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  • 1
    Online Resource
    Online Resource
    Anatomically interpretable deep learning of brain age captures domain-specific cognitive impairment
    Proceedings of the National Academy of Sciences ; 2023
    In:  Proceedings of the National Academy of Sciences Vol. 120, No. 2 ( 2023-01-10)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 120, No. 2 ( 2023-01-10)
    Abstract: The gap between chronological age (CA) and biological brain age, as estimated from magnetic resonance images (MRIs), reflects how individual patterns of neuroanatomic aging deviate from their typical trajectories. MRI-derived brain age (BA) estimates are often obtained using deep learning models that may perform relatively poorly on new data or that lack neuroanatomic interpretability. This study introduces a convolutional neural network (CNN) to estimate BA after training on the MRIs of 4,681 cognitively normal (CN) participants and testing on 1,170 CN participants from an independent sample. BA estimation errors are notably lower than those of previous studies. At both individual and cohort levels, the CNN provides detailed anatomic maps of brain aging patterns that reveal sex dimorphisms and neurocognitive trajectories in adults with mild cognitive impairment (MCI, N  = 351) and Alzheimer’s disease (AD, N  = 359). In individuals with MCI (54% of whom were diagnosed with dementia within 10.9 y from MRI acquisition), BA is significantly better than CA in capturing dementia symptom severity, functional disability, and executive function. Profiles of sex dimorphism and lateralization in brain aging also map onto patterns of neuroanatomic change that reflect cognitive decline. Significant associations between BA and neurocognitive measures suggest that the proposed framework can map, systematically, the relationship between aging-related neuroanatomy changes in CN individuals and in participants with MCI or AD. Early identification of such neuroanatomy changes can help to screen individuals according to their AD risk.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2214634120
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2023
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  • 2
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    Characteristics of amnestic patients with hypometabolism patterns suggestive of Lewy body pathology
    Oxford University Press (OUP) ; 2023
    In:  Brain ( 2023-06-07)
    Details
    In: Brain, Oxford University Press (OUP), ( 2023-06-07)
    Abstract: A clinical diagnosis of Alzheimer’s disease dementia (ADD) encompasses considerable pathological and clinical heterogeneity. While Alzheimer’s disease patients typically show a characteristic temporo-parietal pattern of glucose hypometabolism on 18F-fluorodeoxyglucose (FDG)-PET imaging, previous studies have identified a subset of patients showing a distinct posterior-occipital hypometabolism pattern associated with Lewy body pathology. Here, we aimed to improve the understanding of the clinical relevance of these posterior-occipital FDG-PET patterns in patients with Alzheimer’s disease-like amnestic presentations. Our study included 1214 patients with clinical diagnoses of ADD (n = 305) or amnestic mild cognitive impairment (aMCI, n = 909) from the Alzheimer’s Disease Neuroimaging Initiative, who had FDG-PET scans available. Individual FDG-PET scans were classified as being suggestive of Alzheimer’s (AD-like) or Lewy body (LB-like) pathology by using a logistic regression classifier trained on a separate set of patients with autopsy-confirmed Alzheimer’s disease or Lewy body pathology. AD- and LB-like subgroups were compared on amyloid-β and tau-PET, domain-specific cognitive profiles (memory versus executive function performance), as well as the presence of hallucinations and their evolution over follow-up (≈6 years for aMCI, ≈3 years for ADD). Around 12% of the aMCI and ADD patients were classified as LB-like. For both aMCI and ADD patients, the LB-like group showed significantly lower regional tau-PET burden than the AD-like subgroup, but amyloid-β load was only significantly lower in the aMCI LB-like subgroup. LB- and AD-like subgroups did not significantly differ in global cognition (aMCI: d = 0.15, P = 0.16; ADD: d = 0.02, P = 0.90), but LB-like patients exhibited a more dysexecutive cognitive profile relative to the memory deficit (aMCI: d = 0.35, P = 0.01; ADD: d = 0.85 P & lt; 0.001), and had a significantly higher risk of developing hallucinations over follow-up [aMCI: hazard ratio = 1.8, 95% confidence interval = (1.29, 3.04), P = 0.02; ADD: hazard ratio = 2.2, 95% confidence interval = (1.53, 4.06) P = 0.01]. In summary, a sizeable group of clinically diagnosed ADD and aMCI patients exhibit posterior-occipital FDG-PET patterns typically associated with Lewy body pathology, and these also show less abnormal Alzheimer’s disease biomarkers as well as specific clinical features typically associated with dementia with Lewy bodies.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awad194
