Studying APOE ɛ4 Allele Dose Effects with a Univariate Morphometry Biomarker

Background: A univariate neurodegeneration biomarker (UNB) based on MRI with strong statistical discrimination power would be highly desirable for studying hippocampal surface morphological changes associated with APOE ɛ4 genetic risk for AD in the cognitively unimpaired (CU) population. However, existing UNB work either fails to model large group variances or does not capture AD induced changes. Objective: We proposed a subspace decomposition method capable of exploiting a UNB to represent the hippocampal morphological changes related to the APOE ɛ4 dose effects among the longitudinal APOE ɛ4 homozygotes (HM, N = 30), heterozygotes (HT, N = 49) and non-carriers (NC, N = 61). Methods: Rank minimization mechanism combined with sparse constraint considering the local continuity of the hippocampal atrophy regions is used to extract group common structures. Based on the group common structures of amyloid-β (Aβ) positive AD patients and Aβ negative CU subjects, we identified the regions-of-interest (ROI), which reflect significant morphometry changes caused by the AD development. Then univariate morphometry index (UMI) is constructed from these ROIs. Results: The proposed UMI demonstrates a more substantial statistical discrimination power to distinguish the longitudinal groups with different APOE ɛ4 genotypes than the hippocampal volume measurements. And different APOE ɛ4 allele load affects the shrinkage rate of the hippocampus, i.e., HM genotype will cause the largest atrophy rate, followed by HT, and the smallest is NC. Conclusion: The UMIs may capture the APOE ɛ4 risk allele-induced brain morphometry abnormalities and reveal the dose effects of APOE ɛ4 on the hippocampal morphology in cognitively normal individuals.

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White Matter Hyperintensities Potentiate Hippocampal Volume Reduction in Non-Demented Older Individuals with Abnormal Amyloid-β

Journal of Alzheimer s Disease ◽

10.3233/jad-160474 ◽

2016 ◽

Vol 55 (1) ◽

pp. 333-342 ◽

Cited By ~ 12

Author(s):

Whitney M. Freeze ◽

Heidi I. L. Jacobs ◽

Ed H. Gronenschild ◽

Jacobus F. A. Jansen ◽

Saartje Burgmans ◽

...

Keyword(s):

White Matter ◽

White Matter Hyperintensities ◽

Amyloid Β ◽

Hippocampal Volume ◽

Volume Reduction ◽

Older Individuals

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Depression and Plasma Amyloid β Peptides in the Elderly With and Without the Apolipoprotein E4 Allele

Alzheimer Disease & Associated Disorders ◽

10.1097/wad.0b013e31819cb3ac ◽

2009 ◽

Vol 23 (3) ◽

pp. 238-244 ◽

Cited By ~ 29

Author(s):

Xiaoyan Sun ◽

Chi Chia Chiu ◽

Elizabeth Liebson ◽

Natalia A. Crivello ◽

Lixia Wang ◽

...

Keyword(s):

Amyloid Β ◽

The Elderly ◽

Apolipoprotein E4 ◽

E4 Allele

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The effect of COMT, BDNF, 5-HTT, NRG1 and DTNBP1 genes on hippocampal and lateral ventricular volume in psychosis

Psychological Medicine ◽

10.1017/s0033291709990316 ◽

2009 ◽

Vol 39 (11) ◽

pp. 1783-1797 ◽

Cited By ~ 50

Author(s):

A. Dutt ◽

C. McDonald ◽

E. Dempster ◽

D. Prata ◽

M. Shaikh ◽

...

Keyword(s):

Candidate Genes ◽

Psychotic Disorders ◽

Ventricular Volume ◽

Hippocampal Volume ◽

Epidemiological Studies ◽

Brain Regions ◽

Clinical Group ◽

Linear Regression Models ◽

Brain Volumes ◽

Brain Morphometry

BackgroundMorphometric endophenotypes which have been proposed for psychotic disorders include lateral ventricular enlargement and hippocampal volume reductions. Genetic epidemiological studies support an overlap between schizophrenia and bipolar disorder, and COMT, BDNF, 5-HTT, NRG1 and DTNBP1 genes have been implicated in the aetiology of both these disorders. This study examined associations between these candidate genes and morphometric endophenotypes for psychosis.MethodA total of 383 subjects (128 patients with psychosis, 194 of their unaffected relatives and 61 healthy controls) from the Maudsley Family Psychosis Study underwent structural magnetic resonance imaging and genotyping. The effect of candidate genes on brain morphometry was examined using linear regression models adjusting for clinical group, age, sex and correlations between members of the same family.ResultsThe results showed no evidence of association between variation in COMT genotype and lateral ventricular, and left or right hippocampal volumes. Neither was there any effect of the BDNF, 5-HTTLPR, NRG1 and DTNBP1 genotypes on these regional brain volumes.ConclusionsAbnormal hippocampal and lateral ventricular volumes are among the most replicated endophenotypes for psychosis; however, the influences of COMT, BDNF, 5-HTT, NRG1 and DTNBP1 genes on these key brain regions must be very subtle if at all present.

