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Article ; Online: Heterogeneity in Alzheimer's Disease Diagnosis and Progression Rates: Implications for Therapeutic Trials.

Duara, Ranjan / Barker, Warren

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics

2022 Volume 19, Issue 1, Page(s) 8–25

Abstract: The clinical presentation and the pathological processes underlying Alzheimer's disease (AD) can be very heterogeneous in severity, location, and composition including the amount and distribution of AB deposition and spread of neurofibrillary tangles in ... ...

Abstract	The clinical presentation and the pathological processes underlying Alzheimer's disease (AD) can be very heterogeneous in severity, location, and composition including the amount and distribution of AB deposition and spread of neurofibrillary tangles in different brain regions resulting in atypical clinical patterns and the existence of distinct AD variants. Heterogeneity in AD may be related to demographic factors (such as age, sex, educational and socioeconomic level) and genetic factors, which influence underlying pathology, the cognitive and behavioral phenotype, rate of progression, the occurrence of neuropsychiatric features, and the presence of comorbidities (e.g., vascular disease, neuroinflammation). Heterogeneity is also manifest in the individual resilience to the development of neuropathology (brain reserve) and the ability to compensate for its cognitive and functional impact (cognitive and functional reserve). The variability in specific cognitive profiles and types of functional impairment may be associated with different progression rates, and standard measures assessing progression may not be equivalent for individual cognitive and functional profiles. Other factors, which may govern the presence, rate, and type of progression of AD, include the individuals' general medical health, the presence of specific systemic conditions, and lifestyle factors, including physical exercise, cognitive and social stimulation, amount of leisure activities, environmental stressors, such as toxins and pollution, and the effects of medications used to treat medical and behavioral conditions. These factors that affect progression are important to consider while designing a clinical trial to ensure, as far as possible, well-balanced treatment and control groups.
MeSH term(s)	Alzheimer Disease/complications ; Alzheimer Disease/diagnosis ; Alzheimer Disease/therapy ; Brain/pathology ; Disease Progression ; Humans
Language	English
Publishing date	2022-01-27
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	2316693-9
ISSN	1878-7479 ; 1933-7213
ISSN (online)	1878-7479
ISSN	1933-7213
DOI	10.1007/s13311-022-01185-z
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Book: Positron emission tomography in dementia

Duara, Ranjan

(Frontiers of clinical neuroscience ; 10)

1990

Author's details	ed. by Ranjan Duara
Series title	Frontiers of clinical neuroscience ; 10
Collection
Keywords	Dementia / radionuclide imaging ; Tomography, Emission-Computed ; Demenz ; Positronen-Emissions-Tomografie
Subject	Positronen-Emissions-Tomographie ; PET ; Anoia ; Dementia ; Chronische Verwirrtheit
Size	XIII, 187 S. : Ill., graph. Darst.
Publisher	Wiley-Liss
Publishing place	New York u.a.
Publishing country	United States
Document type	Book
HBZ-ID	HT003736879
ISBN	0-471-56804-X ; 978-0-471-56804-9
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Article: Neuropathology, Neuroimaging, and Fluid Biomarkers in Alzheimer's Disease.

Colvee-Martin, Helena / Parra, Juan Rayo / Gonzalez, Gabriel Antonio / Barker, Warren / Duara, Ranjan

Diagnostics (Basel, Switzerland)

2024 Volume 14, Issue 7

Abstract: An improved understanding of the pathobiology of Alzheimer's disease (AD) should lead ultimately to an earlier and more accurate diagnosis of AD, providing the opportunity to intervene earlier in the disease process and to improve outcomes. The known ... ...

