Characterization of Alzheimer’s tau biomarker discordance using plasma, CSF, and PET

Abstract Background We aimed to investigate the tau biomarker discrepancies of Alzheimer’s disease (AD) using plasma tau phosphorylated at threonine 181 (p-tau181), cerebrospinal fluid (CSF) p-tau181, and AV1451 positron emission tomography (PET). Methods In the Alzheimer’s Disease Neuroimaging Initiative, 724 non-demented participants were categorized into plasma/CSF and plasma/PET groups. Demographic and clinical variables, amyloid-β (Aβ) burden, flortaucipir-PET binding in Braak regions of interest (ROIs), longitudinal changes in clinical outcomes, and conversion risk were compared. Results Across different tau biomarker groups, the proportion of participants with a discordant profile varied (plasma+/CSF− 15.6%, plasma−/CSF+ 15.3%, plasma+/PET− 22.4%, and plasma−/PET+ 6.1%). Within the plasma/CSF categories, we found an increase from concordant-negative to discordant to concordant-positive in the frequency of Aβ pathology or cognitive impairment, rates of cognitive decline, and risk of cognitive conversion. However, the two discordant categories (plasma+/CSF− and plasma−/CSF+) showed comparable performances, resulting in similarly reduced cognitive capacities. Regarding plasma/PET categories, as expected, PET-positive individuals had increased Aβ burden, elevated flortaucipir retention in Braak ROIs, and accelerated cognitive deterioration than concordant-negative persons. Noteworthy, discordant participants with normal PET exhibited reduced flortaucipir uptake in Braak stage ROIs and slower rates of cognitive decline, relative to those PET-positive. Therefore, individuals with PET abnormality appeared to have advanced tau pathological changes and poorer cognitive function, regardless of the plasma status. Furthermore, these results were found only in individuals with Aβ pathology. Conclusions Our results indicate that plasma and CSF p-tau181 abnormalities associated with amyloidosis occur simultaneously in the progression of AD pathogenesis and related cognitive decline, before tau-PET turns positive.

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Progressive loss of cortical acetylcholinesterase activity in association with cognitive decline in Alzheimer's disease: A positron emission tomography study

Annals of Neurology ◽

10.1002/1531-8249(200008)48:2<194::aid-ana9>3.0.co;2-x ◽

2000 ◽

Vol 48 (2) ◽

pp. 194-200 ◽

Cited By ~ 99

Author(s):

Hitoshi Shinotoh ◽

Hiroki Namba ◽

Kiyoshi Fukushi ◽

Shin-Ichiro Nagatsuka ◽

Noriko Tanaka ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Positron Emission Tomography ◽

Cognitive Decline ◽

Acetylcholinesterase Activity ◽

Emission Tomography ◽

Positron Emission Tomography Study ◽

Progressive Loss ◽

Positron Emission

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Neurophysiological signatures in Alzheimer’s disease are distinctly associated with TAU, amyloid-β accumulation, and cognitive decline

Science Translational Medicine ◽

10.1126/scitranslmed.aaz4069 ◽

2020 ◽

Vol 12 (534) ◽

pp. eaaz4069 ◽

Cited By ~ 5

Author(s):

Kamalini G. Ranasinghe ◽

Jungho Cha ◽

Leonardo Iaccarino ◽

Leighton B. Hinkley ◽

Alexander J. Beagle ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Amyloid Β ◽

Tracer Uptake ◽

Therapeutic Approaches ◽

Regional Patterns ◽

Positron Emission ◽

Network Synchrony ◽

Network Disruptions

Neural synchrony is intricately balanced in the normal resting brain but becomes altered in Alzheimer’s disease (AD). To determine the neurophysiological manifestations associated with molecular biomarkers of AD neuropathology, in patients with AD, we used magnetoencephalographic imaging (MEGI) and positron emission tomography with amyloid-beta (Aβ) and TAU tracers. We found that alpha oscillations (8 to 12 Hz) were hyposynchronous in occipital and posterior temporoparietal cortices, whereas delta-theta oscillations (2 to 8 Hz) were hypersynchronous in frontal and anterior temporoparietal cortices, in patients with AD compared to age-matched controls. Regional patterns of alpha hyposynchrony were unique in each neurobehavioral phenotype of AD, whereas the regional patterns of delta-theta hypersynchrony were similar across the phenotypes. Alpha hyposynchrony strongly colocalized with TAU deposition and was modulated by the degree of TAU tracer uptake. In contrast, delta-theta hypersynchrony colocalized with both TAU and Aβ depositions and was modulated by both TAU and Aβ tracer uptake. Furthermore, alpha hyposynchrony but not delta-theta hypersynchrony was correlated with the degree of global cognitive dysfunction in patients with AD. The current study demonstrates frequency-specific neurophysiological signatures of AD pathophysiology and suggests that neurophysiological measures from MEGI are sensitive indices of network disruptions mediated by TAU and Aβ and associated cognitive decline. These findings facilitate the pursuit of novel therapeutic approaches toward normalizing network synchrony in AD.