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Interaction Between BDNF Val66Met and APOE4 on Biomarkers of Alzheimer’s Disease and Cognitive Decline

Journal of Alzheimer s Disease ◽

10.3233/jad-200132 ◽

2020 ◽

Vol 78 (2) ◽

pp. 721-734

Author(s):

Cynthia M. Stonnington ◽

Stefanie N. Velgos ◽

Yinghua Chen ◽

Sameena Syed ◽

Matt Huentelman ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Brain Activity ◽

Amyloid Β ◽

Hippocampal Volume ◽

Rate Of Change ◽

Plaque Burden ◽

Amyloid Burden ◽

Hippocampus Volume

Background: Whether brain-derived neurotrophic factor (BDNF) Met carriage impacts the risk or progression of Alzheimer’s disease (AD) is unknown. Objective: To evaluate the interaction of BDNF Met and APOE4 carriage on cerebral metabolic rate for glucose (CMRgl), amyloid burden, hippocampus volume, and cognitive decline among cognitively unimpaired (CU) adults enrolled in the Arizona APOE cohort study. Methods: 114 CU adults (mean age 56.85 years, 38% male) with longitudinal FDG PET, magnetic resonance imaging, and cognitive measures were BDNF and APOE genotyped. A subgroup of 58 individuals also had Pittsburgh B (PiB) PET imaging. We examined baseline CMRgl, PiB PET amyloid burden, CMRgl, and hippocampus volume change over time, and rate of change in cognition over an average of 15 years. Results: Among APOE4 carriers, BDNF Met carriers had significantly increased amyloid deposition and accelerated CMRgl decline in regions typically affected by AD, but without accompanying acceleration of cognitive decline or hippocampal volume changes and with higher baseline frontal CMRgl and slower frontal decline relative to the Val/Val group. The BDNF effects were not found among APOE4 non-carriers. Conclusion: Our preliminary studies suggest that there is a weak interaction between BDNF Met and APOE4 on amyloid-β plaque burden and longitudinal PET measurements of AD-related CMRgl decline in cognitively unimpaired late-middle-aged and older adults, but with no apparent effect upon rate of cognitive decline. We suggest that cognitive effects of BDNF variants may be mitigated by compensatory increases in frontal brain activity—findings that would need to be confirmed in larger studies.

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Intradialytic hypotension and relationship with cognitive function and brain morphometry

Clinical Kidney Journal ◽

10.1093/ckj/sfaa070 ◽

2020 ◽

Author(s):

Santiago Cedeño ◽

Manuel Desco ◽

Yasser Aleman ◽

Nicolás Macías ◽

Alberto Fernández-Pena ◽

...

Keyword(s):

Cognitive Function ◽

Structural Integrity ◽

Morphological Changes ◽

Study Cohort ◽

Dialysis Session ◽

Intradialytic Hypotension ◽

Brain Morphometry ◽

Haemodynamic Stress ◽

The Brain ◽

Hippocampus Volume

Abstract Background The haemodynamic stress brought about by dialysis could justify the loss of structural and functional integrity of the central nervous system (CNS). The main objective of this study was to analyse the relationship between intradialytic hypotension (IDH) and cognitive function and brain morphometry. Methods The cross-sectional KIDBRAIN study (Cohort Study of Morphological Changes of the Brain by MRI in Chronic Kidney Disease Patients) included 68 prevalent patients with no history of neurological disorders (cerebrovascular disease and cognitive impairment) undergoing haemodialysis (HD). We analysed 18 non-consecutive dialysis sessions (first three of each month over a 6-month period) and various definitions of IDH were recorded. Global cognitive function (GCF) was assessed using the Mini-Mental State Examination (MMSE) and parameters of structural integrity of the CNS were obtained using volume morphometry magnetic resonance imaging analysis [grey matter (GM), white matter (WM) and hippocampus). Results A greater number of sessions with IDH were associated with less volume of WM (r = −0.359,P = 0.003) and hippocampus (r = −0.395, P = 0.001) independent of cardiovascular risk factors according to multivariable linear regression models (β = −0.198, P = 0.046 for WM; β = −0.253, P = 0.017 for hippocampus). The GCF by the MMSE was 27.3 ± 7.3.1 and was associated with WM volume (β = 0.403, P = 0.001) independent of GM and hippocampus volume. Symptomatic IDH was associated with GCF (r = −0.420, P < 0.001) in adjusted analysis (β = −0.339, P = 0.008). Conclusions Even when asymptomatic, IDH is associated with a lower WM and hippocampus volume and reduced GCF in patients undergoing HD, thus suggesting greater vulnerability of the brain to the haemodynamic stress that may be generated by a dialysis session.

