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Apathy as a Treatment Target in Alzheimer's Disease: Implications for Clinical Trials.
Mortby, ME, Adler, L, Agüera-Ortiz, L, Bateman, DR, Brodaty, H, Cantillon, M, Geda, YE, Ismail, Z, Lanctôt, KL, Marshall, GA, et al
The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry. 2022;(2):119-147
Abstract
Apathy is one of the most prevalent, stable and persistent neuropsychiatric symptom across the neurocognitive disorders spectrum. Recent advances in understanding of phenomenology, neurobiology and intervention trials highlight apathy as an important target for clinical intervention. We conducted a comprehensive review and critical evaluation of recent advances to determine the evidence-based suggestions for future trial designs. This review focused on 4 key areas: 1) pre-dementia states; 2) assessment; 3) mechanisms/biomarkers and 4) treatment/intervention efficacy. Considerable progress has been made in understanding apathy as a treatment target and appreciating pharmacological and non-pharmacological apathy treatment interventions. Areas requiring greater investigation include: diagnostic procedures, symptom measurement, understanding the biological mechanisms/biomarkers of apathy, and a well-formed approach to the development of treatment strategies. A better understanding of the subdomains and biological mechanisms of apathy will advance apathy as a treatment target for clinical trials.
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Genome-wide association identifies the first risk loci for psychosis in Alzheimer disease.
DeMichele-Sweet, MAA, Klei, L, Creese, B, Harwood, JC, Weamer, EA, McClain, L, Sims, R, Hernandez, I, Moreno-Grau, S, Tárraga, L, et al
Molecular psychiatry. 2021;(10):5797-5811
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Abstract
Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD with psychosis, AD + P). AD + P affects ~50% of individuals with AD, identifies a subgroup with poor outcomes, and is associated with a greater degree of cognitive impairment and depressive symptoms, compared to subjects without psychosis (AD - P). Although the estimated heritability of AD + P is 61%, genetic sources of risk are unknown. We report a genome-wide meta-analysis of 12,317 AD subjects, 5445 AD + P. Results showed common genetic variation accounted for a significant portion of heritability. Two loci, one in ENPP6 (rs9994623, O.R. (95%CI) 1.16 (1.10, 1.22), p = 1.26 × 10-8) and one spanning the 3'-UTR of an alternatively spliced transcript of SUMF1 (rs201109606, O.R. 0.65 (0.56-0.76), p = 3.24 × 10-8), had genome-wide significant associations with AD + P. Gene-based analysis identified a significant association with APOE, due to the APOE risk haplotype ε4. AD + P demonstrated negative genetic correlations with cognitive and educational attainment and positive genetic correlation with depressive symptoms. We previously observed a negative genetic correlation with schizophrenia; instead, we now found a stronger negative correlation with the related phenotype of bipolar disorder. Analysis of polygenic risk scores supported this genetic correlation and documented a positive genetic correlation with risk variation for AD, beyond the effect of ε4. We also document a small set of SNPs likely to affect risk for AD + P and AD or schizophrenia. These findings provide the first unbiased identification of the association of psychosis in AD with common genetic variation and provide insights into its genetic architecture.
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Long-COVID syndrome-associated brain fog and chemofog: Luteolin to the rescue.
Theoharides, TC, Cholevas, C, Polyzoidis, K, Politis, A
BioFactors (Oxford, England). 2021;47(2):232-241
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Abstract
COVID-19 leads to severe respiratory problems, but also to long-COVID syndrome associated primarily with cognitive dysfunction and fatigue. Long-COVID syndrome symptoms, especially brain fog, are similar to those experienced by patients undertaking or following chemotherapy for cancer (chemofog or chemobrain), as well in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) or mast cell activation syndrome (MCAS). The pathogenesis of brain fog in these illnesses is presently unknown but may involve neuroinflammation via mast cells stimulated by pathogenic and stress stimuli to release mediators that activate microglia and lead to inflammation in the hypothalamus. These processes could be mitigated by phytosomal formulation (in olive pomace oil) of the natural flavonoid luteolin.
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Analysis of protein-DNA interactions in chromatin by UV induced cross-linking and mass spectrometry.
