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Article ; Online: Lewy body pathology modifies risk factors for cerebral amyloid angiopathy when comorbid with Alzheimer's disease pathology.

Pillai, Jagan A / Bena, James / Tousi, Babak / Rothenberg, Kasia / Keene, C Dirk / Leverenz, James B

Alzheimer's & dementia : the journal of the Alzheimer's Association

2024 Volume 20, Issue 4, Page(s) 2564–2574

Abstract: Introduction: Cerebral amyloid angiopathy (CAA) often accompanies dementia-associated pathologies and is important in the context of anti-amyloid monoclonal therapies and risk of hemorrhage.: Methods: We conducted a retrospective neuropathology- ... ...

Abstract	Introduction: Cerebral amyloid angiopathy (CAA) often accompanies dementia-associated pathologies and is important in the context of anti-amyloid monoclonal therapies and risk of hemorrhage. Methods: We conducted a retrospective neuropathology-confirmed study of 2384 participants in the National Alzheimer Coordinating Center cohort (Alzheimer's disease [AD], n = 1175; Lewy body pathology [LBP], n = 316; and mixed AD and LBP [AD-LBP], n = 893). We used logistic regression to evaluate age, sex, education, APOE ε4, neuritic plaques, and neurofibrillary tangles (NFTs) in CAA risk. Results: APOE ε4 increased CAA risk in all three groups, while younger age and higher NFT stages increased risk in AD and AD-LBP. In AD-LBP, male sex and lower education were additional risk factors. The odds of APOE ε4 carrier homozygosity related to CAA was higher in LBP (25.69) and AD-LBP (9.50) than AD (3.17). Discussion: AD and LBPs modify risk factors for CAA and should be considered in reviewing the risk of CAA. Highlights: Lewy body pathology modifies risk factors for cerebral amyloid angiopathy (CAA) when present along with Alzheimer's disease (AD) neuropathology. In the context of anti-amyloid monoclonal therapies and their associated risks for hemorrhage, the risk of underlying CAA in mixed dementia with Lewy body pathology needs to be considered.
MeSH term(s)	Male ; Humans ; Alzheimer Disease/pathology ; Apolipoprotein E4/genetics ; Lewy Bodies/pathology ; Retrospective Studies ; Cerebral Amyloid Angiopathy/epidemiology ; Cerebral Amyloid Angiopathy/pathology ; Amyloid ; Risk Factors ; Hemorrhage ; Plaque, Amyloid/pathology
Chemical Substances	Apolipoprotein E4 ; Amyloid
Language	English
Publishing date	2024-02-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	2211627-8
ISSN	1552-5279 ; 1552-5260
ISSN (online)	1552-5279
ISSN	1552-5260
DOI	10.1002/alz.13704
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Article ; Online: The Media Coverage of Bruce Willis Reveals Unfamiliarity With Frontotemporal Degeneration.

Hurley, Robert S / Pillai, Jagan A / Leverenz, James B

Innovation in aging

2023 Volume 7, Issue 9, Page(s) igad125

Abstract: In 2022, Bruce Willis' family released a statement saying that he had been diagnosed with aphasia (an acquired language impairment) and would no longer be acting. Ten months later, the Willis family released another statement indicating that he received ... ...

Abstract	In 2022, Bruce Willis' family released a statement saying that he had been diagnosed with aphasia (an acquired language impairment) and would no longer be acting. Ten months later, the Willis family released another statement indicating that he received a more specific diagnosis of frontotemporal degeneration (FTD). This resulted in an explosion of media coverage, as prominent news outlets scrambled to produce stories describing FTD to a public largely unfamiliar with the disease. The quality of these stories varied widely, and in many cases the relationship between aphasia and FTD was misrepresented, as were basic descriptions and facts about FTD. FTD refers to a class of protein-misfolding diseases that are a common cause of aphasias due to neurodegeneration, or primary progressive aphasias (PPA). Rather than describing how FTD was discovered to be the underlying source of Mr. Willis' aphasia, many reports described his aphasia as "progressing into" FTD, implying they are two different disorders. Furthermore, these reports used the terminology of frontotemporal "dementia" rather than "degeneration", a term that invokes many stereotypes in the public imagination and may have contributed to misrepresentations in coverage. Instead of focusing on the language symptoms of PPA, reports often emphasized the personality and behavioral changes more closely associated with other variants of FTD. The substance of various facts, such as how common FTD is and how it can be treated, varied widely across reports. In sum, the media coverage of Mr. Willis' diagnosis reveals the extent to which the media and general public are uninformed about FTD and PPA. The remedy for this problem is to promote greater awareness of FTD, in both the public and the medical provider class. The Willis family's disclosure was a courageous act that helped bring much-needed attention to this disease.
Language	English
Publishing date	2023-10-26
Publishing country	England
Document type	Journal Article
ISSN	2399-5300
ISSN (online)	2399-5300
DOI	10.1093/geroni/igad125
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Article ; Online: Initial non-amnestic symptoms relate to faster rate of functional and cognitive decline compared to amnestic symptoms in neuropathologically confirmed dementias.

