81 research outputs found
Genotypic effects of APOE-epsilon 4 on resting-state connectivity in cognitively intact individuals support functional brain compensation
The investigation of resting-state functional connectivity (rsFC) in asymptomatic individuals at genetic risk for Alzheimer's disease (AD) enables discovering the earliest brain alterations in preclinical stages of the disease. The APOE-ε4 variant is the major genetic risk factor for AD, and previous studies have reported rsFC abnormalities in carriers of the ε4 allele. Yet, no study has assessed APOE-ε4 gene-dose effects on rsFC measures, and only a few studies included measures of cognitive performance to aid a clinical interpretation. We assessed the impact of APOE-ε4 on rsFC in a sample of 429 cognitively unimpaired individuals hosting a high number of ε4 homozygotes (n = 58), which enabled testing different models of genetic penetrance. We used independent component analysis and found a reduced rsFC as a function of the APOE-ε4 allelic load in the temporal default-mode and the medial temporal networks, while recessive effects were found in the extrastriate and limbic networks. Some of these results were replicated in a subsample with negative amyloid markers. Interaction with cognitive data suggests that such a network reorganization may support cognitive performance in the ε4-homozygotes. Our data indicate that APOE-ε4 shapes the functional architecture of the resting brain and favor the idea of a network-based functional compensation
Comparative Analysis of Different Definitions of Amyloid-beta Positivity to Detect Early Downstream Pathophysiological Alterations in Preclinical Alzheimer
Amyloid-β (Aβ) positivity is defined using different biomarkers and different criteria. Criteria used in symptomatic patients may conceal meaningful early Aβ pathology in preclinical Alzheimer. Therefore, the description of sensitive cutoffs to study the pathophysiological changes in early stages of the Alzheimer’s continuum is critical. Here, we compare different Aβ classification approaches and we show their performance in detecting pathophysiological changes downstream Aβ pathology. We studied 368 cognitively unimpaired individuals of the ALFA+ study, many of whom in the preclinical stage of the Alzheimer’s continuum. Participants underwent Aβ PET and CSF biomarkers assessment. We classified participants as Aβ -positive using five approaches: (1) CSF Aβ42 12; (4) Aβ PET Centiloid > 30 or (5) Aβ PET Positive visual read. We assessed the correlations between Aβ biomarkers and compared the prevalence of Aβ positivity. We determined which approach significantly detected associations between Aβ pathology and tau/neurodegeneration CSF biomarkers. We found that CSF-based approaches result in a higher Aβ-positive prevalence than PET-based ones. There was a higher number of discordant participants classified as CSF Aβ-positive but PET Aβ-negative than CSF Aβ-negative but PET Aβ-positive. The CSF Aβ 42/40 approach allowed optimal detection of significant associations with CSF p-tau and t-tau in the Aβ-positive group. Altogether, we highlight the need for sensitive Aβ -classifications to study the preclinical Alzheimer’s continuum. Approaches that define Aβ positivity based on optimal discrimination of symptomatic Alzheimer’s disease patients may be suboptimal for the detection of early pathophysiological alterations in preclinical Alzheimer
Longitudinal interplay between subclinical atherosclerosis, cardiovascular risk factors, and cerebral glucose metabolism in midlife: results from the PESA prospective cohort study.
BACKGROUND
Cardiovascular disease and dementia often coexist at advanced stages. Yet, longitudinal studies examining the interplay between atherosclerosis and its risk factors on brain health in midlife are scarce. We aimed to characterise the longitudinal associations between cerebral glucose metabolism, subclinical atherosclerosis, and cardiovascular risk factors in middle-aged asymptomatic individuals.
METHODS
The Progression of Early Subclinical Atherosclerosis (PESA) study is a Spanish longitudinal observational cohort study of 4184 asymptomatic individuals aged 40-54 years (NCT01410318). Participants with subclinical atherosclerosis underwent longitudinal cerebral [18F]fluorodeoxyglucose ([18F]FDG)-PET, and annual percentage change in [18F]FDG uptake was assessed (primary outcome). Cardiovascular risk was quantified with SCORE2 and subclinical atherosclerosis with three-dimensional vascular ultrasound (exposures). Multivariate regression and linear mixed effects models were used to assess associations between outcomes and exposures. Additionally, blood-based biomarkers of neuropathology were quantified and mediation analyses were performed. Secondary analyses were corrected for multiple comparisons using the false discovery rate (FDR) approach.