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 1474117-9
    SSG: 12
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  • 3
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    Comprehensive analysis of epigenetic clocks reveals associations between disproportionate biological ageing and hippocampal volume
    Springer Science and Business Media LLC ; 2022
    In:  GeroScience Vol. 44, No. 3 ( 2022-06), p. 1807-1823
    Details
    In: GeroScience, Springer Science and Business Media LLC, Vol. 44, No. 3 ( 2022-06), p. 1807-1823
    Abstract: The concept of age acceleration, the difference between biological age and chronological age, is of growing interest, particularly with respect to age-related disorders, such as Alzheimer’s Disease (AD). Whilst studies have reported associations with AD risk and related phenotypes, there remains a lack of consensus on these associations. Here we aimed to comprehensively investigate the relationship between five recognised measures of age acceleration, based on DNA methylation patterns (DNAm age), and cross-sectional and longitudinal cognition and AD-related neuroimaging phenotypes (volumetric MRI and Amyloid-β PET) in the Australian Imaging, Biomarkers and Lifestyle (AIBL) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Significant associations were observed between age acceleration using the Hannum epigenetic clock and cross-sectional hippocampal volume in AIBL and replicated in ADNI. In AIBL, several other findings were observed cross-sectionally, including a significant association between hippocampal volume and the Hannum and Phenoage epigenetic clocks. Further, significant associations were also observed between hippocampal volume and the Zhang and Phenoage epigenetic clocks within Amyloid-β positive individuals. However, these were not validated within the ADNI cohort. No associations between age acceleration and other Alzheimer’s disease-related phenotypes, including measures of cognition or brain Amyloid-β burden, were observed, and there was no association with longitudinal change in any phenotype. This study presents a link between age acceleration, as determined using DNA methylation, and hippocampal volume that was statistically significant across two highly characterised cohorts. The results presented in this study contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related phenotypes.
    Type of Medium: Online Resource
    ISSN: 2509-2715 , 2509-2723
    URL: Article
    DOI: 10.1007/s11357-022-00558-8
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2886418-9
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  • 4
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    Accelerated functional brain aging in pre-clinical familial Alzheimer’s disease
    Springer Science and Business Media LLC ; 2021
    In:  Nature Communications Vol. 12, No. 1 ( 2021-09-09)
    Details
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 12, No. 1 ( 2021-09-09)
    Abstract: Resting state functional connectivity (rs-fMRI) is impaired early in persons who subsequently develop Alzheimer’s disease (AD) dementia. This impairment may be leveraged to aid investigation of the pre-clinical phase of AD. We developed a model that predicts brain age from resting state (rs)-fMRI data, and assessed whether genetic determinants of AD, as well as beta-amyloid (Aβ) pathology, can accelerate brain aging. Using data from 1340 cognitively unimpaired participants between 18–94 years of age from multiple sites, we showed that topological properties of graphs constructed from rs-fMRI can predict chronological age across the lifespan. Application of our predictive model to the context of pre-clinical AD revealed that the pre-symptomatic phase of autosomal dominant AD includes acceleration of functional brain aging. This association was stronger in individuals having significant Aβ pathology.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    URL: Article
    DOI: 10.1038/s41467-021-25492-9
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
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  • 5
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    Plasma phosphorylated-tau181 as a predictive biomarker for Alzheimer’s amyloid, tau and FDG PET status
    Springer Science and Business Media LLC ; 2021
    In:  Translational Psychiatry Vol. 11, No. 1 ( 2021-11-13)
    Details
    In: Translational Psychiatry, Springer Science and Business Media LLC, Vol. 11, No. 1 ( 2021-11-13)
