Journal of Alzheimer's Disease - Volume 78, issue 1

Authors: Zygouris, Stelios | Iliadou, Paraskevi | Lazarou, Eftychia | Giakoumis, Dimitrios | Votis, Konstantinos | Alexiadis, Anastasios | Triantafyllidis, Andreas | Segkouli, Sofia | Tzovaras, Dimitrios | Tsiatsos, Thrasyvoulos | Papagianopoulos, Sotirios | Tsolaki, Magda

Article Type: Research Article

Abstract: Background: Literature supports the use of serious games and virtual environments to assess cognitive functions and detect cognitive decline. This promising assessment method, however, has not yet been translated into self-administered screening instruments for pre-clinical dementia. Objective: The aim of this study is to assess the performance of a novel self-administered serious game-based test, namely the Virtual Supermarket Test (VST), in detecting mild cognitive impairment (MCI) in a sample of older adults with subjective memory complaints (SMC), in comparison with two well-established screening instruments, the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE). Methods: …Two groups, one of healthy older adults with SMC (N = 48) and one of MCI patients (N = 47) were recruited from day centers for cognitive disorders and administered the VST, the MoCA, the MMSE, and an extended pencil and paper neuropsychological test battery. Results: The VST displayed a correct classification rate (CCR) of 81.91% when differentiating between MCI patients and older adults with SMC, while the MoCA displayed of CCR of 72.04% and the MMSE displayed a CCR of 64.89%. Conclusion: The three instruments assessed in this study displayed significantly different performances in differentiating between healthy older adults with SMC and MCI patients. The VST displayed a good CCR, while the MoCA displayed an average CCR and the MMSE displayed a poor CCR. The VST appears to be a robust tool for detecting MCI in a population of older adults with SMC. Show more

Keywords: Aging, Alzheimer’s disease, computers, dementia, diagnosis, memory disorders, mild cognitive impairment, serious games, subjective cognitive decline, user-computer interface

DOI: 10.3233/JAD-200880

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 405-412, 2020

Authors: Geerts, Hugo | Spiros, Athan

Article Type: Research Article

Abstract: Background: Many Alzheimer’s disease patients in clinical practice are on polypharmacy for treatment of comorbidities. Objective: While pharmacokinetic interactions between drugs have been relatively well established with corresponding treatment guidelines, many medications and common genotype variants also affect central brain circuits involved in cognitive trajectory, leading to complex pharmacodynamic interactions and a large variability in clinical trials. Methods: We applied a mechanism-based and ADAS-Cog calibrated Quantitative Systems Pharmacology biophysical model of neuronal circuits relevant for cognition in Alzheimer’s disease, to standard-of-care cholinergic therapy with COMTVal158Met, 5-HTTLPR rs25531 , and APOE genotypes and with benzodiazepines, antidepressants, …and antipsychotics, all together 9,585 combinations. Results: The model predicts a variability of up to 14 points on ADAS-Cog at baseline (COMTVV 5-HTTLPRss APOE 4/4 combination is worst) and a four-fold range for the rate of progression. The progression rate is inversely proportional to baseline ADAS-Cog. Antidepressants, benzodiazepines, first-generation more than second generation, and most antipsychotics with the exception of aripiprazole worsen the outcome when added to standard-of-care in mild cases. Low dose second-generation benzodiazepines revert the negative effects of risperidone and olanzapine, but only in mild stages. Non APOE4 carriers with a COMTMM and 5HTTLPRLL are predicted to have the best cognitive performance at baseline but deteriorate somewhat faster over time. However, this effect is significantly modulated by comedications. Conclusion: Once these simulations are validated, the platform can in principle provide optimal treatment guidance in clinical practice at an individual patient level, identify negative pharmacodynamic interactions with novel targets and address protocol amendments in clinical trials. Show more

Keywords: ADAS-Cog, clinical variability, pharmacodynamic interactions, polypharmacy, protocol amendments