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Clinical and biomarker changes in sporadic Alzheimer’s disease

10.1101/2020.05.08.084293 ◽

2020 ◽

Author(s):

Junjie Zhuo ◽

Yuanchao Zhang ◽

Bing Liu ◽

Yong Liu ◽

Xiaoqing Zhou ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Β ◽

Hippocampal Volume ◽

Sporadic Alzheimer’S Disease ◽

Dynamic Changes ◽

Linear Change ◽

Clinical Profiles ◽

Annual Changes ◽

Clinical Measures

AbstractIMPORTANCEThe dynamic changes of biomarkers and clinical profiles in sporadic Alzheimer’s disease (SAD) are poorly understood.OBJECTIVETo evaluate the impact of amyloid-β (Aβ) biomarkers on SAD by measuring the dynamic changes in biomarkers and clinical profiles in the progression of SAD.DESIGN AND SETTINGThis retrospective and longitudinal study analyzed clinical and biomarker data from 665 participants (mean follow-up 4.90 ± 2.83 years) from a subset of the AD Neuroimaging Initiative (ADNI) participants collected from August 2005 to December 2018. By aligning the timing of the changes in the various biomarkers with the stable normal cognition (CN) baseline and mild cognitive impairment (MCI) or AD onset timepoints, we combined data from the stable CN, CN conversion to MCI (CN2MCI), and MCI conversion to AD (MCI2AD) groups to identify the trajectories associated with the progression of AD.PARTICIPANTSThe participants were 294 CN, 69 CN2MCI, 300 MCI2AD, and 24 who converted from CN to MCI to AD (CN2MCI2AD) (of whom 22 were also included in the CN2MCI).EXPOSURESAmyloid-β measured by florbetapir positron emission tomography (PET) or cerebrospinal fluid assay of amyloid-β (CSF Aβ42).MAIN OUTCOMES AND MEASURESThe measures included the 13-item cognitive subscale of the AD Assessment Scale (ADAS13, as a clinical measure), hippocampal volume, and the fluorodeoxyglucose (FDG) PET standardized uptake value ratio (SUVR).RESULTSThe CN, CN2MCI, and MCI2AD subgroups’ median (interquartile range [IQR]) annual changes in ADAS13 were (0.388 [−0.278, 0.818], 1.000 [0.239, 2.330], and 3.388 [1.750, 6.169]). The annual changes in hippocampal volume for each group were (−0.005 %ICV [−0.011, −0.001], −0.006 %ICV [−0.012, −0.002], and −0.014 %ICV [−0.021, −0.009]). The annual changes in FDG PET SUVR for each group were (−0.011 [−0.030, 0.010], −0.027 [−0.056, −0.012], and −0.039 [−0.063, 0.014]). Changes in the amyloid biomarkers were inconsistent with clinical profile changes. The annual changes in CSF Aβ42 for each group were (−1.500 pg/ml [−6.000, 4.000], −2.200 [−5.667, 4.000], and −2.000 [−7.000, 2.650]) and in Aβ PET SUVR for each group were (0.004 [−0.002, 0.012], 0.004 [−0.001,0.011], and 0.005 [−0.006, 0.014]). During the stable CN and CN2MCI stages, subjects with elevated and those with normal amyloid showed no significant differences (likelihood ratio test, p < .01) in clinical measures, hippocampal volume, or FDG.CONCLUSIONS AND RELEVANCEHippocampal volume and FDG associated with clinical profiles impairment in the SAD progression. Aβ alone is not associated with clinical profiles, hippocampal volume, and FDG impairment in the preclinical stage of SAD.Key PointsQuestion: What is the role of amyloid-β in dynamic changes in biomarkers and clinical profiles in the progression of sporadic Alzheimer’s disease?Findings: The changes of the hippocampal volume and FDG that were consistent with the changes of the clinical profiles showed a non-linear change in the initial stage and an accelerated non-linear change during MCI2AD, changes in amyloid biomarkers were inconsistent with the clinical profile. Cognitively normal people with elevated or normal amyloid showed no significant differences in clinical measures, hippocampal volume, or FDG.Meaning: Amyloid-β alone may not be used as the central index for defining the preclinical stage of SAD.