FINDINGS
This longitudinal study included a PESA subcohort of 370 participants (median age at baseline 49·8 years [IQR 46·1-52·2]; 309 [84%] men, 61 [16%] women; median follow-up 4·7 years [IQR 4·2-5·2]). Baseline scans took place between March 6, 2013, and Jan 21, 2015, and follow-up scans between Nov 24, 2017, and Aug 7, 2019. Persistent high risk of cardiovascular disease was associated with an accelerated decline of cortical [18F]FDG uptake compared with low risk (β=-0·008 [95% CI -0·013 to -0·002]; pFDR=0·040), with plasma neurofilament light chain, a marker of neurodegeneration, mediating this association by 20% (β=0·198 [0·008 to 0·740]; pFDR=0·050). Moreover, progression of subclinical carotid atherosclerosis was associated with an additional decline in [18F]FDG uptake in Alzheimer's disease brain regions, not explained by cardiovascular risk (β=-0·269 [95% CI -0·509 to -0·027]; p=0·029).
INTERPRETATION
Middle-aged asymptomatic individuals with persistent high risk of cardiovascular disease and subclinical carotid atherosclerosis already present brain metabolic decline, suggesting that maintenance of cardiovascular health during midlife could contribute to reductions in neurodegenerative disease burden later in life.
FUNDING
Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III, Santander Bank, Pro-CNIC Foundation, BrightFocus Foundation, BBVA Foundation, "la Caixa" Foundation.Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III, Santander Bank, Pro-CNIC
Foundation, BrightFocus Foundation, BBVA Foundation, “la Caixa” Foundation.
We thank the PESA participants and the imaging, administrative, and
medical PESA teams. The PESA study is equally co-funded by the
Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
and Santander Bank (Madrid, Spain) and also receives funding from the
Instituto de Salud Carlos III (ISCIII), Madrid, Spain (PI15/02019),
the European Regional Development Fund (ERDF—A Way to Build
Europe), and the European Social Fund (ESF—Investing in Your
Future). CNIC is a Severo Ochoa Center of Excellence (CEX2020-
001041-S) and is supported by the ISCIII, the Spanish Ministry for
Science and Innovation, and the Pro-CNIC Foundation. CT-P was
supported by a “la Caixa” Foundation fellowship (ID 100010434,
LCF/BQ/DI19/11730052). MC-C was supported by a Miguel Servet
type II research contract (ISCIII, CPII21/00007) and the Fondo de
Investigación Sanitaria (ISCIII, PI20/00819). We acknowledge the
Sephardic Foundation on Aging and other donors of the Alzheimer’s
Disease Research (grant number A2022034S), a programme of the
BrightFocus Foundation, for support of this research. This work was
also partially produced with the support of a 2021 Leonardo Grant for
Researchers and Cultural Creators from the BBVA Foundation awarded
to MC-C (the Foundation takes no responsibility for the opinions,
statements, and contents of this project, which are entirely the
responsibility of its authors). BI was supported by the European
Research Council (ERC-2018-CoG 819775-MATRIX). MS is supported
by the Knut and Alice Wallenberg Foundation (Wallenberg Centre for
Molecular and Translational Medicine; KAW2014.0363), the Swedish
Research Council (2017-02869, 2021-02678, 2021-06545), the Swedish
state under the agreement between the Swedish Government and the
County Councils, the ALF-agreement (ALFGBG-813971,
ALFGBG-965326), the Swedish Brain Foundation (FO2021-0311), and
the Swedish Alzheimer Foundation (AF-740191). MS-C receives
funding from the European Research Council (grant agreement
number 948677), project “PI19/00155”, funded by ISCIII and co-funded
by the EU, and a fellowship from “la Caixa” Foundation (ID 100010434)
and from the EU’s Horizon 2020 research and innovation programme
under the Marie Skłodowska-Curie grant agreement number 847648
(LCF/BQ/PR21/11840004). HZ is a Wallenberg Scholar supported by
grants from the Swedish Research Council (#2022-01018), the EU’s
Horizon Europe research and innovation programme under grant
agreement number 101053962, Swedish State Support for Clinical
Research (#ALFGBG-71320), the Alzheimer Drug Discovery
Foundation, USA (#201809-2016862), the AD Strategic Fund and the
Alzheimer’s Association (#ADSF-21-831376-C, #ADSF-21-831381-C,
#ADSF-21-831377-C), the Bluefield Project, the Olav Thon Foundation,
the Erling-Persson Family Foundation, Stiftelsen för Gamla