Pillai, Jagan A / Bena, James / Maly, Emily F / Leverenz, James B

Alzheimer's & dementia : the journal of the Alzheimer's Association

2023 Volume 19, Issue 7, Page(s) 2956–2965

Abstract: Introduction: The relationship between initial cognitive symptoms and subsequent rate of clinical decline is important in clinical care and the design of dementia clinical trials.: Methods: This retrospective longitudinal, autopsy-confirmed, cohort ... ...

Abstract	Introduction: The relationship between initial cognitive symptoms and subsequent rate of clinical decline is important in clinical care and the design of dementia clinical trials. Methods: This retrospective longitudinal, autopsy-confirmed, cohort study among 2426 participants in the National Alzheimer's Coordinating Center database included Alzheimer's disease (AD) pathology, n = 1187; Lewy body pathology (LBP), n = 331; and mixed pathology (AD-LBP), n = 904. The predominant initial cognitive symptom was assessed clinically. Linear mixed models evaluated the longitudinal outcome of the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score. Results: Non-amnestic initial symptoms had a faster rate of decline than amnestic symptoms in all three groups. Language symptoms had a faster rate of decline in all three groups. Executive symptoms had a faster rate of decline than amnestic in AD and AD-LBP. There was a similar trend for visuospatial symptoms in AD-LBP. Discussion: Initial cognitive symptoms, despite varied underlying pathology, are a predictor of longitudinal functional outcomes among dementias. Highlights: Initial non-amnestic symptoms had a faster rate of longitudinal cognitive and functional decline on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores than amnestic symptoms among Alzheimer's disease, Lewy body pathology, and mixed neuropathology. Given the relative size of CDR-SB changes in Alzheimer's disease clinical trials, clarifying the nature of initial symptoms could be an important variable in ensuring appropriately designed clinical trials.
MeSH term(s)	Humans ; Alzheimer Disease/pathology ; Cohort Studies ; Retrospective Studies ; Neuropsychological Tests ; Disease Progression ; Cognitive Dysfunction/diagnosis
Language	English
Publishing date	2023-01-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2211627-8
ISSN	1552-5279 ; 1552-5260
ISSN (online)	1552-5279
ISSN	1552-5260
DOI	10.1002/alz.12922
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Article ; Online: The Application of Zonisamide to Patients Suffering from Dementia with Lewy Bodies: Emerging Clinical Data.

Tousi, Babak / Leverenz, James B

Drug design, development and therapy

2021 Volume 15, Page(s) 1811–1817

Abstract: Zonisamide is an anti-epileptic medication with multiple mechanisms of action and a favorable safety profile. Zonisamide may interact with Lewy body dementia pathophysiology through a mechanism unrelated to its original indication. Zonisamide has shown ... ...