    Abstract: Plasma phosphorylated-tau181 (p-tau181) showed the potential for Alzheimer’s diagnosis and prognosis, but its role in detecting cerebral pathologies is unclear. We aimed to evaluate whether it could serve as a marker for Alzheimer’s pathology in the brain. A total of 1189 participants with plasma p-tau181 and PET data of amyloid, tau or FDG PET were included from ADNI. Cross-sectional relationships of plasma p-tau181 with PET biomarkers were tested. Longitudinally, we further investigated whether different p-tau181 levels at baseline predicted different progression of Alzheimer’s pathological changes in the brain. We found plasma p-tau181 significantly correlated with brain amyloid (Spearman ρ  = 0.45, P   〈  0.0001), tau (0.25, P  = 0.0003), and FDG PET uptakes (−0.37, P   〈  0.0001), and increased along the Alzheimer’s continuum. Individually, plasma p-tau181 could detect abnormal amyloid, tau pathologies and hypometabolism in the brain, similar with or even better than clinical indicators. The diagnostic accuracy of plasma p-tau181 elevated significantly when combined with clinical information (AUC = 0.814 for amyloid PET, 0.773 for tau PET, and 0.708 for FDG PET). Relationships of plasma p-tau181 with brain pathologies were partly or entirely mediated by the corresponding CSF biomarkers. Besides, individuals with abnormal plasma p-tau181 level ( 〉 18.85 pg/ml) at baseline had a higher risk of pathological progression in brain amyloid (HR: 2.32, 95%CI 1.32–4.08) and FDG PET (3.21, 95%CI 2.06–5.01) status. Plasma p-tau181 may be a sensitive screening test for detecting brain pathologies, and serve as a predictive biomarker for Alzheimer’s pathophysiology.
    Type of Medium: Online Resource
    ISSN: 2158-3188
    URL: Article
    DOI: 10.1038/s41398-021-01709-9
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2609311-X
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  • 6
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    Determinants of cognitive and brain resilience to tau pathology: a longitudinal analysis
    Oxford University Press (OUP) ; 2023
    In:  Brain Vol. 146, No. 9 ( 2023-09-01), p. 3719-3734
    Details
    In: Brain, Oxford University Press (OUP), Vol. 146, No. 9 ( 2023-09-01), p. 3719-3734
    Abstract: Mechanisms of resilience against tau pathology in individuals across the Alzheimer’s disease spectrum are insufficiently understood. Longitudinal data are necessary to reveal which factors relate to preserved cognition (i.e. cognitive resilience) and brain structure (i.e. brain resilience) despite abundant tau pathology, and to clarify whether these associations are cross-sectional or longitudinal. We used a longitudinal study design to investigate the role of several demographic, biological and brain structural factors in yielding cognitive and brain resilience to tau pathology as measured with PET. In this multicentre study, we included 366 amyloid-β-positive individuals with mild cognitive impairment or Alzheimer’s disease dementia with baseline 18F-flortaucipir-PET and longitudinal cognitive assessments. A subset (n = 200) additionally underwent longitudinal structural MRI. We used linear mixed-effects models with global cognition and cortical thickness as dependent variables to investigate determinants of cognitive resilience and brain resilience, respectively. Models assessed whether age, sex, years of education, APOE-ε4 status, intracranial volume (and cortical thickness for cognitive resilience models) modified the association of tau pathology with cognitive decline or cortical thinning. We found that the association between higher baseline tau-PET levels (quantified in a temporal meta-region of interest) and rate of cognitive decline (measured with repeated Mini-Mental State Examination) was adversely modified by older age (Stβinteraction = −0.062, P = 0.032), higher education level (Stβinteraction = −0.072, P = 0.011) and higher intracranial volume (Stβinteraction = −0.07, P = 0.016). Younger age, higher education and greater cortical thickness were associated with better cognitive performance at baseline. Greater cortical thickness was furthermore associated with slower cognitive decline independent of tau burden. Higher education also modified the negative impact of tau-PET on cortical thinning, while older age was associated with higher baseline cortical thickness and slower rate of cortical thinning independent of tau. Our analyses revealed no (cross-sectional or longitudinal) associations for sex and APOE-ε4 status on cognition and cortical thickness. In this longitudinal study of clinically impaired individuals with underlying Alzheimer’s disease neuropathological changes, we identified education as the most robust determinant of both cognitive and brain resilience against tau pathology. The observed interaction with tau burden on cognitive decline suggests that education may be protective against cognitive decline and brain atrophy at lower levels of tau pathology, with a potential depletion of resilience resources with advancing pathology. Finally, we did not find major contributions of sex to brain nor cognitive resilience, suggesting that previous links between sex and resilience might be mainly driven by cross-sectional differences.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awad100
