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1.
The Effects of Pomegranate Seed Oil on Mild Cognitive Impairment.
Chatzikostopoulos, T, Gialaouzidis, M, Koutoupa, A, Tsolaki, M
Journal of Alzheimer's disease : JAD. 2024;(4):1961-1970
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Abstract
BACKGROUND In recent years, there has been a growing interest, supported by many experimental and clinical studies, about the benefits of pomegranate in preventing various pathologic conditions, including brain neurodegeneration. The pomegranate seed oil (PSO) contains high levels of fatty acids that have antioxidant and anti-inflammatory properties. OBJECTIVE Due to the lack of clinical trials, the aim of the present study was to investigate the effects of PSO on cognition of people with mild cognitive impairment (MCI). METHODS Eighty people with the diagnosis of MCI were randomized forty to take 5 drops of PSO and follow the Mediterranean Diet (MeDi) and forty just followed MeDi. All were examined with an extensive neuropsychological assessment before and after one year of treatment. RESULTS The results showed that the participants who took the PSO had statistically significantly better global cognition (p = 0.004), verbal episodic memory (p = 0.009), and processing and executive functions (p < 0.001) in contrast with the participants who did not take it. CONCLUSIONS In conclusion, the PSO can be beneficial for people with MCI as it is helpful for some important cognitive domains. As PSO is a natural product that does not burden the human body, it can be used by people with MCI and be a significant and promising part of holistic approaches for the prevention of dementia.
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Genetic Associations Between Modifiable Risk Factors and Alzheimer Disease.
, , Luo, J, Thomassen, JQ, Bellenguez, C, Grenier-Boley, B, de Rojas, I, Castillo, A, Parveen, K, Küçükali, F, Nicolas, A, et al
JAMA network open. 2023;(5):e2313734
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Abstract
IMPORTANCE An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. OBJECTIVE To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. DESIGN, SETTING, AND PARTICIPANTS This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. EXPOSURES Genetically determined modifiable risk factors. MAIN OUTCOMES AND MEASURES Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. RESULTS The EADB-diagnosed cohort included 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Biobank was excluded from the EADB consortium; odds for AD were similar for HDL cholesterol (OR per 1-SD unit increase, 1.08 [95% CI, 1.02-1.15]) and systolic blood pressure after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.23 [95% CI, 1.01-1.50]). CONCLUSIONS AND RELEVANCE This genetic association study found novel genetic associations between high HDL cholesterol concentrations and high systolic blood pressure with higher risk of AD. These findings may inspire new drug targeting and improved prevention implementation.
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Author Correction: Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.
de Rojas, I, Moreno-Grau, S, Tesi, N, Grenier-Boley, B, Andrade, V, Jansen, IE, Pedersen, NL, Stringa, N, Zettergren, A, Hernández, I, et al
Nature communications. 2023;(1):716
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Mediterranean Diet, Ketogenic Diet or MIND Diet for Aging Populations with Cognitive Decline: A Systematic Review.
Devranis, P, Vassilopoulou, Ε, Tsironis, V, Sotiriadis, PM, Chourdakis, M, Aivaliotis, M, Tsolaki, M
Life (Basel, Switzerland). 2023;(1)
Abstract
(1) Background: Compelling evidence shows that dietary patterns can slow the rate of cognitive decline, suggesting diet is a promising preventive measure against dementia. (2) Objective: This systematic review summarizes the evidence of three dietary patterns, the Mediterranean diet, the ketogenic diet and the MIND diet, for the prevention of cognitive decline. (3) Methods: A systematic search was conducted in major electronic databases (PubMed, ScienceDirect and Web of Science) up until 31 January 2022, using the key search terms "Mediterranean diet", "ketogenic diet", "MIND diet", "dementia", "cognition" and "aging". A statistical analysis was performed using RoB 2 and the Jadad scale to assess the risk of bias and methodological quality in randomized controlled trials. (4) Results: Only RCTs were included in this study; there were eleven studies (n = 2609 participants) of the Mediterranean diet, seven studies (n = 313) of the ketogenic diet and one study (n = 37) of the MIND diet. The participants' cognitive statuses were normal in seven studies, ten studies included patients with mild cognitive impairments and two studies included Alzheimer's disease patients. (5) Conclusion: All three dietary interventions have been shown to slow the rate of cognitive decline in the included studies. The Mediterranean diet was shown to be beneficial for global cognition after 10 weeks of adherence, the ketogenic diet had a beneficial effect for patients with diabetes mellitus and improved verbal recognition, while the MIND diet showed benefits in obese patients, improving working memory, verbal recognition, memory and attention.
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Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers.
Jansen, IE, van der Lee, SJ, Gomez-Fonseca, D, de Rojas, I, Dalmasso, MC, Grenier-Boley, B, Zettergren, A, Mishra, A, Ali, M, Andrade, V, et al
Acta neuropathologica. 2022;(5):821-842
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Abstract
Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.