Abstract	Zonisamide is an anti-epileptic medication with multiple mechanisms of action and a favorable safety profile. Zonisamide may interact with Lewy body dementia pathophysiology through a mechanism unrelated to its original indication. Zonisamide has shown efficacy as adjunct therapy for the management of motor symptoms in patients with Parkinson's disease (PD). Given that dementia with Lewy bodies (DLB) and PD are considered subtypes of a Lewy body disease spectrum, zonisamide was investigated for the treatment of parkinsonism in DLB. Phase II and phase III clinical trials were conducted in patients with DLB in Japan. In both studies, participants were randomized to receive 12 weeks of zonisamide 25 or 50 mg/day or placebo. Zonisamide significantly improved the Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) without affecting the Mini-Mental State Examination (MMSE) or Neuropsychiatry Inventory-10 (NPI-10) scores at week 12. In 2018, zonisamide received Japanese regulatory approval for the additional indication of parkinsonism in DLB. This review discusses the emerging clinical data on zonisamide in the field of DLB.
MeSH term(s)	Clinical Trials, Phase III as Topic ; Dementia/drug therapy ; Humans ; Lewy Body Disease/drug therapy ; Zonisamide/therapeutic use
Chemical Substances	Zonisamide (459384H98V)
Language	English
Publishing date	2021-05-03
Publishing country	New Zealand
Document type	Journal Article ; Review
ZDB-ID	2451346-5
ISSN	1177-8881 ; 1177-8881
ISSN (online)	1177-8881
ISSN	1177-8881
DOI	10.2147/DDDT.S240865
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Article ; Online: Emerging blood-based biomarkers for Alzheimer disease.

Bekris, Lynn M / Leverenz, James B

Cleveland Clinic journal of medicine

2020 Volume 87, Issue 9, Page(s) 537–539

MeSH term(s)	Aged ; Aged, 80 and over ; Alzheimer Disease/diagnosis ; Amyloid beta-Peptides/blood ; Biomarkers/blood ; Female ; Humans ; Male ; Phosphorylation ; tau Proteins/blood
Chemical Substances	Amyloid beta-Peptides ; Biomarkers ; MAPT protein, human ; tau Proteins
Language	English
Publishing date	2020-08-31
Publishing country	United States
Document type	Journal Article
ZDB-ID	639116-3
ISSN	1939-2869 ; 0891-1150
ISSN (online)	1939-2869
ISSN	0891-1150
DOI	10.3949/ccjm.87a.20133
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Article ; Online: Multi-shell diffusion MRI of the fornix as a biomarker for cognition in Alzheimer's disease.

Sakaie, Ken / Koenig, Katherine / Lerner, Alan / Appleby, Brian / Ogrocki, Paula / Pillai, Jagan A / Rao, Stephen / Leverenz, James B / Lowe, Mark J

Magnetic resonance imaging

2024 Volume 109, Page(s) 221–226

Abstract: Background and purpose: A substantial fraction of those who had Alzheimer's Disease (AD) pathology on autopsy did not have dementia in life. While biomarkers for AD pathology are well-developed, biomarkers specific to cognitive domains affected by early ...

Abstract	Background and purpose: A substantial fraction of those who had Alzheimer's Disease (AD) pathology on autopsy did not have dementia in life. While biomarkers for AD pathology are well-developed, biomarkers specific to cognitive domains affected by early AD are lagging. Diffusion MRI (dMRI) of the fornix is a candidate biomarker for early AD-related cognitive changes but is susceptible to bias due to partial volume averaging (PVA) with cerebrospinal fluid. The purpose of this work is to leverage multi-shell dMRI to correct for PVA and to evaluate PVA-corrected dMRI measures in fornix as a biomarker for cognition in AD. Methods: Thirty-three participants in the Cleveland Alzheimer's Disease Research Center (CADRC) (19 with normal cognition (NC), 10 with mild cognitive impairment (MCI), 4 with dementia due to AD) were enrolled in this study. Multi-shell dMRI was acquired, and voxelwise fits were performed with two models: 1) diffusion tensor imaging (DTI) that was corrected for PVA and 2) neurite orientation dispersion and density imaging (NODDI). Values of tissue integrity in fornix were correlated with neuropsychological scores taken from the Uniform Data Set (UDS), including the UDS Global Composite 5 score (UDSGC5). Results: Statistically significant correlations were found between the UDSGC5 and PVA-corrected measure of mean diffusivity (MDc, r = -0.35, p < 0.05) from DTI and the intracelluar volume fraction (ficvf, r = 0.37, p < 0.04) from NODDI. A sensitivity analysis showed that the relationship to MDc was driven by episodic memory, which is often affected early in AD, and language. Conclusion: This cross-sectional study suggests that multi-shell dMRI of the fornix that has been corrected for PVA is a potential biomarker for early cognitive domain changes in AD. A longitudinal study will be necessary to determine if the imaging measure can predict cognitive decline.
MeSH term(s)	Humans ; Alzheimer Disease/diagnostic imaging ; Alzheimer Disease/pathology ; Diffusion Tensor Imaging/methods ; Longitudinal Studies ; Cross-Sectional Studies ; Cognition ; Diffusion Magnetic Resonance Imaging ; Cognitive Dysfunction/diagnostic imaging ; Cognitive Dysfunction/pathology ; Biomarkers
Chemical Substances	Biomarkers
Language	English
Publishing date	2024-03-21
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	604885-7
ISSN	1873-5894 ; 0730-725X
ISSN (online)	1873-5894
ISSN	0730-725X
DOI	10.1016/j.mri.2024.03.030
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Article ; Online: Association of Variation in Behavioral Symptoms With Initial Cognitive Phenotype in Adults With Dementia Confirmed by Neuropathology.

