Publications by authors named "Mahnaz Shekari"

7 Publications

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Perivascular spaces are associated with tau pathophysiology and synaptic dysfunction in early Alzheimer's continuum.

Alzheimers Res Ther 2021 08 5;13(1):135. Epub 2021 Aug 5.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.

Background: Perivascular spaces (PVS) have an important role in the elimination of metabolic waste from the brain. It has been hypothesized that the enlargement of PVS (ePVS) could be affected by pathophysiological mechanisms involved in Alzheimer's disease (AD), such as abnormal levels of CSF biomarkers. However, the relationship between ePVS and these pathophysiological mechanisms remains unknown.

Objective: We aimed to investigate the association between ePVS and CSF biomarkers of several pathophysiological mechanisms for AD. We hypothesized that ePVS will be associated to CSF biomarkers early in the AD continuum (i.e., amyloid positive cognitively unimpaired individuals). Besides, we explored associations between ePVS and demographic and cardiovascular risk factors.

Methods: The study included 322 middle-aged cognitively unimpaired participants from the ALFA + study, many within the Alzheimer's continuum. NeuroToolKit and Elecsys® immunoassays were used to measure CSF Aβ42, Aβ40, p-tau and t-tau, NfL, neurogranin, TREM2, YKL40, GFAP, IL6, S100, and α-synuclein. PVS in the basal ganglia (BG) and centrum semiovale (CS) were assessed based on a validated 4-point visual rating scale. Odds ratios were calculated for associations of cardiovascular and AD risk factors with ePVS using logistic and multinomial models adjusted for relevant confounders. Models were stratified by Aβ status (positivity defined as Aβ42/40 < 0.071).

Results: The degree of PVS significantly increased with age in both, BG and CS regions independently of cardiovascular risk factors. Higher levels of p-tau, t-tau, and neurogranin were significantly associated with ePVS in the CS of Aβ positive individuals, after accounting for relevant confounders. No associations were detected in the BG neither in Aβ negative participants.

Conclusions: Our results support that ePVS in the CS are specifically associated with tau pathophysiology, neurodegeneration, and synaptic dysfunction in asymptomatic stages of the Alzheimer's continuum.
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http://dx.doi.org/10.1186/s13195-021-00878-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8340485PMC
August 2021

Cognitively unimpaired individuals with a low burden of Aβ pathology have a distinct CSF biomarker profile.

Alzheimers Res Ther 2021 07 27;13(1):134. Epub 2021 Jul 27.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Wellington 30, 08005, Barcelona, Spain.

Background: Understanding the changes that occur in the transitional stage between absent and overt amyloid-β (Aβ) pathology within the Alzheimer's continuum is crucial to develop therapeutic and preventive strategies. The objective of this study is to test whether cognitively unimpaired individuals with a low burden of Aβ pathology have a distinct CSF, structural, and functional neuroimaging biomarker profile.

Methods: Cross-sectional study of 318 middle-aged, cognitively unimpaired individuals from the ALFA+ cohort. We measured CSF Aβ42/40, phosphorylated tau (p-tau), total tau (t-tau), neurofilament light (NfL), neurogranin, sTREM2, YKL40, GFAP, IL6, S100B, and α-synuclein. Participants also underwent cognitive assessments, APOE genotyping, structural MRI, [F]-FDG, and [F]-flutemetamol PET. To ensure the robustness of our results, we used three definitions of low burden of Aβ pathology: (1) positive CSF Aβ42/40 and < 30 Centiloids in Aβ PET, (2) positive CSF Aβ42/40 and negative Aβ PET visual read, and (3) 20-40 Centiloid range in Aβ PET. We tested CSF and neuroimaging biomarker differences between the low burden group and the corresponding Aβ-negative group, adjusted by age and sex.

Results: The prevalence and demographic characteristics of the low burden group differed between the three definitions. CSF p-tau and t-tau were increased in the low burden group compared to the Aβ-negative in all definitions. CSF neurogranin was increased in the low burden group definitions 1 and 3, while CSF NfL was only increased in the low burden group definition 1. None of the defined low burden groups showed signs of atrophy or glucose hypometabolism. Instead, we found slight increases in cortical thickness and metabolism in definition 2.

Conclusions: There are biologically meaningful Aβ-downstream effects in individuals with a low burden of Aβ pathology, while structural and functional changes are still subtle or absent. These findings support considering individuals with a low burden of Aβ pathology for clinical trials.

Trial Registration: NCT02485730.
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http://dx.doi.org/10.1186/s13195-021-00863-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8314554PMC
July 2021

A multisite analysis of the concordance between visual image interpretation and quantitative analysis of [F]flutemetamol amyloid PET images.

Eur J Nucl Med Mol Imaging 2021 07 12;48(7):2183-2199. Epub 2021 Apr 12.

Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.

Background: [F]flutemetamol PET scanning provides information on brain amyloid load and has been approved for routine clinical use based upon visual interpretation as either negative (equating to none or sparse amyloid plaques) or amyloid positive (equating to moderate or frequent plaques). Quantitation is however fundamental to the practice of nuclear medicine and hence can be used to supplement amyloid reading methodology especially in unclear cases.

Methods: A total of 2770 [F]flutemetamol images were collected from 3 clinical studies and 6 research cohorts with available visual reading of [F]flutemetamol and quantitative analysis of images. These were assessed further to examine both the discordance and concordance between visual and quantitative imaging primarily using thresholds robustly established using pathology as the standard of truth. Scans covered a wide range of cases (i.e. from cognitively unimpaired subjects to patients attending the memory clinics). Methods of quantifying amyloid ranged from using CE/510K cleared marked software (e.g. CortexID, Brass), to other research-based methods (e.g. PMOD, CapAIBL). Additionally, the clinical follow-up of two types of discordance between visual and quantitation (V+Q- and V-Q+) was examined with competing risk regression analysis to assess possible differences in prediction for progression to Alzheimer's disease (AD) and other diagnoses (OD).

Results: Weighted mean concordance between visual and quantitation using the autopsy-derived threshold was 94% using pons as the reference region. Concordance from a sensitivity analysis which assessed the maximum agreement for each cohort using a range of cut-off values was also estimated at approximately 96% (weighted mean). Agreement was generally higher in clinical cases compared to research cases. V-Q+ discordant cases were 11% more likely to progress to AD than V+Q- for the SUVr with pons as reference region.

Conclusions: Quantitation of amyloid PET shows a high agreement vs binary visual reading and also allows for a continuous measure that, in conjunction with possible discordant analysis, could be used in the future to identify possible earlier pathological deposition as well as monitor disease progression and treatment effectiveness.
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http://dx.doi.org/10.1007/s00259-021-05311-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175298PMC
July 2021

Cerebral amyloid-β load is associated with neurodegeneration and gliosis: Mediation by p-tau and interactions with risk factors early in the Alzheimer's continuum.

Alzheimers Dement 2021 05 4;17(5):788-800. Epub 2021 Mar 4.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.

Introduction: The association between cerebral amyloid-β accumulation and downstream CSF biomarkers is not fully understood, particularly in asymptomatic stages.

Methods: In 318 cognitively unimpaired participants, we assessed the association between amyloid-β PET (Centiloid), and cerebrospinal fluid (CSF) biomarkers of several pathophysiological pathways. Interactions by Alzheimer's disease risk factors (age, sex and APOE-ε4), and the mediation effect of tau and neurodegeneration were also investigated.

Results: Centiloids were positively associated with CSF biomarkers of tau pathology (p-tau), neurodegeneration (t-tau, NfL), synaptic dysfunction (neurogranin) and neuroinflammation (YKL-40, GFAP, sTREM2), presenting interactions with age (p-tau, t-tau, neurogranin) and sex (sTREM2, NfL). Most of these associations were mediated by p-tau, except for NfL. The interaction between sex and amyloid-β on sTREM2 and NfL was also tau-independent.

Discussion: Early amyloid-β accumulation has a tau-independent effect on neurodegeneration and a tau-dependent effect on neuroinflammation. Besides, sex has a modifier effect on these associations independent of tau.
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http://dx.doi.org/10.1002/alz.12245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252618PMC
May 2021

Visual assessment of [F]flutemetamol PET images can detect early amyloid pathology and grade its extent.

Eur J Nucl Med Mol Imaging 2021 07 22;48(7):2169-2182. Epub 2021 Feb 22.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.

Purpose: To investigate the sensitivity of visual read (VR) to detect early amyloid pathology and the overall utility of regional VR.

Methods: [F]Flutemetamol PET images of 497 subjects (ALFA+ N = 352; ADC N = 145) were included. Scans were visually assessed according to product guidelines, recording the number of positive regions (0-5) and a final negative/positive classification. Scans were quantified using the standard and regional Centiloid (CL) method. The agreement between VR-based classification and published CL-based cut-offs for early (CL = 12) and established (CL = 30) pathology was determined. An optimal CL cut-off maximizing Youden's index was derived. Global and regional CL quantification was compared to VR. Finally, 28 post-mortem cases from the [F]flutemetamol phase III trial were included to assess the percentage agreement between VR and neuropathological classification of neuritic plaque density.