Tjänarinnor, Hjärnfonden, Sweden (#FO2022-0270), the EU’s Horizon
2020 research and innovation programme under the
Marie Skłodowska-Curie grant agreement number 860197 (MIRIADE),
the EU Joint Programme – Neurodegenerative Disease Research
(JPND2021-00694), and the UK Dementia Research Institute at UCL
(UKDRI-1003). KB is supported by the Swedish Research Council
(#2017-00915, #2022-00732), the Swedish state under the agreement
between the Swedish Government and the County Councils, the ALFagreement (#ALFGBG-715986, #ALFGBG-965240), the Swedish
Alzheimer Foundation (#AF-930351, #AF-939721, #AF-968270),
Hjärnfonden, Sweden (#FO2017-0243, #ALZ2022-0006), the
Alzheimer’s Association 2021 Zenith Award (ZEN-21-848495), and the
Alzheimer’s Association 2022–2025 grant (SG-23-1038904 QC).S
Longitudinal interplay between subclinical atherosclerosis, cardiovascular risk factors, and cerebral glucose metabolism in midlife: results from the PESA prospective cohort study
BACKGROUND: Cardiovascular disease and dementia often coexist at advanced stages. Yet, longitudinal studies examining the interplay between atherosclerosis and its risk factors on brain health in midlife are scarce. We aimed to characterise the longitudinal associations between cerebral glucose metabolism, subclinical atherosclerosis, and cardiovascular risk factors in middle-aged asymptomatic individuals. METHODS: The Progression of Early Subclinical Atherosclerosis (PESA) study is a Spanish longitudinal observational cohort study of 4184 asymptomatic individuals aged 40-54 years (NCT01410318). Participants with subclinical atherosclerosis underwent longitudinal cerebral [18F]fluorodeoxyglucose ([18F]FDG)-PET, and annual percentage change in [18F]FDG uptake was assessed (primary outcome). Cardiovascular risk was quantified with SCORE2 and subclinical atherosclerosis with three-dimensional vascular ultrasound (exposures). Multivariate regression and linear mixed effects models were used to assess associations between outcomes and exposures. Additionally, blood-based biomarkers of neuropathology were quantified and mediation analyses were performed. Secondary analyses were corrected for multiple comparisons using the false discovery rate (FDR) approach. FINDINGS: This longitudinal study included a PESA subcohort of 370 participants (median age at baseline 49·8 years [IQR 46·1-52·2]; 309 [84%] men, 61 [16%] women; median follow-up 4·7 years [IQR 4·2-5·2]). Baseline scans took place between March 6, 2013, and Jan 21, 2015, and follow-up scans between Nov 24, 2017, and Aug 7, 2019. Persistent high risk of cardiovascular disease was associated with an accelerated decline of cortical [18F]FDG uptake compared with low risk (β=-0·008 [95% CI -0·013 to -0·002]; pFDR=0·040), with plasma neurofilament light chain, a marker of neurodegeneration, mediating this association by 20% (β=0·198 [0·008 to 0·740]; pFDR=0·050). Moreover, progression of subclinical carotid atherosclerosis was associated with an additional decline in [18F]FDG uptake in Alzheimer's disease brain regions, not explained by cardiovascular risk (β=-0·269 [95% CI -0·509 to -0·027]; p=0·029). INTERPRETATION: Middle-aged asymptomatic individuals with persistent high risk of cardiovascular disease and subclinical carotid atherosclerosis already present brain metabolic decline, suggesting that maintenance of cardiovascular health during midlife could contribute to reductions in neurodegenerative disease burden later in life. FUNDING: Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III, Santander Bank, Pro-CNIC Foundation, BrightFocus Foundation, BBVA Foundation, "la Caixa" Foundation
Exploring cognitive and biological correlates of sleep quality and their potential links with Alzheimer's disease (ALFASleep project): protocol for an observational study