Abstract	An improved understanding of the pathobiology of Alzheimer's disease (AD) should lead ultimately to an earlier and more accurate diagnosis of AD, providing the opportunity to intervene earlier in the disease process and to improve outcomes. The known hallmarks of Alzheimer's disease include amyloid-β plaques and neurofibrillary tau tangles. It is now clear that an imbalance between production and clearance of the amyloid beta protein and related Aβ peptides, especially Aβ42, is a very early, initiating factor in Alzheimer's disease (AD) pathogenesis, leading to aggregates of hyperphosphorylation and misfolded tau protein, inflammation, and neurodegeneration. In this article, we review how the AD diagnostic process has been transformed in recent decades by our ability to measure these various elements of the pathological cascade through the use of imaging and fluid biomarkers. The more recently developed plasma biomarkers, especially phosphorylated-tau217 (p-tau217), have utility for screening and diagnosis of the earliest stages of AD. These biomarkers can also be used to measure target engagement by disease-modifying therapies and the response to treatment.
Language	English
Publishing date	2024-03-27
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2662336-5
ISSN	2075-4418
ISSN	2075-4418
DOI	10.3390/diagnostics14070704
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Article ; Online: The Broad Range of Research in Alzheimer's Disease and Related Dementias.

DeKosky, Steven T / Duara, Ranjan

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics

2022 Volume 19, Issue 1, Page(s) 1–7

MeSH term(s)	Alzheimer Disease/therapy ; Dementia ; Humans
Language	English
Publishing date	2022-05-13
Publishing country	United States
Document type	Editorial
ZDB-ID	2316693-9
ISSN	1878-7479 ; 1933-7213
ISSN (online)	1878-7479
ISSN	1933-7213
DOI	10.1007/s13311-022-01245-4
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Article ; Online: Association of Physical Frailty and Cognitive Function in a Population-Based Cross-Sectional Study of American Older Adults.

Karanth, Shama / Braithwaite, Dejana / Katsumata, Yuriko / Duara, Ranjan / Norrod, Paul / Aukhil, Ikramuddin / Abner, Erin

Gerontology

2023 Volume 70, Issue 1, Page(s) 48–58

Abstract: Introduction: Cognitive impairment and frailty are prevalent in older persons. Physical frailty is associated with cognitive decline; however, the role of effect modifiers such as age, sex, race/ethnicity, and cognitive reserve is not well understood.!## ...

Abstract	Introduction: Cognitive impairment and frailty are prevalent in older persons. Physical frailty is associated with cognitive decline; however, the role of effect modifiers such as age, sex, race/ethnicity, and cognitive reserve is not well understood. Methods: Cross-sectional data from the National Health and Nutrition Examination Survey (2011-2014) were obtained for participants aged ≥60 years. Complete availability of cognitive scores was an inclusion criterion. Physical frailty was defined by the presence of exhaustion, weakness, low body mass, and/or low physical activity, and categorized into three groups: robust (0 present), pre-frail (1-2 present), or frail (3-4 present). Four cognitive test scores were converted to z-scores, and global cognition (composite z-score) was calculated by averaging the four-individual z-scores. Multivariable linear regression models were fit to estimate the associations between frailty and cognitive function. Frailty was also evaluated as a risk factor for self-reported subjective memory complaint (SMC) using logistic regression. All models were adjusted for age, sex, race/ethnicity, education, alcohol use, income, marital status, diabetes, hypertension, and history of stroke. Effect measure modification analyses were conducted by age, sex, race/ethnicity, education, and occupational cognitive demand. Results: The study population comprised 2,863 participants aged ≥60 years. 50.6% of the participants were categorized into robust, 43.2% pre-frail, and 6.2% frail. After adjusting for covariates, compared to robust participants, frail and prefrail participants had lower adjusted mean global cognitive z-scores, <inline-formula><mml:math id="m1" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mover accent="true"><mml:mi>β</mml:mi><mml:mo>^</mml:mo></mml:mover></mml:mrow></mml:math></inline-formula> = -0.61, 95% CI: -0.83, -0.38 and <inline-formula><mml:math id="m2" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mover accent="true"><mml:mi>β</mml:mi><mml:mo>^</mml:mo></mml:mover></mml:mrow></mml:math></inline-formula> = -0.21, 95% CI: -0.30, -0.12, respectively. Both prefrail and frail participants had higher odds of SMC compared to the robust participants. We did not see strong evidence that the association between frailty and cognition was modified by the factors we studied. Discussion/conclusion: Both pre-frailty and frailty were associated with lower cognitive performance and were more likely to report subjective memory complaints relative to persons without frailty. These findings provide additional evidence that physical frailty may serve as a prognostic factor for cognitive deterioration or dementia, and prevention of frailty may be an important public health strategy.
MeSH term(s)	Aged ; Humans ; Aged, 80 and over ; Frailty/diagnosis ; Frail Elderly ; Cross-Sectional Studies ; Nutrition Surveys ; Geriatric Assessment ; Cognitive Dysfunction/epidemiology ; Cognitive Dysfunction/complications ; Cognition
Language	English
Publishing date	2023-10-30
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	193798-4
ISSN	1423-0003 ; 0304-324X
ISSN (online)	1423-0003
ISSN	0304-324X
DOI	10.1159/000533919
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Article ; Online: Mediation of Reduced Hippocampal Volume by Cerebral Amyloid Angiopathy in Pathologically Confirmed Patients with Alzheimer's Disease.