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 1474117-9
    SSG: 12
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  • 7
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    The BIN1 rs744373 SNP is associated with increased tau-PET levels and impaired memory
    Springer Science and Business Media LLC ; 2019
    In:  Nature Communications Vol. 10, No. 1 ( 2019-04-16)
    Details
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 10, No. 1 ( 2019-04-16)
    Abstract: The single nucleotide polymorphism (SNP) rs744373 in the bridging integrator-1 gene (BIN1) is a risk factor for Alzheimer’s disease (AD). In the brain, BIN1 is involved in endocytosis and sustaining cytoskeleton integrity. Post-mortem and in vitro studies suggest that BIN1-associated AD risk is mediated by increased tau pathology but whether rs744373 is associated with increased tau pathology in vivo is unknown. Here we find in 89 older individuals without dementia, that BIN1 rs744373 risk-allele carriers show higher AV1451 tau-PET across brain regions corresponding to Braak stages II–VI. In contrast, the BIN1 rs744373 SNP was not associated with AV45 amyloid-PET uptake. Furthermore, the rs744373 risk-allele was associated with worse memory performance, mediated by increased global tau levels. Together, our findings suggest that the BIN1 rs744373 SNP is associated with increased tau but not beta-amyloid pathology, suggesting that alterations in BIN1 may contribute to memory deficits via increased tau pathology.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    URL: Article
    DOI: 10.1038/s41467-019-09564-5
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2019
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  • 8
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    Ferritin levels in the cerebrospinal fluid predict Alzheimer’s disease outcomes and are regulated by APOE
    Springer Science and Business Media LLC ; 2015
    In:  Nature Communications Vol. 6, No. 1 ( 2015-05-19)
    Details
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 6, No. 1 ( 2015-05-19)
    Abstract: Brain iron elevation is implicated in Alzheimer’s disease (AD) pathogenesis, but the impact of iron on disease outcomes has not been previously explored in a longitudinal study. Ferritin is the major iron storage protein of the body; by using cerebrospinal fluid (CSF) levels of ferritin as an index, we explored whether brain iron status impacts longitudinal outcomes in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. We show that baseline CSF ferritin levels were negatively associated with cognitive performance over 7 years in 91 cognitively normal, 144 mild cognitive impairment (MCI) and 67 AD subjects, and predicted MCI conversion to AD. Ferritin was strongly associated with CSF apolipoprotein E levels and was elevated by the Alzheimer’s risk allele, APOE-ɛ4 . These findings reveal that elevated brain iron adversely impacts on AD progression, and introduce brain iron elevation as a possible mechanism for APOE-ɛ4 being the major genetic risk factor for AD.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    URL: Article
    DOI: 10.1038/ncomms7760
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2015
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  • 9
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    Prevalence and Clinical Implications of a β-Amyloid–Negative, Tau-Positive Cerebrospinal Fluid Biomarker Profile in Alzheimer Disease
    American Medical Association (AMA) ; 2023
    In:  JAMA Neurology Vol. 80, No. 9 ( 2023-09-01), p. 969-
    Details
    In: JAMA Neurology, American Medical Association (AMA), Vol. 80, No. 9 ( 2023-09-01), p. 969-
