Journal of Alzheimer's Disease - Volume 74, issue 1

Authors: Postolache, Teodor T. | Wadhawan, Abhishek | Can, Adem | Lowry, Christopher A. | Woodbury, Margaret | Makkar, Hina | Hoisington, Andrew J. | Scott, Alison J. | Potocki, Eileen | Benros, Michael E. | Stiller, John W.

Article Type: Review Article

Abstract: There is an increasing evidence that inflammation contributes to clinical and functional outcomes in traumatic brain injury (TBI). Many successful target-engaging, lesion-reducing, symptom-alleviating, and function-improving interventions in animal models of TBI have failed to show efficacy in clinical trials. Timing and immunological context are paramount for the direction, quality, and intensity of immune responses to TBI and the resulting neuroanatomical, clinical, and functional course. We present components of the immune system implicated in TBI, potential immune targets, and target-engaging interventions. The main objective of our article is to point toward modifiable molecular and cellular mechanisms that may modify the outcomes …in TBI, and contribute to increasing the translational value of interventions that have been identified in animal models of TBI. Show more

Keywords: Depression, glia, immune challenge, immunomodulation, inflammation, priming, probiotic, traumatic brain injury

DOI: 10.3233/JAD-191150

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 1-28, 2020

Authors: Li, Xiaoran | Liu, Chunyan | Wang, Rong

Article Type: Review Article

Abstract:  Light modulation plays an important role in understanding the pathology of brain disorders and improving brain function. Optogenetic techniques can activate or silence targeted neurons with high temporal and spatial accuracy and provide precise control, and have recently become a method for quick manipulation of genetically identified types of neurons. Photobiomodulation (PBM) is light therapy that utilizes non-ionizing light sources, including lasers, light emitting diodes, or broadband light. It provides a safe means of modulating brain activity without any irreversible damage and has established optimal treatment parameters in clinical practice. This manuscript reviews 1) how optogenetic approaches have been used …to dissect neural circuits in animal models of Alzheimer’s disease, Parkinson’s disease, and depression, and 2) how low level transcranial lasers and LED stimulation in humans improves brain activity patterns in these diseases. State-of-the-art brain machine interfaces that can record neural activity and stimulate neurons with light have good prospects in the future. Show more

Keywords: Alzheimer’s disease, brain-machine interfaces, depression, optogenetics, Parkinson’s disease, photobiomodulation, transcranial near-infrared stimulation

DOI: 10.3233/JAD-191240

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 29-41, 2020

Authors: Kuhn, Ariel J. | Raskatov, Jevgenij

Article Type: Review Article

Abstract: Despite the vast heterogeneity of amyloid plaques isolated from the brains of those with Alzheimer’s Disease (AD), the basis of the Amyloid Cascade Hypothesis targets a single peptide, the amyloid-β (Aβ) peptide. The countless therapeutic efforts targeting the production and aggregation of this specific peptide have been met with disappointment, leaving many to question the role of Aβ in AD. An alternative cleavage product of the Amyloid-β protein precursor, called the p3 peptide, which has also been isolated from the brains of AD patients, has been largely absent from most Aβ-related studies. Typically referred to as non-amyloidogenic and even suggested …as neuroprotective, the p3 peptide has garnered little attention aside from some conflicting findings on cytotoxicity and potential self-assembly to form higher order aggregates. Herein, we report an extensive analysis of the findings surrounding p3 and offer some evidence as to why it may not be as innocuous as previously suggested. Show more

Keywords: Amyloid-β, amyloids, intrinsically disordered proteins, p3, peptides

DOI: 10.3233/JAD-191201

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 43-53, 2020

Authors: Ezzati, Ali | Lipton, Richard B. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: The ideal participants for Alzheimer’s disease (AD) clinical trials would show cognitive decline in the absence of treatment (i.e., placebo arm) and also would be responsive to the therapeutic intervention being studied (i.e., drug arm). One strategy to boost the power of trials is to enroll individuals who are more likely to progress targeted using data-driven predictive models. Objective: To investigate if machine learning (ML) models can effectively predict clinical disease progression (cognitive decline) in mild-to-moderate AD patients during the timeframe of a phase III clinical trial. Methods: Data from 202 participants with a diagnosis …of AD at baseline from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) was used to train ML classifiers that can differentiate between individuals who had declining cognitive function (DC) and individuals with stable cognitive function (SC). DC was defined as any downward change in the Alzheimer’s Disease Assessment Scale cognitive subscale (ADAS-cog) score over 12 months of follow-up. SC was defined by the absence of decline in ADAS-cog. Trained models were applied to data from 77 participants from the placebo arm of the phase III trial of Semagacestat (LFAN study) to identify subgroups of SC versus DC. Results: Only 74.8% of ADNI participants and 63.6% of LFAN participants had cognitive decline after one year of follow up. K-nearest neighbors (kNN) classifier had an accuracy of 68.3%, sensitivity of 80.1%, and specificity of 33.3% for identifying decliners in ADNI (training sample). In LFAN (validation sample), the model showed an overall accuracy of 61.3%, sensitivity of 65.5%, and specificity of 47.0% in identifying decliners at the 12 months of follow-up. The model had a positive predictive value of 80.8%, which was 17.2% more than the base prevalence of decliners. Conclusions: Machine learning predictive models can be effectively used to boost the power of clinical trials by reducing the sample size. Show more