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Relationship between sensory characteristics and cortical thickness/volume in autism spectrum disorders

Translational Psychiatry ◽

10.1038/s41398-021-01743-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Kaie Habata ◽

Yongjeon Cheong ◽

Taku Kamiya ◽

Daichi Shiotsu ◽

Ichiro M. Omori ◽

...

Keyword(s):

Cortical Thickness ◽

Morphological Changes ◽

Hippocampal Volume ◽

Autism Spectrum ◽

Sensory Characteristics ◽

Sensory Profile ◽

Spectrum Disorders ◽

The Right ◽

Adults With Asd ◽

Brain Image Analysis

AbstractIndividuals with autism spectrum disorders (ASDs) exhibit atypical sensory characteristics, impaired social skills, deficits in verbal and nonverbal communication, and restricted and repetitive behaviors. The relationship between sensory characteristics and brain morphological changes in ASD remains unclear. In this study, we investigated the association between brain morphological changes and sensory characteristics in individuals with ASD using brain image analysis and a sensory profile test. Forty-three adults with ASD and 84 adults with typical development underwent brain image analysis using FreeSurfer. The brain cortex was divided into 64 regions, and the cortical thickness and volume of the limbic system were calculated. The sensory characteristics of the participants were evaluated using the Adolescent/Adult Sensory Profile (AASP). Correlation analysis was performed for cortical thickness, limbic area volume, and AASP scores. In the ASD group, there was a significant positive correlation between visual sensory sensitivity scores and the right lingual cortical thickness (r = 0.500). There were also significant negative correlations between visual sensation avoiding scores and the right lateral orbitofrontal cortical thickness (r = −0.513), taste/smell sensation avoiding scores and the right hippocampal volume (r = −0.510), and taste/smell sensation avoiding scores and the left hippocampal volume (r = −0.540). The study identified associations among the lingual cortical thickness, lateral orbitofrontal cortical thickness, and hippocampal volume and sensory characteristics. These findings suggest that brain morphological changes may trigger sensory symptoms in adults with ASD.

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A missense variant in SHARPIN mediates Alzheimer’s disease-specific brain damages

Translational Psychiatry ◽

10.1038/s41398-021-01680-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jun Young Park ◽

Dongsoo Lee ◽

Jang Jae Lee ◽

Jungsoo Gim ◽

Tamil Iniyan Gunasekaran ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cortical Thickness ◽

Association Studies ◽

Brain Magnetic Resonance Imaging ◽

Amyloid Β ◽

Missense Variant ◽

Hippocampal Volume ◽

Genome Wide Association Studies ◽

Increased Risk

AbstractEstablished genetic risk factors for Alzheimer’s disease (AD) account for only a portion of AD heritability. The aim of this study was to identify novel associations between genetic variants and AD-specific brain atrophy. We conducted genome-wide association studies for brain magnetic resonance imaging measures of hippocampal volume and entorhinal cortical thickness in 2643 Koreans meeting the clinical criteria for AD (n = 209), mild cognitive impairment (n = 1449) or normal cognition (n = 985). A missense variant, rs77359862 (R274W), in the SHANK-associated RH Domain Interactor (SHARPIN) gene was associated with entorhinal cortical thickness (p = 5.0 × 10−9) and hippocampal volume (p = 5.1 × 10−12). It revealed an increased risk of developing AD in the mediation analyses. This variant was also associated with amyloid-β accumulation (p = 0.03) and measures of memory (p = 1.0 × 10−4) and executive function (p = 0.04). We also found significant association of other SHARPIN variants with hippocampal volume in the Alzheimer’s Disease Neuroimaging Initiative (rs3417062, p = 4.1 × 10−6) and AddNeuroMed (rs138412600, p = 5.9 × 10−5) cohorts. Further, molecular dynamics simulations and co-immunoprecipitation indicated that the variant significantly reduced the binding of linear ubiquitination assembly complex proteins, SHPARIN and HOIL-1 Interacting Protein (HOIP), altering the downstream NF-κB signaling pathway. These findings suggest that SHARPIN plays an important role in the pathogenesis of AD.

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