Stützer, A, Welp, LM, Raabe, M, Sachsenberg, T, Kappert, C, Wulf, A, Lau, AM, David, SS, Chernev, A, Kramer, K, et al
Nature communications. 2020;(1):5250
Abstract
Protein-DNA interactions are key to the functionality and stability of the genome. Identification and mapping of protein-DNA interaction interfaces and sites is crucial for understanding DNA-dependent processes. Here, we present a workflow that allows mass spectrometric (MS) identification of proteins in direct contact with DNA in reconstituted and native chromatin after cross-linking by ultraviolet (UV) light. Our approach enables the determination of contact interfaces at amino-acid level. With the example of chromatin-associated protein SCML2 we show that our technique allows differentiation of nucleosome-binding interfaces in distinct states. By UV cross-linking of isolated nuclei we determined the cross-linking sites of several factors including chromatin-modifying enzymes, demonstrating that our workflow is not restricted to reconstituted materials. As our approach can distinguish between protein-RNA and DNA interactions in one single experiment, we project that it will be possible to obtain insights into chromatin and its regulation in the future.
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Pharmacological and Nonpharmacological Treatment for Apathy in Alzheimer Disease : A systematic review across modalities.
Theleritis, C, Siarkos, K, Katirtzoglou, E, Politis, A
Journal of geriatric psychiatry and neurology. 2017;(1):26-49
Abstract
OBJECTIVE Apathy is one of the most frequent neuropsychiatric symptoms encountered in Alzheimer disease (AD). Early diagnosis and timely treatment of apathy in AD seem to be of great importance, since apathy has been associated with poor disease outcome, reduced daily functioning, and caregiver distress. DESIGN Within this context, we conducted an extensive electronic search from the databases included in the National Library of Medicine as well as PsychInfo and Google Scholar for studies that have investigated the effect of pharmacological and nonpharmacological treatments of apathy in AD. RESULTS Acetylcholinesterase inhibitors, gingko biloba, methylphenidate, and a variety of nonpharmacological interventions were found to be successful in reducing apathy in patients with AD. Methodological heterogeneity of the studies and the small amount of studies where apathy was a primary outcome measure are limiting factors to evaluate for group effects. CONCLUSION Treatment of apathy in AD is a complicated and an underexplored field. Standardized and systematic efforts primarily focused on the study of apathy in AD may establish a benefit from individualized treatment for specific disease groups that would stem from a combination of both pharmacological and nonpharmacological interventions.
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Mass spectrometry defines the C-terminal dimerization domain and enables modeling of the structure of full-length OmpA.
Marcoux, J, Politis, A, Rinehart, D, Marshall, DP, Wallace, MI, Tamm, LK, Robinson, CV
Structure (London, England : 1993). 2014;(5):781-90
Abstract
The transmembrane domain of the outer membrane protein A (OmpA) from Escherichia coli is an excellent model for structural and folding studies of β-barrel membrane proteins. However, full-length OmpA resists crystallographic efforts, and the link between its function and tertiary structure remains controversial. Here we use site-directed mutagenesis and mass spectrometry of different constructs of OmpA, released in the gas phase from detergent micelles, to define the minimal region encompassing the C-terminal dimer interface. Combining knowledge of the location of the dimeric interface with molecular modeling and ion mobility data allows us to propose a low-resolution model for the full-length OmpA dimer. Our model of the dimer is in remarkable agreement with experimental ion mobility data, with none of the unfolding or collapse observed for full-length monomeric OmpA, implying that dimer formation stabilizes the overall structure and prevents collapse of the flexible linker that connects the two domains.
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Ion mobility-mass spectrometry of a rotary ATPase reveals ATP-induced reduction in conformational flexibility.
Zhou, M, Politis, A, Davies, R, Liko, I, Wu, KJ, Stewart, AG, Stock, D, Robinson, CV
Nature chemistry. 2014;(3):208-215
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Abstract
Rotary ATPases play fundamental roles in energy conversion as their catalytic rotation is associated with interdomain fluctuations and heterogeneity of conformational states. Using ion mobility mass spectrometry we compared the conformational dynamics of the intact ATPase from Thermus thermophilus with those of its membrane and soluble subcomplexes. Our results define regions with enhanced flexibility assigned to distinct subunits within the overall assembly. To provide a structural context for our experimental data we performed molecular dynamics simulations and observed conformational changes of the peripheral stalks that reflect their intrinsic flexibility. By isolating complexes at different phases of cell growth and manipulating nucleotides, metal ions and pH during isolation, we reveal differences that can be related to conformational changes in the Vo complex triggered by ATP binding. Together these results implicate nucleotides in modulating flexibility of the stator components and uncover mechanistic detail that underlies operation and regulation in the context of the holoenzyme.