Pillai, Jagan A / Bena, James / Rothenberg, Kasia / Boron, Bryce / Leverenz, James B

JAMA network open

2022 Volume 5, Issue 3, Page(s) e220729

Abstract: Importance: Behavioral and psychological symptoms of dementia (BPSDs) in association with amnestic and nonamnestic cognitive phenotypes have not been evaluated across diagnoses of Alzheimer disease pathology (ADP), Lewy body-related pathology (LRP), and ...

Abstract	Importance: Behavioral and psychological symptoms of dementia (BPSDs) in association with amnestic and nonamnestic cognitive phenotypes have not been evaluated across diagnoses of Alzheimer disease pathology (ADP), Lewy body-related pathology (LRP), and mixed pathology (ADP-LRP). Objectives: To determine the clinical phenotypes at the initial visit that are associated with the nature and severity of BPSDs in patients with ADP, LRP, and ADP-LRP. Design, setting, and participants: This retrospective longitudinal cohort study included 2422 participants with neuropathologically confirmed ADP, LRP, or mixed ADP-LRP in the National Alzheimer Coordinating Center database from June 20, 2005, to September 4, 2019. Participants had a mean (SD) interval of 5.5 (2.8) years from initial visit to autopsy. Main outcomes and measures: Clinician-determined diagnosis of change across 10 BPSDs (agitation, apathy, depression, delusions, disinhibition, auditory hallucinations, visual hallucinations, irritability, personality change, and rapid eye movement [REM] sleep behavior) and the highest severity score for behavioral change on the Neuropsychiatric Inventory Questionnaire (NPI-Q). Results: A total of 2422 participants (1187 with ADP, 904 with ADP-LRP, and 331 with LRP) were included in the analysis (1446 men [59.7%]; mean [SD] age, 74.4 [10.1] years). Compared with initial amnestic symptoms, executive symptoms were associated with a higher risk for 7 of the 10 BPSDs (hazard ratio [HR] range, 1.28-2.45), and visuospatial symptoms were associated with a higher risk for 2 of the 10 BPSDs (HR range, 1.91-2.51), but neither were associated with a low risk for any BPSD. Language symptoms were associated with a low risk of onset for 3 of 10 BPSDs (HR range, 0.43-0.79) and a high risk for 1 BPSD (personality change) (HR, 1.42 [95% CI, 1.10-1.83]). Participants with LRP had a lower risk for agitation (HR, 0.74 [95% CI, 0.60-0.92]), disinhibition (HR, 0.78 [95% CI, 0.62-0.99]), and irritability (HR, 0.81 [95% CI, 0.68-0.96]) and a higher risk for apathy (HR, 1.19 [95% CI, 1.02-1.38]), depression (HR, 1.32 [95% CI, 1.12-1.55]), auditory (HR, 2.00 [95% CI, 1.37-2.93]) and visual (HR, 2.78 [95% CI, 2.21-3.49]) hallucinations, and REM sleep behavior changes (HR, 4.77 [95% CI, 3.61-6.31]) compared with the ADP group. The ADP-LRP group had a higher risk for delusions (HR, 1.27 [95% CI, 1.08-1.48]), auditory (HR, 1.62 [95% CI, 1.21-2.15]) and visual (HR, 1.57 [95% CI, 1.30-1.89]) hallucinations, and REM sleep behavior changes (HR, 2.10 [95% CI, 1.63-2.70]) than the ADP group and a lower risk for visual hallucinations (HR, 0.56 [95% CI, 0.45-0.71]) and REM sleep behavior changes (HR, 0.44 [95% CI, 0.34-0.57) than the LRP group. Overall, women showed a lower risk of agitation (HR, 0.86 [95% CI, 0.75-0.98]), apathy (HR, 0.79 [95% CI, 0.71-0.87]), visual hallucinations (HR, 0.76 [95% CI, 0.64-0.90]), irritability (HR, 0.77 [95% CI, 0.69-0.86]), and REM sleep behavior change (HR, 0.45 [95% CI, 0.35-0.58]) and a higher risk of depression (HR, 1.26 [95% CI, 1.13-1.41]). Older age was associated with a lower risk of most BPSDs (HR range, 0.98-0.99) except delusions (HR, 1.00 [95% CI, 1.00-1.01]) and auditory hallucinations (HR, 0.99 [95% CI, 0.97-1.00]) and a low NPI-Q composite score (β = -0.07 [95% CI, -0.08 to -0.05]; P < .001). Conclusions and relevance: These findings suggest that the risks of BPSDs differ with respect to the initial cognitive phenotype, underlying neuropathology, age, and sex. Awareness of these associations could be helpful in dementia management.
MeSH term(s)	Female ; Humans ; Alzheimer Disease/genetics ; Behavioral Symptoms/epidemiology ; Cognition ; Hallucinations ; Longitudinal Studies ; Phenotype ; Retrospective Studies
Language	English
Publishing date	2022-03-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2574-3805
ISSN (online)	2574-3805
DOI	10.1001/jamanetworkopen.2022.0729
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Article ; Online: Impact of APOE ε4 genotype on initial cognitive symptoms differs for Alzheimer's and Lewy body neuropathology.