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Brain accumulation of amyloid β protein visualized by positron emission tomography and BF-227 in Alzheimer's disease patients with or without diabetes mellitus

Geriatrics and Gerontology International ◽

10.1111/j.1447-0594.2012.00880.x ◽

2012 ◽

Vol 13 (1) ◽

pp. 215-221 ◽

Cited By ~ 15

Author(s):

Naoki Tomita ◽

Katsutoshi Furukawa ◽

Nobuyuki Okamura ◽

Manabu Tashiro ◽

Kaori Une ◽

...

Keyword(s):

Diabetes Mellitus ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Positron Emission Tomography ◽

Amyloid Β ◽

Emission Tomography ◽

Amyloid Β Protein ◽

Positron Emission ◽

Β Protein

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[18 F]flutemetamol amyloid positron emission tomography in preclinical and symptomatic Alzheimer's disease: Specific detection of advanced phases of amyloid-β pathology

Alzheimer s & Dementia ◽

10.1016/j.jalz.2015.05.018 ◽

2015 ◽

Vol 11 (8) ◽

pp. 975-985 ◽

Cited By ~ 75

Author(s):

Dietmar Rudolf Thal ◽

Thomas G. Beach ◽

Michelle Zanette ◽

Kerstin Heurling ◽

Aruna Chakrabarty ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Positron Emission Tomography ◽

Amyloid Β ◽

Emission Tomography ◽

Specific Detection ◽

Amyloid Positron Emission Tomography ◽

Positron Emission ◽

Disease Specific

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Longitudinal Observation of Early-Onset Alzheimer’s Disease Dementia with Positive CSF Biomarkers/Negative Amyloid-β Positron-Emission Tomography

Journal of the Korean Neurological Association ◽

10.17340/jkna.2021.3.19 ◽

2021 ◽

Vol 39 (3) ◽

pp. 214-218

Author(s):

Min Hye Kim ◽

Joonho Lee ◽

Hong Nam Kim ◽

In Ja Shin ◽

Keun Lee ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Positron Emission Tomography ◽

Early Onset ◽

Brain Magnetic Resonance Imaging ◽

Amyloid Β ◽

Emission Tomography ◽

Csf Biomarkers ◽

Amyloid Pet ◽

Positron Emission

We report a 61-year-old woman with clinical course for Alzheimer’s disease (AD) dementia and discordant amyloid-β positron-emission tomography (PET) and cerebrospinal fluid biomarkers. Brain magnetic resonance imaging revealed remarkable atrophy in the hippocampus. However, repeated delayed <sup>18</sup>F-flutemetamol brain amyloid PET images with 1 year-interval revealed no amyloid deposition, whereas her CSF revealed low Aβ42, high total tau and p-tau181. This discordant amyloid-β PET and CSF biomarkers in this early-onset AD dementia might be associated with her low resilience or mixed pathology.

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Benfotiamine and Cognitive Decline in Alzheimer’s Disease: Results of a Randomized Placebo-Controlled Phase IIa Clinical Trial

Journal of Alzheimer s Disease ◽

10.3233/jad-200896 ◽

2020 ◽

Vol 78 (3) ◽

pp. 989-1010

Author(s):

Gary E. Gibson ◽

José A. Luchsinger ◽

Rosanna Cirio ◽

Huanlian Chen ◽

Jessica Franchino-Elder ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Placebo Group ◽

Cognitive Decline ◽

Controlled Trial ◽

Amyloid Β ◽

Cognitive Outcomes ◽

Disease Assessment ◽

Clinical Dementia Rating ◽

Positron Emission

Background: In preclinical models, benfotiamine efficiently ameliorates the clinical and biological pathologies that define Alzheimer’s disease (AD) including impaired cognition, amyloid-β plaques, neurofibrillary tangles, diminished glucose metabolism, oxidative stress, increased advanced glycation end products (AGE), and inflammation. Objective: To collect preliminary data on feasibility, safety, and efficacy in individuals with amnestic mild cognitive impairment (aMCI) or mild dementia due to AD in a placebo-controlled trial of benfotiamine. Methods: A twelve-month treatment with benfotiamine tested whether clinical decline would be delayed in the benfotiamine group compared to the placebo group. The primary clinical outcome was the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Secondary outcomes were the clinical dementia rating (CDR) score and fluorodeoxyglucose (FDG) uptake, measured with brain positron emission tomography (PET). Blood AGE were examined as an exploratory outcome. Results: Participants were treated with benfotiamine (34) or placebo (36). Benfotiamine treatment was safe. The increase in ADAS-Cog was 43% lower in the benfotiamine group than in the placebo group, indicating less cognitive decline, and this effect was nearly statistically significant (p = 0.125). Worsening in CDR was 77% lower (p = 0.034) in the benfotiamine group compared to the placebo group, and this effect was stronger in the APOE ɛ4 non-carriers. Benfotiamine significantly reduced increases in AGE (p = 0.044), and this effect was stronger in the APOE ɛ4 non-carriers. Exploratory analysis derivation of an FDG PET pattern score showed a treatment effect at one year (p = 0.002). Conclusion: Oral benfotiamine is safe and potentially efficacious in improving cognitive outcomes among persons with MCI and mild AD.

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