Publications by authors named "Liana G Apostolova"

114 Publications

Temporal stability of the ventral attention network and general cognition along the Alzheimer's disease spectrum.

Neuroimage Clin 2021 Jun 14;31:102726. Epub 2021 Jun 14.

Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA; Indiana University Network Science Institute, Bloomington, IN, USA; Department of Radiology and Imaging Sciences, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA; Indiana Alzheimer's Disease Research Center, IUSM, Indianapolis, IN, USA.

Understanding the interrelationships of clinical manifestations of Alzheimer's disease (AD) and functional connectivity (FC) as the disease progresses is necessary for use of FC as a potential neuroimaging biomarker. Degradation of resting-state networks in AD has been observed when FC is estimated over the entire scan, however, the temporal dynamics of these networks are less studied. We implemented a novel approach to investigate the modular structure of static (sFC) and time-varying (tvFC) connectivity along the AD spectrum in a two-sample Discovery/Validation design (n = 80 and 81, respectively). Cortical FC networks were estimated across 4 diagnostic groups (cognitively normal, subjective cognitive decline, mild cognitive impairment, and AD) for whole scan (sFC) and with sliding window correlation (tvFC). Modularity quality (across a range of spatial scales) did not differ in either sFC or tvFC. For tvFC, group differences in temporal stability within and between multiple resting state networks were observed; however, these differences were not consistent between samples. Correlation analyses identified a relationship between global cognition and temporal stability of the ventral attention network, which was reproduced in both samples. While the ventral attention system has been predominantly studied in task-evoked designs, the relationship between its intrinsic dynamics at-rest and general cognition along the AD spectrum highlights its relevance regarding clinical manifestation of the disease.
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http://dx.doi.org/10.1016/j.nicl.2021.102726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220588PMC
June 2021

Differential effects of risk factors on the cognitive trajectory of early- and late-onset Alzheimer's disease.

Alzheimers Res Ther 2021 06 14;13(1):113. Epub 2021 Jun 14.

Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

Background: Although few studies have shown that risk factors for Alzheimer's disease (AD) are associated with cognitive decline in AD, not much is known whether the impact of risk factors differs between early-onset AD (EOAD, symptom onset < 65 years of age) versus late-onset AD (LOAD). Therefore, we evaluated whether the impact of Alzheimer's disease (AD) risk factors on cognitive trajectories differ in EOAD and LOAD.

Methods: We followed-up 193 EOAD and 476 LOAD patients without known autosomal dominant AD mutation for 32.3 ± 23.2 months. Mixed-effects model analyses were performed to evaluate the effects of APOE ε4, low education, hypertension, diabetes, dyslipidemia, and obesity on cognitive trajectories.

Results: APOE ε4 carriers showed slower cognitive decline in general cognitive function, language, and memory domains than APOE ε4 carriers in EOAD but not in LOAD. Although patients with low education showed slower cognitive decline than patients with high education in both EOAD and LOAD, the effect was stronger in EOAD, specifically in frontal-executive function. Patients with hypertension showed faster cognitive decline than did patients without hypertension in frontal-executive and general cognitive function in LOAD but not in EOAD. Patients with obesity showed slower decline in general cognitive function than non-obese patients in EOAD but not in LOAD.

Conclusions: Known risk factors for AD were associated with slower cognitive decline in EOAD but rapid cognitive decline in LOAD.
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http://dx.doi.org/10.1186/s13195-021-00857-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204422PMC
June 2021

The Longitudinal Early-onset Alzheimer's Disease Study (LEADS): Framework and methodology.

Alzheimers Dement 2021 May 21. Epub 2021 May 21.

Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Patients with early-onset Alzheimer's disease (EOAD) are commonly excluded from large-scale observational and therapeutic studies due to their young age, atypical presentation, or absence of pathogenic mutations. The goals of the Longitudinal EOAD Study (LEADS) are to (1) define the clinical, imaging, and fluid biomarker characteristics of EOAD; (2) develop sensitive cognitive and biomarker measures for future clinical and research use; and (3) establish a trial-ready network. LEADS will follow 400 amyloid beta (Aβ)-positive EOAD, 200 Aβ-negative EOnonAD that meet National Institute on Aging-Alzheimer's Association (NIA-AA) criteria for mild cognitive impairment (MCI) or AD dementia, and 100 age-matched controls. Participants will undergo clinical and cognitive assessments, magnetic resonance imaging (MRI), [ F]Florbetaben and [ F]Flortaucipir positron emission tomography (PET), lumbar puncture, and blood draw for DNA, RNA, plasma, serum and peripheral blood mononuclear cells, and post-mortem assessment. To develop more effective AD treatments, scientists need to understand the genetic, biological, and clinical processes involved in EOAD. LEADS will develop a public resource that will enable future planning and implementation of EOAD clinical trials.
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http://dx.doi.org/10.1002/alz.12350DOI Listing
May 2021

Optimizing differential identifiability improves connectome predictive modeling of cognitive deficits from functional connectivity in Alzheimer's disease.

Hum Brain Mapp 2021 Aug 5;42(11):3500-3516. Epub 2021 May 5.

Indiana University School of Medicine, Indianapolis, Indiana, USA.

Functional connectivity, as estimated using resting state functional MRI, has shown potential in bridging the gap between pathophysiology and cognition. However, clinical use of functional connectivity biomarkers is impeded by unreliable estimates of individual functional connectomes and lack of generalizability of models predicting cognitive outcomes from connectivity. To address these issues, we combine the frameworks of connectome predictive modeling and differential identifiability. Using the combined framework, we show that enhancing the individual fingerprint of resting state functional connectomes leads to robust identification of functional networks associated to cognitive outcomes and also improves prediction of cognitive outcomes from functional connectomes. Using a comprehensive spectrum of cognitive outcomes associated to Alzheimer's disease (AD), we identify and characterize functional networks associated to specific cognitive deficits exhibited in AD. This combined framework is an important step in making individual level predictions of cognition from resting state functional connectomes and in understanding the relationship between cognition and connectivity.
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http://dx.doi.org/10.1002/hbm.25448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249900PMC
August 2021

Donanemab in Early Alzheimer's Disease.

N Engl J Med 2021 05 13;384(18):1691-1704. Epub 2021 Mar 13.

From Eli Lilly (M.A.M., A.C.L., C.D.E., A.M.W., P.A.A., S.W.A., S.S., J.S., J.R.S., M.B., D.M.S.) and the Departments of Neurology, of Radiology and Imaging Sciences, and of Medical and Molecular Genetics and the Indiana Alzheimer Disease Center, Indiana University School of Medicine (L.G.A.) - both in Indianapolis; and the Departments of Psychiatry and Human Behavior and of Neurology, Butler Hospital, Warren Alpert Medical School of Brown University, Providence, RI (S.P.S.).

Background: A hallmark of Alzheimer's disease is the accumulation of amyloid-β (Aβ) peptide. Donanemab, an antibody that targets a modified form of deposited Aβ, is being investigated for the treatment of early Alzheimer's disease.

Methods: We conducted a phase 2 trial of donanemab in patients with early symptomatic Alzheimer's disease who had tau and amyloid deposition on positron-emission tomography (PET). Patients were randomly assigned in a 1:1 ratio to receive donanemab (700 mg for the first three doses and 1400 mg thereafter) or placebo intravenously every 4 weeks for up to 72 weeks. The primary outcome was the change from baseline in the score on the Integrated Alzheimer's Disease Rating Scale (iADRS; range, 0 to 144, with lower scores indicating greater cognitive and functional impairment) at 76 weeks. Secondary outcomes included the change in scores on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB), the 13-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog), the Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living Inventory (ADCS-iADL), and the Mini-Mental State Examination (MMSE), as well as the change in the amyloid and tau burden on PET.

Results: A total of 257 patients were enrolled; 131 were assigned to receive donanemab and 126 to receive placebo. The baseline iADRS score was 106 in both groups. The change from baseline in the iADRS score at 76 weeks was -6.86 with donanemab and -10.06 with placebo (difference, 3.20; 95% confidence interval, 0.12 to 6.27; P = 0.04). The results for most secondary outcomes showed no substantial difference. At 76 weeks, the reductions in the amyloid plaque level and the global tau load were 85.06 centiloids and 0.01 greater, respectively, with donanemab than with placebo. Amyloid-related cerebral edema or effusions (mostly asymptomatic) occurred with donanemab.