Pillai, Jagan A / Bena, James / Bonner-Jackson, Aaron / Leverenz, James B

Alzheimer's research & therapy

2021 Volume 13, Issue 1, Page(s) 31

Abstract: Background: APOE ε4 carrier status is known to increase odds of amnestic presentations with Alzheimer's pathology. It is unknown how APOE ε4 carrier status impacts odds of specific initial cognitive symptoms in the presence of Lewy body pathology. Here ... ...

Abstract	Background: APOE ε4 carrier status is known to increase odds of amnestic presentations with Alzheimer's pathology. It is unknown how APOE ε4 carrier status impacts odds of specific initial cognitive symptoms in the presence of Lewy body pathology. Here we evaluate the impact of APOE ε4 genotype on initial cognitive symptoms among those with Alzheimer's disease pathology (ADP) and Lewy-related pathology (LRP). Methods: A retrospective cohort study of 2288 participants with neuropathology confirmed ADP or LRP in the National Alzheimer's Coordinating Center database, who had initial cognitive symptoms documented and had a Clinical Dementia Rating-Global (CDR-G) score ≤ 1 (cognitively normal, MCI, or early dementia). Unadjusted and adjusted logistic regression models taking into account age at evaluation, sex, and education examined the relationship between APOE ε4 genotype and initial symptoms (memory, executive, language visuospatial) among ADP with LRP and ADP-LRP groups. Results: One thousand three hundred three participants met criteria for ADP alone, 90 for LRP alone, and 895 for co-existing ADP and LRP (ADP-LRP). Younger age increased odds of non-amnestic symptoms across all three groups. In the adjusted model among ADP, APOE ε4 carriers had higher odds of amnestic initial symptoms 1.5 [95% CI, 1.7-2.14, p = 0.003] and lower odds of initial language symptoms 0.67 [95% CI, 0.47-0.96, p = 0.03] than non-carriers. The odds for these two symptoms were not different between ADP and mixed ADP-LRP groups. Female sex and higher education increased odds of initial language symptoms in the ADP group in the adjusted model. In the unadjusted model, APOE ε4 carriers with LRP had a higher odds of visuospatial initial symptoms 21.96 [95% CI, 4.02-110.62, p < 0.0001], while no difference was noted for initial executive/attention symptoms. Among LRP, the odds of APOE ε4 on amnestic symptom was not significant; however, the interaction effect evaluating the difference in odds ratios of amnestic symptom between ADP and LRP groups also did not reach statistical significance. Conclusions: The odds of specific initial cognitive symptoms differed between ADP and LRP among APOE ε4 carriers compared to non-carriers. The odds of initial amnestic symptom was higher among ADP APOE ε4 carriers and the odds of visuospatial initial symptom was higher with LRP APOE ε4 carriers. This supports the hypothesis that APOE ε4 differentially impacts initial cognitive symptoms together with underlying neuropathology.
MeSH term(s)	Alzheimer Disease/genetics ; Apolipoprotein E4/genetics ; Cognition ; Female ; Genotype ; Humans ; Lewy Bodies ; Retrospective Studies
Chemical Substances	Apolipoprotein E4
Language	English
Publishing date	2021-01-23
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2506521-X
ISSN	1758-9193 ; 1758-9193
ISSN (online)	1758-9193
ISSN	1758-9193
DOI	10.1186/s13195-021-00771-1
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Article ; Online: Metabolic syndrome biomarkers relate to rate of cognitive decline in MCI and dementia stages of Alzheimer's disease.