The growing worldwide prevalence of Alzheimer's disease (AD) and the lack of effective treatments pose a dire medical challenge. Sleep disruption is also prevalent in the ageing population and is increasingly recognised as a risk factor and an early sign of AD. The ALFASleep project aims to characterise sleep with subjective and objective measurements in cognitively unimpaired middle/late middle-aged adults at increased risk of AD who are phenotyped with fluid and neuroimaging AD biomarkers. This will contribute to a better understanding of the pathophysiological mechanisms linking sleep with AD, thereby paving the way for the development of non-invasive biomarkers and preventive strategies targeting sleep.We will invite 200 participants enrolled in the ALFA+ (for ALzheimer and FAmilies) prospective observational study to join the ALFASleep study. ALFA+ participants are cognitively unimpaired middle-aged/late middle-aged adults who are followed up every 3 years with a comprehensive set of evaluations including neuropsychological tests, blood and cerebrospinal fluid (CSF) sampling, and MRI and positron emission tomography acquisition. ALFASleep participants will be additionally characterised with actigraphy and CSF-orexin-A measurements, and a subset (n=90) will undergo overnight polysomnography. We will test associations of sleep measurements and CSF-orexin-A with fluid biomarkers of AD and glial activation, neuroimaging outcomes and cognitive performance. In case we found any associations, we will test whether changes in AD and/or glial activation markers mediate the association between sleep and neuroimaging or cognitive outcomes and whether sleep mediates associations between CSF-orexin-A and AD biomarkers.The ALFASleep study protocol has been approved by the independent Ethics Committee Parc de Salut Mar, Barcelona (2018/8207/I). All participants have signed a written informed consent before their inclusion (approved by the same ethics committee). Study findings will be presented at national and international conferences and submitted for publication in peer-reviewed journals.NCT04932473.© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ
Striatal Dopamine Transmission Is Subtly Modified in Human A53Tα-Synuclein Overexpressing Mice
Mutations in, or elevated dosage of, SNCA, the gene for α-synuclein (α-syn), cause familial Parkinson's disease (PD). Mouse lines overexpressing the mutant human A53Tα-syn may represent a model of early PD. They display progressive motor deficits, abnormal cellular accumulation of α-syn, and deficits in dopamine-dependent corticostriatal plasticity, which, in the absence of overt nigrostriatal degeneration, suggest there are age-related deficits in striatal dopamine (DA) signalling. In addition A53Tα-syn overexpression in cultured rodent neurons has been reported to inhibit transmitter release. Therefore here we have characterized for the first time DA release in the striatum of mice overexpressing human A53Tα-syn, and explored whether A53Tα-syn overexpression causes deficits in the release of DA. We used fast-scan cyclic voltammetry to detect DA release at carbon-fibre microelectrodes in acute striatal slices from two different lines of A53Tα-syn-overexpressing mice, at up to 24 months. In A53Tα-syn overexpressors, mean DA release evoked by a single stimulus pulse was not different from wild-types, in either dorsal striatum or nucleus accumbens. However the frequency responsiveness of DA release was slightly modified in A53Tα-syn overexpressors, and in particular showed slight deficiency when the confounding effects of striatal ACh acting at presynaptic nicotinic receptors (nAChRs) were antagonized. The re-release of DA was unmodified after single-pulse stimuli, but after prolonged stimulation trains, A53Tα-syn overexpressors showed enhanced recovery of DA release at old age, in keeping with elevated striatal DA content. In summary, A53Tα-syn overexpression in mice causes subtle changes in the regulation of DA release in the striatum. While modest, these modifications may indicate or contribute to striatal dysfunction
Restriction of trophic factors and nutrients induces PARKIN expression
Parkinson’s disease (PD) is the most frequent neurodegenerative movement disorder and manifests at old age. While many details of its pathogenesis remain to be elucidated, in particular the protein and mitochondrial quality control during stress responses have been implicated in monogenic PD variants. Especially the mitochondrial kinase PINK1 and the ubiquitin ligase PARKIN are known to cooperate in autophagy after mitochondrial damage. As autophagy is also induced by loss of trophic signaling and PINK1 gene expression is modulated after deprivation of cytokines, we analyzed to what extent trophic signals and starvation stress regulate PINK1 and PARKIN expression. Time course experiments with serum deprivation and nutrient starvation of human SH-SY5Y neuroblastoma cells and