Conclusions: In patients with early Alzheimer's disease, donanemab resulted in a better composite score for cognition and for the ability to perform activities of daily living than placebo at 76 weeks, although results for secondary outcomes were mixed. Longer and larger trials are necessary to study the efficacy and safety of donanemab in Alzheimer's disease. (Funded by Eli Lilly; TRAILBLAZER-ALZ ClinicalTrials.gov number, NCT03367403.).
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http://dx.doi.org/10.1056/NEJMoa2100708DOI Listing
May 2021

New insights into atypical Alzheimer's disease in the era of biomarkers.

Lancet Neurol 2021 03;20(3):222-234

Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.

Most patients with Alzheimer's disease present with amnestic problems; however, a substantial proportion, over-represented in young-onset cases, have atypical phenotypes including predominant visual, language, executive, behavioural, or motor dysfunction. In the past, these individuals often received a late diagnosis; however, availability of CSF and PET biomarkers of Alzheimer's disease pathologies and incorporation of atypical forms of Alzheimer's disease into new diagnostic criteria increasingly allows them to be more confidently diagnosed early in their illness. This early diagnosis in turn allows patients to be offered tailored information, appropriate care and support, and individualised treatment plans. These advances will provide improved access to clinical trials, which often exclude atypical phenotypes. Research into atypical Alzheimer's disease has revealed previously unrecognised neuropathological heterogeneity across the Alzheimer's disease spectrum. Neuroimaging, genetic, biomarker, and basic science studies are providing key insights into the factors that might drive selective vulnerability of differing brain networks, with potential mechanistic implications for understanding typical late-onset Alzheimer's disease.
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http://dx.doi.org/10.1016/S1474-4422(20)30440-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056394PMC
March 2021

Tau-related white-matter alterations along spatially selective pathways.

Neuroimage 2021 02 12;226:117560. Epub 2020 Nov 12.

Department of Radiology and Imaging Sciences, Indiana University School of Medicine,, Indianapolis, IN 46202, USA; Indiana Alzheimer Disease Research Center, Indiana University School of Medicine, Indianapolis, IN, USA. Electronic address:

Progressive accumulation of tau neurofibrillary tangles in the brain is a defining pathologic feature of Alzheimer's disease (AD). Tau pathology exhibits a predictable spatiotemporal spreading pattern, but the underlying mechanisms of this spread are poorly understood. Although AD is conventionally considered a disease of the gray matter, it is also associated with pronounced and progressive deterioration of the white matter (WM). A link between abnormal tau and WM degeneration is suggested by findings from both animal and postmortem studies, but few studies demonstrated their interplay in vivo. Recent advances in diffusion magnetic resonance imaging and the availability of tau positron emission tomography (PET) have made it possible to evaluate the association of tau and WM degeneration (tau-WM) in vivo. In this study, we explored the spatial pattern of tau-WM associations across the whole brain to evaluate the hypothesis that tau deposition is associated with WM microstructural alterations not only in isolated tracts, but in continuous structural connections in a stereotypic pattern. Sixty-two participants, including 22 cognitively normal subjects, 22 individuals with subjective cognitive decline, and 18 with mild cognitive impairment were included in the study. WM characteristics were inferred by classic diffusion tensor imaging (DTI) and a complementary diffusion compartment model - neurite orientation dispersion and density imaging (NODDI) that provides a proxy for axonal density. A data-driven iterative searching (DDIS) approach, coupled with whole-brain graph theory analyses, was developed to continuously track tau-WM association patterns. Without applying prior knowledge of the tau spread, we observed a distinct spatial pattern that resembled the typical propagation of tau pathology in AD. Such association pattern was not observed between diffusion and amyloid-β PET signal. Tau-related WM degeneration is characterized by an increase in the mean diffusivity (with a dominant change in the radial direction) and a decrease in the intra-axonal volume fraction. These findings suggest that cortical tau deposition (as measured in tau PET) is associated with a lower axonal packing density and greater diffusion freedom. In conclusion, our in vivo findings using a data-driven method on cross-sectional data underline the important role of WM alterations in the AD pathological cascade with an association pattern similar to the postmortem Braak staging of AD. Future studies will focus on longitudinal analyses to provide in vivo evidence of tau pathology spreads along neuroanatomically connected brain areas.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117560DOI Listing
February 2021

Neurodegenerative changes in early- and late-onset cognitive impairment with and without brain amyloidosis.