Nagaraja, Nandakumar / Wang, Wei-En / Duara, Ranjan / DeKosky, Steven T / Vaillancourt, David

Journal of Alzheimer's disease : JAD

2023 Volume 93, Issue 2, Page(s) 495–507

Abstract: Background: Hippocampal atrophy in cerebral amyloid angiopathy (CAA) has been reported to be similar to that in Alzheimer's disease (AD).: Objective: To evaluate if CAA pathology partly mediates reduced hippocampal volume in patients with AD.: ... ...

Abstract	Background: Hippocampal atrophy in cerebral amyloid angiopathy (CAA) has been reported to be similar to that in Alzheimer's disease (AD). Objective: To evaluate if CAA pathology partly mediates reduced hippocampal volume in patients with AD. Methods: Patients with a clinical diagnosis of AD and neuropathological confirmation of AD+/-CAA in the National Alzheimer's Coordinating Center database were included in the study. The volumes of temporal lobe structures were calculated on T1-weighted imaging (T1-MRI) using automated FreeSurfer software, from images acquired on average 5 years prior to death. Multivariate regression analysis was performed to compare brain volumes in four CAA groups. The hippocampal volume on T1-MRI was correlated with Clinical Dementia Rating sum of boxes (CDRsb) score, apolipoprotein E (APOE) genotype, and hippocampal atrophy at autopsy. Results: The study included 231 patients with no (n = 45), mild (n = 70), moderate (n = 67), and severe (n = 49) CAA. Among the four CAA groups, patients with severe CAA had a smaller mean left hippocampal volume (p = 0.023) but this was not significant when adjusted for APOE ɛ4 (p = 0.07). The left hippocampal volume on MRI correlated significantly with the hippocampal atrophy grading on neuropathology (p = 0.0003). Among patients with severe CAA, the left hippocampal volume on T1-MRI: (a) decreased with an increase in the number of APOE ɛ4 alleles (p = 0.04); but (b) had no evidence of correlation with CDRsb score (p = 0.57). Conclusion: Severe CAA was associated with smaller left hippocampal volume on T1-MRI up to five years prior to death among patients with neuropathologically confirmed AD. This relationship was dependent on APOE ɛ4 genotype.
MeSH term(s)	Humans ; Alzheimer Disease/diagnostic imaging ; Alzheimer Disease/genetics ; Alzheimer Disease/pathology ; Cerebral Amyloid Angiopathy/diagnostic imaging ; Cerebral Amyloid Angiopathy/genetics ; Cerebral Amyloid Angiopathy/pathology ; Apolipoproteins E/genetics ; Apolipoprotein E4/genetics ; Hippocampus/diagnostic imaging ; Hippocampus/pathology
Chemical Substances	Apolipoproteins E ; Apolipoprotein E4
Language	English
Publishing date	2023-04-07
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-220624
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Article ; Online: The prognostic value of ATN Alzheimer biomarker profiles in cognitively normal individuals.

Vos, Stephanie J B / Duara, Ranjan

Neurology

2019 Volume 92, Issue 14, Page(s) 643–644

MeSH term(s)	Alzheimer Disease ; Amyloid beta-Peptides ; Biomarkers ; Cognition ; Humans ; Prognosis
Chemical Substances	Amyloid beta-Peptides ; Biomarkers
Language	English
Publishing date	2019-03-06
Publishing country	United States
Document type	Editorial ; Comment
ZDB-ID	207147-2
ISSN	1526-632X ; 0028-3878
ISSN (online)	1526-632X
ISSN	0028-3878
DOI	10.1212/WNL.0000000000007223
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Article ; Online: Imaging features of small vessel disease in cerebral amyloid angiopathy among patients with Alzheimer's disease.