Pillai, Jagan A / Bena, James / Bekris, Lynn / Kodur, Nandan / Kasumov, Takhar / Leverenz, James B / Kashyap, Sangeeta R

Alzheimer's research & therapy

2023 Volume 15, Issue 1, Page(s) 54

Abstract: Background: The relationship between biomarkers of metabolic syndrome and insulin resistance, plasma triglyceride/HDL cholesterol (TG/HDL-C) ratio, on the rate of cognitive decline in mild cognitive impairment (MCI) and dementia stages of Alzheimer's ... ...

Abstract	Background: The relationship between biomarkers of metabolic syndrome and insulin resistance, plasma triglyceride/HDL cholesterol (TG/HDL-C) ratio, on the rate of cognitive decline in mild cognitive impairment (MCI) and dementia stages of Alzheimer's disease (AD) is unknown. The role of peripheral and cerebrospinal fluid (CSF) levels of Apolipoprotein A1 (ApoA1), a key functional component of HDL, on cognitive decline also remains unclear among them. Here we evaluate baseline plasma TG/HDL-C ratio and CSF and plasma ApoA1 levels and their relation with cognitive decline in the MCI and Dementia stages of AD. Patients and methods: A retrospective longitudinal study (156 participants; 106 MCI, 50 AD dementia) from the Alzheimer's Disease Neuroimaging Initiative, with an average of 4.0 (SD 2.8) years follow-up. Baseline plasma TG/HDL-C, plasma, and CSF ApoA1 and their relationship to inflammation and blood-brain barrier (BBB) biomarkers and longitudinal cognitive outcomes were evaluated. Multivariable linear mixed effect models were used to assess the effect of baseline analytes with longitudinal changes in Mini-Mental State Exam (MMSE), Clinical Dementia Rating-Sum of Boxes (CDR-SB), and Logical Memory delayed recall (LM) score after controlling for well-known covariates. Results: A total of 156 participants included 98 women, 63%; mean age was 74.9 (SD 7.3) years. At baseline, MCI and dementia groups did not differ significantly in TG/HDL-C (Wilcoxon W statistic = 0.39, p = 0.39) and CSF ApoA1 levels (W = 3642, p = 0.29), but the dementia group had higher plasma ApoA1 than the MCI group (W = 4615, p = 0.01). Higher TG/HDL-C ratio was associated with faster decline in CDR-SB among MCI and dementia groups. Higher plasma ApoA1 was associated with faster decline in MMSE and LM among MCI, while in contrast higher CSF ApoA1 levels related to slower cognitive decline in MMSE among MCI. CSF and plasma ApoA1 also show opposite directional correlations with biomarkers of BBB integrity. CSF but not plasma levels of ApoA1 positively correlated to inflammation analytes in the AGE-RAGE signaling pathway in diabetic complications (KEGG ID:KO04933). Conclusions: Biomarkers of metabolic syndrome relate to rate of cognitive decline among MCI and dementia individuals. Elevated plasma TG/HDL-C ratio and plasma ApoA1 are associated with worse cognitive outcomes in MCI and dementia participants. CSF ApoA1 and plasma ApoA1 likely have different roles in AD progression in MCI stage.
MeSH term(s)	Humans ; Female ; Aged ; Alzheimer Disease/cerebrospinal fluid ; Longitudinal Studies ; Metabolic Syndrome/complications ; Amyloid beta-Peptides/cerebrospinal fluid ; Retrospective Studies ; Cognitive Dysfunction/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; Inflammation ; Disease Progression ; tau Proteins/cerebrospinal fluid
Chemical Substances	Amyloid beta-Peptides ; Biomarkers ; tau Proteins
Language	English
Publishing date	2023-03-16
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2506521-X
ISSN	1758-9193 ; 1758-9193
ISSN (online)	1758-9193
ISSN	1758-9193
DOI	10.1186/s13195-023-01203-y
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Article ; Online: Microglial immunometabolism endophenotypes contribute to sex difference in Alzheimer's disease.