Keywords: Alzheimer’s disease, clinical trial, cognitive decline, machine learning, predictive analytics

DOI: 10.3233/JAD-190822

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 55-63, 2020

Authors: Shinto, Lynne | Lahna, David | Murchison, Charles F. | Dodge, Hiroko | Hagen, Kirsten | David, Jason | Kaye, Jeffrey | Quinn, Joseph F. | Wall, Rachel | Silbert, Lisa C.

Article Type: Research Article

Abstract: Background: Cerebrovascular disease is a common cause of dementia in older adults, and potentially preventable with early intervention. Oxylipins are produced from the oxidation of long-chain polyunsaturated fatty acids (PUFA) possessing potent vascular effects. Oxylipins generated from the cytochrome P450 pathway are enzymatically converted to diols by soluble epoxide hydrolase (sEH); sEH products have been associated with small vessel ischemic disease. Little is known about oxylipins’ impact on markers of dementia risk. Objective: An exploratory examination of the association between omega-6 and omega-3 derived oxylipins, brain MRI, and cognition. Methods: Thirty-seven non-demented participants with controlled hypertension …(mean age 65.6 years) were enrolled in a dementia prevention study investigating fish oil and lipoic acid on preserving cognitive function. Baseline associations between plasma oxylipins, white matter hyperintensity (WMH), and Trails-B were examined using linear regression. P450-derived diol/epoxide ratio was an indirect measure of sEH activity. Results: Omega-6 derived 9-HODE was associated with increased WMH (p  = 0.017) and reduced grey matter volume (p  = 0.02). Omega-6 P450-derived diol/epoxide ratio 9,10-DiHOME/9,10-EpOME was associated with increased WMH (p  = 0.035) and poorer performance on Trails-B (p  = 0.05); ratio14,15-DHET/14,15-EET was associated with increased WMH (p  = 0.045). Omega-3 P450-derived diol/epoxide ratio 19,20-DiHDPE/19,20-EpDPE was associated with increased WMH (p  = 0.04) and poorer performance on Trails-B (p  = 0.04). Arachidonic acid was associated with better performance on Trails-B (p  = 0.012); Omega-3 derived 16,17-EpDPE was associated with decreased WMH (p  = 0.005). Conclusions: With the exception of arachidonic acid, it was specific oxylipin products, not their parent PUFAs, that were associated with unfavorable and favorable MRI and cognitive markers of dementia risk. Show more

Keywords: Alzheimer’s disease, cross-sectional studies, fatty acids, humans, oxylipins, vascular dementia

DOI: 10.3233/JAD-191197

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 65-77, 2020

Authors: Dorey, Jean-Michel | Rouch, Isabelle | Padovan, Catherine | Boublay, Nawèle | Pongan, Elodie | Laurent, Bernard | PACO Group | von Gunten, Armin | Krolak-Salmon, Pierre

Article Type: Research Article

Abstract: Background: Neuroticism is recognized as the personality domain that is most strongly associated with behavioral and psychological symptoms (BPS) of Alzheimer’s disease (AD). Two sub-components of neuroticism have been recently isolated. Neuroticism-withdrawal (N-withdrawal) refers to the tendency to internalize negative emotion, whereas neuroticism-volatility (N-volatility) reflect the predisposition to externalize negative emotions. Objective: The objective of the current study was to investigate the specific influence of these two sub-components of neuroticism on BPS. Methods: One hundred eighty-seven patients with prodromal or mild AD were drawn from the PACO study (Personalité Alzheimer COmportement). Neuroticism and its facets were …assessed at baseline using the NEO-PI-R inventory. N-withdrawal and N-volatility were isolated using a principal component analysis led on the six facets composing neuroticism. BPS were measured with the short version of Neuropsychiatric Inventory (NPI-Q) and collected at baseline, then every 6 months over an 18-month follow-up. Linear mixed-effect analyses were conducted to investigate the association between N-withdrawal, N-volatility, and the severity of BPS over the follow-up. Results: Mean age of the participant was 79.2±6.5; 59% were female; mean MMSE was 24.5±2.5. Both N-volatility and N-withdrawal were related with the NPI-Q (p  < 0.001; p  = 0,004). N-withdrawal was positively associated with anxiety (p  = 0.001) and depression (p  = 0.002), while N-volatility was positively related to delusions (p  = 0.004), agitation/aggression (p  < 0.001), irritability/volatility (p  = 0.037), and apathy (p  = 0.021). Conclusion: The present study demonstrates that N-volatility and N-withdrawal influence the risk of developing BPS in a different way. These results highlight the relevance of considering sub-components of neuroticism when studying links between personality and BPS. Show more