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Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.
de Rojas, I, Moreno-Grau, S, Tesi, N, Grenier-Boley, B, Andrade, V, Jansen, IE, Pedersen, NL, Stringa, N, Zettergren, A, Hernández, I, et al
Nature communications. 2021;(1):3417
Abstract
Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.
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Greek High Phenolic Early Harvest Extra Virgin Olive Oil Reduces the Over-Excitation of Information-Flow Based on Dominant Coupling Mode (DoCM) Model in Patients with Mild Cognitive Impairment: An EEG Resting-State Validation Approach.
Dimitriadis, SI, Lyssoudis, C, Tsolaki, AC, Lazarou, E, Kozori, M, Tsolaki, M
Journal of Alzheimer's disease : JAD. 2021;(1):191-207
Abstract
BACKGROUND Extra virgin olive oil (EVOO) constitutes a natural compound with high protection over cognitive function that could positively alter brain dynamics and the mixture of within and between-frequency connectivity. OBJECTIVE The balance of cross-frequency coupling over within-frequency coupling can build a nonlinearity index (NI) that encapsulates the over-excitation of information flow between brain areas and across experimental time. The present study investigated for the very first time how the Greek High Phenolic Early Harvest Extra Virgin Olive Oil (HP-EH-EVOO) versus Moderate Phenolic (MP-EVOO) and Mediterranean Diet (MeDi) intervention in people with mild cognitive impairment (MCI) could affect their spontaneous EEG dynamic connectivity. METHODS Forty-three subjects (14 in MeDi, 16 in MP-EVOO, and 13 in HP-EH-EVOO) followed an EEG resting-state recording session (eyes-open and closed) before and after the treatment. Following our dominant coupling mode model, we built a dynamic integrated dynamic functional connectivity graph that tabulates the functional strength and the dominant coupling mode model of every pair of brain areas. RESULTS Signal spectrum within 1-13 Hz and theta/beta ratio have decreased in the HP-EH-EVOO group in the eyes-open condition. The intervention improved the FIDoCM across groups and conditions but was more prominent in the HP-EH-EVOO group (p < 0.001). Finally, we revealed a significant higher post-intervention reduction of NI (ΔNITotal and α) for the HP-EH-EVOO compared to the MP-EVOO and MeDi groups (p < 0.0001). CONCLUSION Long-term intervention with HP-EH-EVOO reduced the over-excitation of information flow in spontaneous brain activity and altered the signal spectrum of EEG rhythms.
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Α Virtual Reality App for Physical and Cognitive Training of Older People With Mild Cognitive Impairment: Mixed Methods Feasibility Study.
Hassandra, M, Galanis, E, Hatzigeorgiadis, A, Goudas, M, Mouzakidis, C, Karathanasi, EM, Petridou, N, Tsolaki, M, Zikas, P, Evangelou, G, et al
JMIR serious games. 2021;(1):e24170
Abstract
BACKGROUND Therapeutic virtual reality (VR) has emerged as an effective treatment modality for cognitive and physical training in people with mild cognitive impairment (MCI). However, to replace existing nonpharmaceutical treatment training protocols, VR platforms need significant improvement if they are to appeal to older people with symptoms of cognitive decline and meet their specific needs. OBJECTIVE This study aims to design and test the acceptability, usability, and tolerability of an immersive VR platform that allows older people with MCI symptoms to simultaneously practice physical and cognitive skills on a dual task. METHODS On the basis of interviews with 20 older people with MCI symptoms (15 females; mean age 76.25, SD 5.03 years) and inputs from their health care providers (formative study VR1), an interdisciplinary group of experts developed a VR system called VRADA (VR Exercise App for Dementia and Alzheimer's Patients). Using an identical training protocol, the VRADA system was first tested with a group of 30 university students (16 females; mean age 20.86, SD 1.17 years) and then with 27 older people (19 females; mean age 73.22, SD 9.26 years) who had been diagnosed with MCI (feasibility studies VR2a and VR2b). Those in the latter group attended two Hellenic Association Day Care Centers for Alzheimer's Disease and Related Disorders. Participants in both groups were asked to perform a dual task training protocol that combined physical and cognitive exercises in two different training conditions. In condition A, participants performed a cycling task in a lab environment while being asked by the researcher to perform oral math calculations (single-digit additions and subtractions). In condition B, participants performed a cycling task in the virtual environment while performing calculations that appeared within the VR app. Participants in both groups were assessed in the same way; this included questionnaires and semistructured interviews immediately after the experiment to capture perceptions of acceptability, usability, and tolerability, and to determine which of the two training conditions each participant preferred. RESULTS Participants in both groups showed a significant preference for the VR condition (students: mean 0.66, SD 0.41, t29=8.74, P<.001; patients with MCI: mean 0.72, SD 0.51, t26=7.36, P<.001), as well as high acceptance scores for intended future use, attitude toward VR training, and enjoyment. System usability scale scores (82.66 for the students and 77.96 for the older group) were well above the acceptability threshold (75/100). The perceived adverse effects were minimal, indicating a satisfactory tolerability. CONCLUSIONS The findings suggest that VRADA is an acceptable, usable, and tolerable system for physical and cognitive training of older people with MCI and university students. Randomized controlled trial studies are needed to assess the efficacy of VRADA as a tool to promote physical and cognitive health in patients with MCI.