Hou, Yuan / Caldwell, Jessica Z K / Lathia, Justin D / Leverenz, James B / Pieper, Andrew A / Cummings, Jeffrey / Cheng, Feixiong

Alzheimer's & dementia : the journal of the Alzheimer's Association

2023 Volume 20, Issue 2, Page(s) 1334–1349

Abstract: Introduction: The molecular mechanisms that contribute to sex differences, in particular female predominance, in Alzheimer's disease (AD) prevalence, symptomology, and pathology, are incompletely understood.: Methods: To address this problem, we ... ...

Abstract	Introduction: The molecular mechanisms that contribute to sex differences, in particular female predominance, in Alzheimer's disease (AD) prevalence, symptomology, and pathology, are incompletely understood. Methods: To address this problem, we investigated cellular metabolism and immune responses ("immunometabolism endophenotype") across AD individuals as a function of sex with diverse clinical diagnosis of cognitive status at death (cogdx), Braak staging, and Consortium to Establish a Registry for AD (CERAD) scores using human cortex metabolomics and transcriptomics data from the Religious Orders Study / Memory and Aging Project (ROSMAP) cohort. Results: We identified sex-specific metabolites, immune and metabolic genes, and pathways associated with the AD diagnosis and progression. We identified female-specific elevation in glycerophosphorylcholine and N-acetylglutamate, which are AD inflammatory metabolites involved in interleukin (IL)-17 signaling, C-type lectin receptor, interferon signaling, and Toll-like receptor pathways. We pinpointed distinct microglia-specific immunometabolism endophenotypes (i.e., lipid- and amino acid-specific IL-10 and IL-17 signaling pathways) between female and male AD subjects. In addition, female AD subjects showed evidence of diminished excitatory neuron and microglia communications via glutamate-mediated immunometabolism. Discussion: Our results point to new understanding of the molecular basis for female predominance in AD, and warrant future independent validations with ethnically diverse patient cohorts to establish a likely causal relationship of microglial immunometabolism in the sex differences in AD. Highlights: Sex-specific immune metabolites, gene networks and pathways, are associated with Alzheimer's disease pathogenesis and disease progression. Female AD subjects exhibit microglial immunometabolism endophenotypes characterized by decreased glutamate metabolism and elevated interleukin-10 pathway activity. Female AD subjects showed a shift in glutamate-mediated cell-cell communications between excitatory neurons to microglia and astrocyte.
MeSH term(s)	Humans ; Male ; Female ; Alzheimer Disease/pathology ; Microglia/metabolism ; Endophenotypes ; Sex Characteristics ; Glutamates/genetics ; Glutamates/metabolism
Chemical Substances	Glutamates
Language	English
Publishing date	2023-11-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	2211627-8
ISSN	1552-5279 ; 1552-5260
ISSN (online)	1552-5279
ISSN	1552-5260
DOI	10.1002/alz.13546
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 6316: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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