Keywords: Alzheimer’s disease, behavior, dementia, neuroticism, personality

DOI: 10.3233/JAD-190884

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 79-89, 2020

Authors: Fernando, W.M.A.D. Binosha | Martins, Ian J. | Morici, Michael | Bharadwaj, Prashant | Rainey-Smith, Stephanie R. | Lim, Wei Ling Florence | Martins, Ralph N.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and neuropathological features, including abnormal deposition of amyloid-β (Aβ) peptides, intracellular neurofibrillary tangles, and neuronal death. Identifying therapeutics which can reduce memory deficits at an early stage of the disease has the advantage of slowing or even reversing disease progression before irreversible brain damage has occurred. Consequently, in this study, we investigated the ability of the histone deacetylase inhibitor sodium butyrate (NaB) to attenuate memory deficits in the 5xFAD mouse model of AD following a 12-week feeding regimen. 5xFAD mice demonstrate a unique time course of Aβ pathology, …developing Aβ plaques as early as 2 months. Male mice were assigned to either a control diet or a NaB-supplemented diet which was administered at either 5 mg/kg/day, or 15 mg/kg/day for 12 weeks (each group, N = 15). Supplementation commenced at an early disease stage (8–10 weeks of age). Behavioral testing (contextual and cued fear conditioning) was undertaken, and brain Aβ levels measured, at the end of the 12-week intervention. NaB had profound effects on Aβ levels and on associative learning and cognitive functioning. A 40% reduction in brain Aβ levels and a 25% increase in fear response in both the cued and contextual testing was observed in the NaB-treated animals compared to the control group. These findings suggest that NaB warrants further investigation as a potential therapeutic agent in the treatment of cognitive deficits associated with early stages of AD. Show more

Keywords: Alzheimer’s disease, amyloid-β , fear conditioning, sodium butyrate

DOI: 10.3233/JAD-190120

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 91-99, 2020

Authors: Beyer, Leonie | Brendel, Matthias | Scheiwein, Franziska | Sauerbeck, Julia | Hosakawa, Chisa | Alberts, Ian | Shi, Kuangyu | Bartenstein, Peter | Ishii, Kazunari | Seibyl, John | Cumming, Paul | Rominger, Axel | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Amyloid-β (Aβ) accumulation in brain of patients with suspected Alzheimer’s disease (AD) can be assessed by positron emission tomography (PET) in vivo. While visual classification prevails in the clinical routine, semiquantitative PET analyses may enable more reliable evaluation of cases with a visually uncertain, borderline Aβ accumulation. Objective: We evaluated different analysis approaches (visual/semiquantitative) to find the most accurate and sensitive interpretation of Aβ-PET for predicting risk of progression from mild cognitive impairment (MCI) to AD. Methods: Based on standard uptake value (SUV) ratios of a cortical-composite volume of interest of 18 F-AV45-PET from MCI …subjects (n = 396, ADNI database), we compared three different reference region (cerebellar grey matter, CBL; brainstem, BST; white matter, WM) normalizations and the visual read by receiver operator characteristics for calculating a hazard ratio (HR) for progression to Alzheimer’s disease dementia (ADD). Results: During a mean follow-up time of 45.6±13.0 months, 28% of the MCI cases (110/396) converted to ADD. Among the tested methods, the WM reference showed best discriminatory power and progression-risk stratification (HRWM of 4.4 [2.6–7.6]), but the combined results of the visual and semiquantitative analysis with all three reference regions showed an even higher discriminatory power. Conclusion: A multi-analytical composite of visual and semiquantitative reference tissue analyses of 18F-AV45-PET gave improved risk stratification for progression from MCI to ADD relative to performance of single read-outs. This optimized approach is of special interest for prospective treatment trials, which demand a high accuracy. Show more

Keywords: Alzheimer’s disease, amyloid-β, biomarkers, dementia, mild cognitive impairment, positron emission tomography

DOI: 10.3233/JAD-190818

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 101-112, 2020

Authors: Ademowo, Opeyemi S. | Dias, Irundika H.K. | Diaz-Sanchez, Lorena | Sanchez-Aranguren, Lissette | Stahl, Wilhelm | Griffiths, Helen R.