primary mouse neurons demonstrated phasic induction of PINK1 transcript up to twofold and PARKIN transcript levels up to sixfold. The corresponding threefold starvation induction of PARKIN protein was limited by its translocation to lysosomes. Analysis of primary mouse cells from PINK1-knockout mice indicated that PARKIN induction and lysosomal translocation occurred independent of PINK1. Suppression of the PI3K-Akt-mTOR signaling by pharmacological agents modulated PARKIN expression accordingly. In conclusion, this expression survey demonstrates that PARKIN and PINK1 are coregulated during starvation and suggest a role of both PD genes in response to trophic signals and starvation stress
Description of a European memory clinic cohort undergoing amyloid-PET: The AMYPAD Diagnostic and Patient Management Study
INTRODUCTION: AMYPAD Diagnostic and Patient Management Study (DPMS) aims to investigate the clinical utility and cost-effectiveness of amyloid-PET in Europe. Here we present participants' baseline features and discuss the representativeness of the cohort. METHODS: Participants with subjective cognitive decline plus (SCD+), mild cognitive impairment (MCI), or dementia were recruited in eight European memory clinics from April 16, 2018, to October 30, 2020, and randomized into three arms: ARM1, early amyloid-PET; ARM2, late amyloid-PET; and ARM3, free-choice. RESULTS: A total of 840 participants (244 SCD+, 341 MCI, and 255 dementia) were enrolled. Sociodemographic/clinical features did not differ significantly among recruiting memory clinics or with previously reported cohorts. The randomization assigned 35% of participants to ARM1, 32% to ARM2, and 33% to ARM3; cognitive stages were distributed equally across the arms. DISCUSSION: The features of AMYPAD-DPMS participants are as expected for a memory clinic population. This ensures the generalizability of future study results
Progression of pathology in PINK1-deficient mouse brain from splicing via ubiquitination, ER stress, and mitophagy changes to neuroinflammation
Spatial patterns of white matter hyperintensities associated with Alzheimer's disease risk factors in a cognitively healthy middle-aged cohort
Background
White matter hyperintensities (WMH) of presumed vascular origin have been associated with an increased risk of Alzheimer’s disease (AD). This study aims to describe the patterns of WMH associated with dementia risk estimates and individual risk factors in a cohort of middle-aged/late middle-aged individuals (mean 58 (interquartile range 51–64) years old).
Methods
Magnetic resonance imaging and AD risk factors were collected from 575 cognitively unimpaired participants. WMH load was automatically calculated in each brain lobe and in four equidistant layers from the ventricular surface to the cortical interface. Global volumes and regional patterns of WMH load were analyzed as a function of the Cardiovascular Risk Factors, Aging and Incidence of Dementia (CAIDE) dementia risk score, as well as family history of AD and Apolipoprotein E (APOE) genotype. Additional analyses were performed after correcting for the effect of age and hypertension.
Results
The studied cohort showed very low WMH burden (median 1.94 cm3) and 20-year dementia risk estimates (median 1.47 %). Even so, higher CAIDE scores were significantly associated with increased global WMH load. The main drivers of this association were age and hypertension, with hypercholesterolemia and body mass index also displaying a minor, albeit significant, influence. Regionally, CAIDE scores were positively associated with WMH in anterior areas, mostly in the frontal lobe. Age and hypertension showed significant association with WMH in almost all regions analyzed. The APOE-ε2 allele showed a protective effect over global WMH with a pattern that comprised juxtacortical temporo-occipital and fronto-parietal deep white matter regions. Participants with maternal family history of AD had higher WMH load than those without, especially in temporal and occipital lobes.
Conclusions
WMH load is associated with AD risk factors even in cognitively unimpaired subjects with very low WMH burden and dementia risk estimates. Our results suggest that tight control of modifiable risk factors in middle-age/late middle-age could have a significant impact on late-life dementia
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