DOI: 10.3233/JAD-200688

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 413-424, 2020

Authors: Yuan, Xiaodong | Wang, Lu | Tandon, Neha | Sun, Huili | Tian, Jing | Du, Heng | Pascual, Juan M. | Guo, Lan

Article Type: Research Article

Abstract: Background: Brain energy failure is an early pathological event associated with synaptic dysfunction in Alzheimer’s disease (AD). Thus, mitigation or enhancement of brain energy metabolism may offer a therapeutic avenue. However, there is uncertainty as to what metabolic process(es) may be more appropriate to support or augment since metabolism is a multiform process such that each of the various metabolic precursors available is utilized via a specific metabolic pathway. In the brain, these pathways sustain not only a robust rate of energy production but also of carbon replenishment. Objective: Triheptanoin, an edible odd-chain fatty acid triglyceride, is uncommon …in that it replenishes metabolites in the tricarboxylic acid cycle (TCA) cycle via anaplerosis in addition to fueling the cycle via oxidation, thus potentially leading to both carbon replenishment and enhanced mitochondrial ATP production. Methods: To test the hypothesis that triheptanoin is protective in AD, we supplied mice with severe brain amyloidosis (5×FAD mice) with dietary triheptanoin for four and a half months, followed by biological and biochemical experiments to examine mice metabolic as well as synaptic function. Results: Triheptanoin treatment had minimal impact on systemic metabolism and brain amyloidosis as well as tauopathy while attenuating brain ATP deficiency and mitochondrial dysfunction including respiration and redox balance in 5×FAD mice. Synaptic density, a disease hallmark, was also preserved in hippocampus and neocortex despite profound amyloid deposition. None of these effects took place in treated control mice. Conclusion: These findings support the energy failure hypothesis of AD and justify investigating the mechanisms in greater depth with ultimate therapeutic intent. Show more

Keywords: Alzheimer’s disease, amyloid-β, anaplerosis, mitochondrial function, triheptanoin

DOI: 10.3233/JAD-200594

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 425-437, 2020

Authors: Li, Dongxue | Liu, Yuancheng | Zeng, Xianchun | Xiong, Zhenliang | Yao, Yuanrong | Liang, Daiyi | Qu, Hao | Xiang, Hui | Yang, Zhenggui | Nie, Lisha | Wu, Pu-Yeh | Wang, Rongpin

Article Type: Research Article

Abstract: Background: Advanced Alzheimer’s disease (AD) has no effective treatment, and identifying early diagnosis markers can provide a time window for treatment. Objective: To quantify the changes in cerebral blood flow (CBF) and iron deposition during progression of AD. Methods: 94 subjects underwent brain imaging on a 3.0-T MRI scanner with techniques of three-dimensional arterial spin labeling (3D-ASL) and quantitative susceptibility mapping (QSM). The subjects included 22 patients with probable AD, 22 patients with mild cognitive impairment (MCI), 25 patients with subjective cognitive decline (SCD), and 25 normal controls (NC). The CBF and QSM values were obtained …using a standardized brain region method based on the Brainnetome Atlas. The differences in CBF and QSM values were analyzed between and within groups using variance analysis and correlation analysis. Results: CBF and QSM identified several abnormal brain regions of interest (ROIs) at different stages of AD (p  < 0.05). Regionally, the CBF values in several ROIs of the AD and MCI subjects were lower than for NC subjects (p  < 0.001). Higher QSM values were observed in the globus pallidus. The CBF and QSM values in multiple ROI were negatively correlated, while the putamen was the common ROI of the three study groups (p  < 0.05). The CBF and QSM values in hippocampus were cross-correlated with scale scores during the progression of AD (p  < 0.05). Conclusion: Iron deposition in the basal ganglia and reduction in blood perfusion in multiple regions existed during the progression of AD. The QSM values in putamen can be used as an imaging biomarker for early diagnosis of AD. Show more

Keywords: Alzheimer’s disease, Brainnetome Atlas, 3D-arterial spin labeling, quantitative susceptibility mapping