Article Type: Research Article

Abstract: Mitochondria are important (patho)physiological sources of reactive oxygen species (ROS) that mediate mitochondrial dysfunction and phospholipid oxidation; an increase in mitochondrial content of oxidized phospholipid (OxPL) associates with cell death. Previously we showed that the circulating OxPL 1-palmitoyl-2-(5’-oxo-valeroyl)-sn -glycero-3-phosphocholine (POVPC) increases in patients with Alzheimer’s disease (AD), and associates with lower plasma antioxidant oxocarotenoids, zeaxanthin, and lutein. Since oxocarotenoids are metabolized in mitochondria, we propose that during AD, lower concentrations of mitochondrial zeaxanthin and lutein may result in greater phospholipid oxidation and predispose to neurodegeneration. Here, we have investigated whether non-toxic POVPC concentrations impair mitochondrial metabolism in differentiated (d)SH-SY5Y neuronal …cells and whether there is any protective role for oxocarotenoids against mitochondrial dysfunction. After 24 hours, glutathione (GSH) concentration was lower in neuronal cells exposed to POVPC (1–20 μM) compared with vehicle control without loss of viability compared to control. However, mitochondrial ROS production (determined by MitoSOX oxidation) was increased by 50% only after 20 μM POVPC. Following delivery of lutein (0.1-1 μM) and zeaxanthin (0.5-5 μM) over 24 hours in vitro , oxocarotenoid recovery from dSH-SY5Y cells was > 50%. Co-incubation with oxocarotenoids prevented loss of GSH after 1 μM but not 20 μM POVPC, whereas the increase in ROS production induced by 20 μM POVPC was prevented by lutein and zeaxanthin. Mitochondrial uncoupling increases and ATP production is inhibited by 20 μM but not 1 μM POVPC; carotenoids protected against uncoupling although did not restore ATP production. In summary, 20 μM POVPC induced loss of GSH and a mitochondrial bioenergetic deficit in neuronal cells that was not mitigated by oxocarotenoids. Show more

Keywords: Bioenergetics, carotenoids, lutein, mitochondria, oxidative stress, oxidized phospholipids, POVPC, viability, zeaxanthin

DOI: 10.3233/JAD-190923

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 113-126, 2020

Authors: Nakanishi, Miharu | Igarashi, Ataru | Ueda, Kaname | Brnabic, Alan J.M. | Treuer, Tamas | Sato, Masayo | Kahle-Wrobleski, Kristin | Meguro, Kenichi | Yamada, Masahito | Mimura, Masaru | Arai, Heii

Article Type: Research Article

Abstract: Background: As the Japanese population ages, caring for people with Alzheimer’s disease (AD) dementia is becoming a major socioeconomic issue. Objective: To determine the contribution of patient and caregiver costs to total societal costs associated with AD dementia. Methods: Baseline data was used from the longitudinal, observational GERAS-J study. Using the Mini-Mental State Examination (MMSE) score, patients routinely visiting memory clinics were stratified into three groups based on AD severity. Health care resource utilizationwas recorded using the Resource Utilization in Dementia questionnaire. Total monthly societal costs were estimated using Japan-specific unit costs of services and products …(patient direct health care use, patient social care use, and informal caregiving time). Uncertainty around mean costs was estimated using bootstrapping methods. Results: Overall, 553 community-dwelling patients withADdementia (28.3% mild[MMSE21-26], 37.8% moderate[MMSE 15-20], and 34.0% moderately severe/severe [MMSE < 14]) and their caregivers were enrolled. Patient characteristics were: mean age 80.3 years, 72.7% female, and 13.6% living alone. Caregiver characteristics were: mean age 62.1 years, 70.7% female, 78.8% living with patient, 49.0% child of patient, and 39.2% sole caregiver. Total monthly societal costs of AD dementia (Japanese yen) were: 158,454 (mild), 211,301 (moderate), and 294,224 (moderately severe/severe). Informal caregiving costs comprised over 50% of total costs. Conclusion: Baseline results of GERAS-J showed that total monthly societal costs associated with AD dementia increased with AD severity. Caregiver-related costs were the largest cost component. Interventions are needed to decrease informal costs and decrease caregiver burden. Show more

Keywords: Alzheimer’s disease, cost and cost analysis, Japan, observational study

DOI: 10.3233/JAD-190811

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 127-138, 2020