Results: VR showed excellent agreement against CL = 12 (κ = .89, 95.2%) and CL = 30 (κ = .88, 95.4%) cut-offs. ROC analysis resulted in an optimal CL = 17 cut-off against VR (sensitivity = 97.9%, specificity = 97.8%). Each additional positive VR region corresponded to a clear increase in global CL. Regional VR was also associated with regional CL quantification. Compared to mCERAD-based classification (i.e., any region mCERAD > 1.5), VR was in agreement in 89.3% of cases, with 13 true negatives, 12 true positives, and 3 false positives (FP). Regional sparse-to-moderate neuritic and substantial diffuse Aβ plaque was observed in all FP cases. Regional VR was also associated with regional plaque density.

Conclusion: VR is an appropriate method for assessing early amyloid pathology and that grading the extent of visual amyloid positivity could present clinical value.
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http://dx.doi.org/10.1007/s00259-020-05174-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175297PMC
July 2021

Association of weight change with cerebrospinal fluid biomarkers and amyloid positron emission tomography in preclinical Alzheimer's disease.

Alzheimers Res Ther 2021 02 17;13(1):46. Epub 2021 Feb 17.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.

Background: Recognizing clinical manifestations heralding the development of Alzheimer's disease (AD)-related cognitive impairment could improve the identification of individuals at higher risk of AD who may benefit from potential prevention strategies targeting preclinical population. We aim to characterize the association of body weight change with cognitive changes and AD biomarkers in cognitively unimpaired middle-aged adults.

Methods: This prospective cohort study included data from cognitively unimpaired adults from the ALFA study (n = 2743), a research platform focused on preclinical AD. Cognitive and anthropometric data were collected at baseline between April 2013 and November 2014. Between October 2016 and February 2020, 450 participants were visited in the context of the nested ALFA+ study and underwent cerebrospinal fluid (CSF) extraction and acquisition of positron emission tomography images with [F]flutemetamol (FTM-PET). From these, 408 (90.1%) were included in the present study. We used data from two visits (average interval 4.1 years) to compute rates of change in weight and cognitive performance. We tested associations between these variables and between weight change and categorical and continuous measures of CSF and neuroimaging AD biomarkers obtained at follow-up. We classified participants with CSF data according to the AT (amyloid, tau) system and assessed between-group differences in weight change.

Results: Weight loss predicted a higher likelihood of positive FTM-PET visual read (OR 1.27, 95% CI 1.00-1.61, p = 0.049), abnormal CSF p-tau levels (OR 1.50, 95% CI 1.19-1.89, p = 0.001), and an A+T+ profile (OR 1.64, 95% CI 1.25-2.20, p = 0.001) and was greater among participants with an A+T+ profile (p < 0.01) at follow-up. Weight change was positively associated with CSF Aβ42/40 ratio (β = 0.099, p = 0.032) and negatively associated with CSF p-tau (β = - 0.141, p = 0.005), t-tau (β = - 0.147 p = 0.004) and neurogranin levels (β = - 0.158, p = 0.002). In stratified analyses, weight loss was significantly associated with higher t-tau, p-tau, neurofilament light, and neurogranin, as well as faster cognitive decline in A+ participants only.

Conclusions: Weight loss predicts AD CSF and PET biomarker results and may occur downstream to amyloid-β accumulation in preclinical AD, paralleling cognitive decline. Accordingly, it should be considered as an indicator of increased risk of AD-related cognitive impairment.

Trial Registration: NCT01835717 , NCT02485730 , NCT02685969 .
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http://dx.doi.org/10.1186/s13195-021-00781-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890889PMC
February 2021

Novel tau biomarkers phosphorylated at T181, T217 or T231 rise in the initial stages of the preclinical Alzheimer's continuum when only subtle changes in Aβ pathology are detected.

EMBO Mol Med 2020 12 10;12(12):e12921. Epub 2020 Nov 10.

Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain.

In Alzheimer's disease (AD), tau phosphorylation in the brain and its subsequent release into cerebrospinal fluid (CSF) and blood is a dynamic process that changes during disease evolution. The main aim of our study was to characterize the pattern of changes in phosphorylated tau (p-tau) in the preclinical stage of the Alzheimer's continuum. We measured three novel CSF p-tau biomarkers, phosphorylated at threonine-181 and threonine-217 with an N-terminal partner antibody and at threonine-231 with a mid-region partner antibody. These were compared with an automated mid-region p-tau181 assay (Elecsys) as the gold standard p-tau measure. We demonstrate that these novel p-tau biomarkers increase more prominently in preclinical Alzheimer, when only subtle changes of amyloid-β (Aβ) pathology are detected, and can accurately differentiate Aβ-positive from Aβ-negative cognitively unimpaired individuals. Moreover, we show that the novel plasma N-terminal p-tau181 biomarker is mildly but significantly increased in the preclinical stage. Our results support the idea that early changes in neuronal tau metabolism in preclinical Alzheimer, likely in response to Aβ exposure, can be detected with these novel p-tau assays.
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http://dx.doi.org/10.15252/emmm.202012921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721364PMC
December 2020
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