Nagaraja, Nandakumar / DeKosky, Steven / Duara, Ranjan / Kong, Lan / Wang, Wei-En / Vaillancourt, David / Albayram, Mehmet

NeuroImage. Clinical

2023 Volume 38, Page(s) 103437

Abstract: Background and purpose: Cerebral small vessel disease biomarkers including white matter hyperintensities (WMH), lacunes, and enlarged perivascular spaces (ePVS) are under investigation to identify those specific to cerebral amyloid angiopathy (CAA). In ... ...

Abstract	Background and purpose: Cerebral small vessel disease biomarkers including white matter hyperintensities (WMH), lacunes, and enlarged perivascular spaces (ePVS) are under investigation to identify those specific to cerebral amyloid angiopathy (CAA). In subjects with Alzheimer's disease (AD), we assessed characteristic features and amounts of WMH, lacunes, and ePVS in four CAA categories (no, mild, moderate and severe CAA) and correlated these with Clinical Dementia Rating sum of boxes (CDRsb) score, ApoE genotype, and neuropathological changes at autopsy. Methods: The study included patients with a clinical diagnosis of dementia due to AD and neuropathological confirmation of AD and CAA in the National Alzheimer's Coordinating Center (NACC) database. The WMH, lacunes, and ePVS were evaluated using semi-quantitative scales. Statistical analyses compared the WMH, lacunes, and ePVS values in the four CAA groups with vascular risk factors and AD severity treated as covariates, and to correlate the imaging features with CDRsb score, ApoE genotype, and neuropathological findings. Results: The study consisted of 232 patients, of which 222 patients had FLAIR data available and 105 patients had T2-MRI. Occipital predominant WMH were significantly associated with the presence of CAA (p = 0.007). Among the CAA groups, occipital predominant WMH was associated with severe CAA (β = 1.22, p = 0.0001) compared with no CAA. Occipital predominant WMH were not associated with the CDRsb score performed at baseline (p = 0.68) or at follow-up 2-4 years after the MRI (p = 0.92). There was no significant difference in high grade ePVS in the basal ganglia (p = 0.63) and centrum semiovale (p = 0.95) among the four CAA groups. The WMH and ePVS on imaging did not correlate with the number of ApoE ε4 alleles but the WMH (periventricular and deep) correlated with the presence of infarcts, lacunes and microinfarcts on neuropathology. Conclusion: Among patients with AD, occipital predominant WMH is more likely to be found in patients with severe CAA than in those without CAA. The high-grade ePVS in centrum semiovale were common in all AD patients regardless of CAA severity.
MeSH term(s)	Humans ; Alzheimer Disease/genetics ; Cerebral Amyloid Angiopathy/complications ; Cerebral Amyloid Angiopathy/diagnostic imaging ; Magnetic Resonance Imaging ; Apolipoproteins E/genetics ; Basal Ganglia/pathology ; Cerebral Small Vessel Diseases/complications ; Cerebral Small Vessel Diseases/diagnostic imaging
Chemical Substances	Apolipoproteins E
Language	English
Publishing date	2023-05-17
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2701571-3
ISSN	2213-1582 ; 2213-1582
ISSN (online)	2213-1582
ISSN	2213-1582
DOI	10.1016/j.nicl.2023.103437
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Article: Clinical utility of plasma Aβ42/40 ratio by LC-MS/MS in Alzheimer's disease assessment.

Weber, Darren M / Taylor, Steven W / Lagier, Robert J / Kim, Jueun C / Goldman, Scott M / Clarke, Nigel J / Vaillancourt, David E / Duara, Ranjan / McFarland, Karen N / Wang, Wei-En / Golde, Todd E / Racke, Michael K

Frontiers in neurology

2024 Volume 15, Page(s) 1364658

Abstract: Introduction: Plasma Aβ42/40 ratio can help predict amyloid PET status, but its clinical utility in Alzheimer's disease (AD) assessment is unclear.: Methods: Aβ42/40 ratio was measured by LC-MS/MS for 250 specimens with associated amyloid PET imaging, ...