    Abstract: Knowledge is lacking on the prevalence and prognosis of individuals with a β-amyloid–negative, tau-positive (A−T+) cerebrospinal fluid (CSF) biomarker profile. Objective To estimate the prevalence of a CSF A−T+ biomarker profile and investigate its clinical implications. Design, Setting, and Participants This was a retrospective cohort study of the cross-sectional multicenter University of Gothenburg (UGOT) cohort (November 2019-January 2021), the longitudinal multicenter Alzheimer Disease Neuroimaging Initiative (ADNI) cohort (individuals with mild cognitive impairment [MCI] and no cognitive impairment; September 2005-May 2022), and 2 Wisconsin cohorts, Wisconsin Alzheimer Disease Research Center and Wisconsin Registry for Alzheimer Prevention (WISC; individuals without cognitive impairment; February 2007-November 2020). This was a multicenter study, with data collected from referral centers in clinical routine (UGOT) and research settings (ADNI and WISC). Eligible individuals had 1 lumbar puncture (all cohorts), 2 or more cognitive assessments (ADNI and WISC), and imaging (ADNI only) performed on 2 separate occasions. Data were analyzed on August 2022 to April 2023. Exposures Baseline CSF Aβ42/40 and phosphorylated tau (p-tau)181; cognitive tests (ADNI: modified preclinical Alzheimer cognitive composite [mPACC]; WISC: modified 3-test PACC [PACC-3] ). Exposures in the ADNI cohort included [ 18 F]-florbetapir amyloid positron emission tomography (PET), magnetic resonance imaging (MRI), [ 18 F]-fluorodeoxyglucose PET (FDG-PET), and cross-sectional tau-PET (ADNI: [ 18 F]-flortaucipir, WISC: [ 18 F]-MK6240). Main Outcomes and Measures Primary outcomes were the prevalence of CSF AT biomarker profiles and continuous longitudinal global cognitive outcome and imaging biomarker trajectories in A−T+ vs A−T− groups. Secondary outcomes included cross-sectional tau-PET. Results A total of 7679 individuals (mean [SD] age, 71.0 [8.4] years; 4101 male [53%]) were included in the UGOT cohort, 970 individuals (mean [SD] age, 73 [7.0] years; 526 male [54%] ) were included in the ADNI cohort, and 519 individuals (mean [SD] age, 60 [7.3] years; 346 female [67%]) were included in the WISC cohort. The prevalence of an A−T+ profile in the UGOT cohort was 4.1% (95% CI, 3.7%-4.6%), being less common than the other patterns. Longitudinally, no significant differences in rates of worsening were observed between A−T+ and A−T− profiles for cognition or imaging biomarkers. Cross-sectionally, A−T+ had similar tau-PET uptake to individuals with an A−T− biomarker profile. Conclusion and Relevance Results suggest that the CSF A−T+ biomarker profile was found in approximately 5% of lumbar punctures and was not associated with a higher rate of cognitive decline or biomarker signs of disease progression compared with biomarker-negative individuals.
    Type of Medium: Online Resource
    ISSN: 2168-6149
    URL: Article
    DOI: 10.1001/jamaneurol.2023.2338
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2023
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  • 10
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    Genome-wide scan of healthy human connectome discovers SPON1 gene variant influencing dementia severity
    Proceedings of the National Academy of Sciences ; 2013
    In:  Proceedings of the National Academy of Sciences Vol. 110, No. 12 ( 2013-03-19), p. 4768-4773
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 110, No. 12 ( 2013-03-19), p. 4768-4773
    Abstract: Aberrant connectivity is implicated in many neurological and psychiatric disorders, including Alzheimer’s disease and schizophrenia. However, other than a few disease-associated candidate genes, we know little about the degree to which genetics play a role in the brain networks; we know even less about specific genes that influence brain connections. Twin and family-based studies can generate estimates of overall genetic influences on a trait, but genome-wide association scans (GWASs) can screen the genome for specific variants influencing the brain or risk for disease. To identify the heritability of various brain connections, we scanned healthy young adult twins with high-field, high-angular resolution diffusion MRI. We adapted GWASs to screen the brain’s connectivity pattern, allowing us to discover genetic variants that affect the human brain’s wiring. The association of connectivity with the SPON1 variant at rs2618516 on chromosome 11 (11p15.2) reached connectome-wide, genome-wide significance after stringent statistical corrections were enforced, and it was replicated in an independent subsample. rs2618516 was shown to affect brain structure in an elderly population with varying degrees of dementia. Older people who carried the connectivity variant had significantly milder clinical dementia scores and lower risk of Alzheimer’s disease. As a posthoc analysis, we conducted GWASs on several organizational and topological network measures derived from the matrices to discover variants in and around genes associated with autism ( MACROD2 ), development ( NEDD4 ), and mental retardation ( UBE2A ) significantly associated with connectivity. Connectome-wide, genome-wide screening offers substantial promise to discover genes affecting brain connectivity and risk for brain diseases.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1216206110
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2013
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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