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The Influence of Baseline Alzheimer's Disease Severity on Cognitive Decline and CSF Biomarkers in the NILVAD Trial.
Abdullah, L, Crawford, F, Tsolaki, M, Börjesson-Hanson, A, Olde Rikkert, M, Pasquier, F, Wallin, A, Kennelly, S, Ait-Ghezala, G, Paris, D, et al
Frontiers in neurology. 2020;:149
Abstract
We examined the effects of a dihydropyridine calcium channel blocker nilvadipine with anti-inflammatory properties on cognition and cerebrospinal fluid (CSF) biomarkers by baseline Alzheimer's disease (AD) severity. Exploratory analyses were performed on the dataset (n = 497) of a phase III randomized placebo-controlled trial to examine the response to nilvadipine in AD subjects stratified by baseline AD severity into very mild (MMSE ≥ 25), mild (MMSE 20-24) and moderate AD (MMSE < 20). The outcome measures included total and subscale scores of the Alzheimer's Disease Assessment Scale Cognitive 12 (ADAS-Cog 12), the Clinical Dementia Rating Scale sum of boxes (CDR-sb) and the AD composite score (ADCOMS). Cerebrospinal fluid biomarkers Aβ38, Aβ40, Aβ42, neurofilament light chain (NFL), neurogranin, YKL-40, total tau and P181 tau (ptau) were measured in a subset of samples (n = 55). Regression analyses were adjusted for confounders to specifically examine the influence of nilvadipine and baseline AD severity on cognitive outcomes over 78-weeks. Compared to their respective placebo-controls, nilvadipine-treated, very mild AD subjects showed less decline, whereas moderate AD subjects showed a greater cognitive decline on the ADAS-Cog 12 test and the ADCOMS. A lower decline was observed after nilvadipine treatment for a composite memory trait in very mild AD subjects and a composite language trait in mild AD subjects. Cerebrospinal fluid Aβ42/Aβ40 ratios were increased in mild AD and decreased in moderate AD patients treated with nilvadipine, compared to their respective controls. Among moderate AD subjects, levels of ptau, total tau, neurogranin and YKL-40 increased in subjects treated with nilvadipine compared to placebo. These studies suggest that baseline AD severity influenced the treatment outcome in the NILVAD trial and that future clinical trials of nilvadipine should be restricted to mild and very mild AD patients. Trial Registration: NCT02017340 Registered 20 December 2013, https://clinicaltrials.gov/ct2/show/NCT02017340 EUDRACT Reference Number 2012-002764-27 Registered 04 February 2013, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2012-002764-27.
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A Randomized Clinical Trial of Greek High Phenolic Early Harvest Extra Virgin Olive Oil in Mild Cognitive Impairment: The MICOIL Pilot Study.
Tsolaki, M, Lazarou, E, Kozori, M, Petridou, N, Tabakis, I, Lazarou, I, Karakota, M, Saoulidis, I, Melliou, E, Magiatis, P
Journal of Alzheimer's disease : JAD. 2020;(2):801-817
Abstract
BACKGROUND Extra virgin olive oil (EVOO) constitutes a natural compound with high protection over cognitive function. OBJECTIVE To investigate for the first time the effect of Greek High Phenolic Early Harvest Extra Virgin Olive Oil (HP-EH-EVOO) versus Moderate Phenolic (MP-EVOO) and Mediterranean Diet (MeDi) in people with mild cognitive impairment (MCI). METHODS We conducted a randomized prospective study so as to examine the HP-EH-EVOO and MP-EVOO versus MeDi in MCI. Genetic predisposition (APOEɛ4) to Alzheimer's disease (AD) was tested and an extensive neuropsychological battery was administered at baseline and after 12 months. Each participant was randomized and assigned one of three groups: 1) Group 1 received the HP-EH-EVOO (50 mL/day); 2) Group 2 received the MP-EVOO (50 mL/day), and 3) Group 3 received only the MeDi instructions. RESULTS Better follow-up performance was found in Group 1 compared to Group 2 and Group 3 in the almost all cognitive domains. Moreover, Group 2 showed also significant improvement compared to Group 3 in ADAS-cog (p = 0.001) and MMSE (p = 0.05), whereas Group 3 exhibited worse or similar to baseline performance in almost all domains. In particular, Group 1 and Group 2 had better outcomes with regards to ADAS-cog (p = 0.003), Digit Span (p = 0.006), and Letter fluency (p = 0.003). Moreover, there was a significant difference (p = 0.001) in the presence of APOEɛ4 between the Groups 1 and 2 versus Group 3. CONCLUSION Long-term intervention with HP-EH-EVOO or MP-EVOO was associated with significant improvement in cognitive function compared to MeDi, independent of the presence of APOEɛ4.