Abstract	Introduction: Plasma Aβ42/40 ratio can help predict amyloid PET status, but its clinical utility in Alzheimer's disease (AD) assessment is unclear. Methods: Aβ42/40 ratio was measured by LC-MS/MS for 250 specimens with associated amyloid PET imaging, diagnosis, and demographic data, and for 6,192 consecutive clinical specimens submitted for Aβ42/40 testing. Results: High diagnostic sensitivity and negative predictive value (NPV) for Aβ-PET positivity were observed, consistent with the clinical performance of other plasma LC-MS/MS assays, but with greater separation between Aβ42/40 values for individuals with positive vs. negative Aβ-PET results. Assuming a moderate prevalence of Aβ-PET positivity, a cutpoint was identified with 99% NPV, which could help predict that AD is likely not the cause of patients' cognitive impairment and help reduce PET evaluation by about 40%. Conclusion: High-throughput plasma Aβ42/40 LC-MS/MS assays can help identify patients with low likelihood of AD pathology, which can reduce PET evaluations, allowing for cost savings.
Language	English
Publishing date	2024-03-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564214-5
ISSN	1664-2295
ISSN	1664-2295
DOI	10.3389/fneur.2024.1364658
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Article ; Online: Diffusion MRI relates to plasma Aβ42/40 in PET negative participants without dementia.

DeSimone, Jesse C / Wang, Wei-En / Loewenstein, David A / Duara, Ranjan / Smith, Glenn E / McFarland, Karen N / Armstrong, Melissa J / Weber, Darren M / Barker, Warren / Coombes, Stephen A / Vaillancourt, David E

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

2024 Volume 20, Issue 4, Page(s) 2830–2842

Abstract: Introduction: Magnetic resonance imaging (MRI) biomarkers are needed for indexing early biological stages of Alzheimer's disease (AD), such as plasma amyloid-β (Aβ42/40) positivity in Aβ positron emission tomography (PET) negative individuals.: ... ...

Abstract	Introduction: Magnetic resonance imaging (MRI) biomarkers are needed for indexing early biological stages of Alzheimer's disease (AD), such as plasma amyloid-β (Aβ42/40) positivity in Aβ positron emission tomography (PET) negative individuals. Methods: Diffusion free-water (FW) MRI was acquired in individuals with normal cognition (NC) and mild cognitive impairment (MCI) with Aβ plasma-/PET- (NC = 22, MCI = 60), plasma+/PET- (NC = 5, MCI = 20), and plasma+/PET+ (AD dementia = 21) biomarker status. Gray and white matter FW and fractional anisotropy (FAt) were compared cross-sectionally and the relationships between imaging, plasma and PET biomarkers were assessed. Results: Plasma+/PET- demonstrated increased FW (24 regions) and decreased FAt (66 regions) compared to plasma-/PET-. FW (16 regions) and FAt (51 regions) were increased in plasma+/PET+ compared to plasma+/PET-. Composite brain FW correlated with plasma Aβ42/40 and p-tau181. Discussion: FW imaging changes distinguish plasma Aβ42/40 positive and negative groups, independent of group differences in cognitive status, Aβ PET status, and other plasma biomarkers (i.e., t-tau, p-tau181, glial fibrillary acidic protein, neurofilament light). Highlights: Plasma Aβ42/40 positivity is associated with brain microstructure decline. Plasma+/PET- demonstrated increased FW in 24 total GM and WM regions. Plasma+/PET- demonstrated decreased FAt in 66 total GM and WM regions. Whole-brain FW correlated with plasma Aβ42/40 and p-tau181 measures. Plasma+/PET- demonstrated decreased cortical volume and thickness.
MeSH term(s)	Humans ; Alzheimer Disease/pathology ; Amyloid beta-Peptides/metabolism ; Positron-Emission Tomography/methods ; Cognitive Dysfunction/metabolism ; Diffusion Magnetic Resonance Imaging ; Biomarkers ; tau Proteins
Chemical Substances	Amyloid beta-Peptides ; Biomarkers ; tau Proteins
Language	English
Publishing date	2024-03-05
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.13693
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