DOI: 10.3233/JAD-200843

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 439-452, 2020

Authors: Alafuzoff, Irina | Libard, Sylwia

Article Type: Research Article

Abstract: Background: Systemic diseases, diabetes mellitus (DM), and cardiovascular disease (CaVD) have been suggested being risk factors for cognitive impairment (CI) and/or influence Alzheimer’s disease neuropathologic change (ADNC). Objective: The purpose was to assess the type and the extent of neuropathological alterations in the brain and to assess whether brain pathology was associated with CaVD or DM related alterations in peripheral organs, i.e., vessels, heart, and kidney. Methods: 119 subjects, 15% with DM and 24% with CI, age range 80 to 89 years, were chosen and neuropathological alterations were assessed applying immunohistochemistry. Results: Hyperphosphorylated τ …(HPτ ) was seen in 99%, amyloid-β (Aβ) in 71%, transactive DNA binding protein 43 (TDP43) in 62%, and α -synuclein (α S) in 21% of the subjects. Primary age related tauopathy was diagnosed in 29% (more common in females), limbic predominant age-related TDP encephalopathy in 4% (14% of subjects with CI), and dementia with Lewy bodies in 3% (14% of subjects with CI) of the subjects. High/intermediate level of ADNC was seen in 47% and the extent of HPτ increased with age. The extent of ADNC was not associated with the extent of pathology observed in peripheral organs, i.e., DM or CaVD. Contrary, brain alterations such as pTDP43 and cerebrovascular lesions (CeVL) were influenced by DM, and CeVL correlated significantly with the extent of vessel pathology. Conclusion: In most (66%) subjects with CI, the cause of impairment was “mixed pathology”, i.e., ADNC combined with TDP43, α S, or vascular brain lesions. Furthermore, our results suggest that systemic diseases, DM and CaVD, are risk factors for CI but not related to ADNC. Show more

Keywords: Aging, α-synuclein, amyloid-β , cardiac pathology, cerebrovascular lesions, hyperphosphorylated-τ , nephrosclerosis, transactive DNA binding protein 43

DOI: 10.3233/JAD-200925

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 453-465, 2020

Authors: Mezlini, Aziz M. | Magdamo, Colin | Merrill, Emily | Chibnik, Lori B. | Blacker, Deborah L. | Hyman, Bradley T. | Das, Sudeshna

Article Type: Research Article

Abstract: Background: The APOE ɛ 4 allele is the largest genetic risk factor for late-onset Alzheimer’s disease (AD). Recent literature suggested that the contribution of APOE ɛ 4 to AD risk could be population-specific, with ɛ 4 conferring a lower risk to Blacks or African Americans. Objective: To investigate the effect of APOE haplotypes on AD risk in individuals with European ancestry (EU) and Blacks or African Americans (AA). Methods: We selected data from 1) the National Alzheimer’s Coordinating Center: a total of 3,486 AD cases and 4,511 controls (N = 7,997, 60% female) with genotypes …from the Alzheimer’s Disease Genetics Consortium (ADGC), and 2) the Rush University Religious Orders Study and Memory and Aging Project (ROSMAP) cohort with 578 AD and 670 controls (N = 1,248, 60% female). Using ɛ 3 homozygotes as the reference, we compared the association of various APOE haplotypes with the clinical and neuropathological correlates of dementia in AA and EU. Results: In both cohorts, we find no difference in the odds or age of onset of AD among the ɛ 4-linked haplotypes defined by rs769449 within either AA or EU. Additionally, while APOE ɛ 4 was associated with a faster rate of decline, no differences were found in rate of decline, clinical or neuropathological features among the ɛ 4-linked haplotypes. Further analysis with other variants near the APOE locus failed to identify any effect modification. Conclusion: Our study finds similar effects of the ɛ 4-linked haplotypes defined by rs769449 on AD as compared to ɛ 3 in both AA and EU. Future studies are required to understand the heterogeneity of APOE conferred risk of AD among various genotypes and populations. Show more

Keywords: African Americans, APOE , clinicopathological features, Europeans, genotype

DOI: 10.3233/JAD-200228

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 467-477, 2020