched controls of Italian origin. APOE data were …available for a subgroup of almost 600 subjects. Methods: Genotyping for rs1801133 was performed with PCR-RFLP techniques. Results: In the total population, the MTHFR 677T allele (OR = 1.20; 95% CI = 1.01–1.43) and carriers of the MTHFR 677T allele (CT+TT versus CC: OR = 1.34; 95% CI = 1.03–1.73) resulted in increased LOAD risk. Similarly, in APOE ɛ 4 carriers, we observed an increased frequency of MTHFR 677CT carriers (CT versus CC: OR = 2.82; 95% CI = 1.25–6.32). Very interestingly, also in non-APOE ɛ 4 carriers, both MTHFR 677T allele (OR = 1.38; 95% CI = 1.03–1.85) and MTHFR 677TT genotype (OR = 2.08; 95% CI = 1.11–3.90) were associated with LOAD. All these associations survived after corrections for age, gender, and multiple testing. Conclusions: The present results suggest that the MTHFR C677T polymorphism is likely a LOAD risk factor in our cohort, either in APOE ɛ 4 or in non-APOE ɛ 4 carriers. Show more

Keywords: Alzheimer’s disease, APOE, folate, homocysteine, methylenetetrahydrofolate reductase, MTHFR C677T

DOI: 10.3233/JAD-161081

Citation: Journal of Alzheimer's Disease, vol. 56, no. 4, pp. 1451-1457, 2017

Authors: Castellano, Christian-Alexandre | Paquet, Nancy | Dionne, Isabelle J. | Imbeault, Hélène | Langlois, Francis | Croteau, Etienne | Tremblay, Sébastien | Fortier, Mélanie | Matte, J. Jacques | Lacombe, Guy | Fülöp, Tamás | Bocti, Christian | Cunnane, Stephen C.

Article Type: Research Article

Abstract: Background: Aerobic training has some benefits for delaying the onset or progression of Alzheimer’s disease (AD). Little is known about the implication of the brain’s two main fuels, glucose and ketones (acetoacetate), associated with thesebenefits. Objective: To determine whether aerobic exercise training modifies brain energy metabolism in mild AD. Methods: In this uncontrolled study, ten patients with mild AD participated in a 3-month, individualized, moderate-intensity aerobic training on a treadmill (Walking). Quantitative measurement of brain uptake of glucose (CMRglu ) and acetoacetate (CMRacac ) using neuroimaging and cognitive testing were done before and after the …Walking program. Results: Four men and six women with an average global cognitive score (MMSE) of 26/30 and an average age of 73 y completed the Walking program. Average total distance and treadmill speed were 8 km/week and 4 km/h, respectively. Compared to the Baseline, after Walking, CMRacac was three-fold higher (0.6±0.4 versus 0.2±0.1 μmol/100 g/min; p  = 0.01). Plasma acetoacetate concentration and the blood-to-brain acetoacetate influx rate constant were also increased by 2–3-fold (all p ≤0.03). CMRglu was unchanged after Walking (28.0±0.1 μmol/100 g/min; p  = 0.96). There was a tendency toward improvement in the Stroop–color naming test (–10% completion time, p  = 0.06). Performance on the Trail Making A&B tests was also directly related to plasma acetoacetate and CMRacac (all p ≤0.01). Conclusion: In mild AD, aerobic training improved brain energy metabolism by increasing ketone uptake and utilization while maintaining brain glucose uptake, and could potentially be associated with some cognitive improvement. Show more

Keywords: Acetoacetate, aerobic training, Alzheimer’s disease, brain energy, cognition, ketones, neuroimaging, PET

DOI: 10.3233/JAD-161163

Citation: Journal of Alzheimer's Disease, vol. 56, no. 4, pp. 1459-1468, 2017