Alzheimers Res Ther 2020 08 5;12(1):93. Epub 2020 Aug 5.

Department of Neurology, Indiana University School of Medicine, 355 W 16th Street, Suite 4022, Indianapolis, IN, 46202, USA.

Background: A substantial number of patients clinically diagnosed with Alzheimer's disease do not harbor amyloid pathology. We analyzed the presence and extent of tau deposition and neurodegeneration in amyloid-positive (AD) and amyloid-negative (nonAD) ADNI subjects while also taking into account age of onset (< or > 65 years) as we expected that the emerging patterns could vary by age and presence or absence of brain amyloidosis.

Methods: One hundred and ten early-onset AD (EOAD), 121 EOnonAD, 364 late-onset AD (LOAD), and 175 LOnonAD mild cognitive impairment (MCI) and dementia (DEM) subjects were compared to 291 ADNI amyloid-negative control subjects using voxel-wise regression in SPM12 with cluster-level family-wise error correction at p < 0.05). A subset of these subjects also received F-flortaucipir scans and allowed for analysis of global tau burden.

Results: As expected, relative to LOAD, EOAD subjects showed more extensive neurodegeneration and tau deposition in AD-relevant regions. EOnonAD showed no significant neurodegeneration, while EOnonAD showed bilateral medial and lateral temporal, and temporoparietal hypometabolism. LOnonAD and LOnonAD showed diffuse brain atrophy and a fronto-temporo-parietal hypometabolic pattern. LOnonAD and EOnonAD subjects failed to show significant tau binding.

Conclusions: LOnonAD subjects show a fronto-temporal neurodegenerative pattern in the absence of tau binding, which may represent underlying hippocampal sclerosis with TDP-43, also known as limbic-predominant age-related TDP-43 encephalopathy (LATE). The hypometabolic pattern observed in EOnonAD seems similar to the one observed in EOAD. Further investigation into the underlying etiology of EOnonAD is warranted.
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http://dx.doi.org/10.1186/s13195-020-00647-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409508PMC
August 2020

Genome-wide transcriptome analysis identifies novel dysregulated genes implicated in Alzheimer's pathology.

Alzheimers Dement 2020 09 5;16(9):1213-1223. Epub 2020 Aug 5.

Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana.

Introduction: Abnormal gene expression patterns may contribute to the onset and progression of late-onset Alzheimer's disease (LOAD).

Methods: We performed transcriptome-wide meta-analysis (N = 1440) of blood-based microarray gene expression profiles as well as neuroimaging and cerebrospinal fluid (CSF) endophenotype analysis.

Results: We identified and replicated five genes (CREB5, CD46, TMBIM6, IRAK3, and RPAIN) as significantly dysregulated in LOAD. The most significantly altered gene, CREB5, was also associated with brain atrophy and increased amyloid beta (Aβ) accumulation, especially in the entorhinal cortex region. cis-expression quantitative trait loci mapping analysis of CREB5 detected five significant associations (P < 5 × 10 ), where rs56388170 (most significant) was also significantly associated with global cortical Aβ deposition measured by [ F]Florbetapir positron emission tomography and CSF Aβ .

Discussion: RNA from peripheral blood indicated a differential gene expression pattern in LOAD. Genes identified have been implicated in biological processes relevant to Alzheimer's disease. CREB, in particular, plays a key role in nervous system development, cell survival, plasticity, and learning and memory.
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http://dx.doi.org/10.1002/alz.12092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541709PMC
September 2020

Testing influences of APOE and BDNF genes and heart failure on cognitive function.

Heart Lung 2021 Jan - Feb;50(1):51-58. Epub 2020 Jul 20.

Professor, Indiana University School of Nursing, 600 Barnhill Drive, Indianapolis, IN 46202, USA. Electronic address:

Background: Apolipoprotein E (APOE) ε2, ε4 and brain-derived neurotrophic factor (BDNF) Val66Met alleles have been associated with cognition. Associations of these alleles with cognition in heart failure (HF) and influences of HF across the cognitive spectrum (i.e., cognitively normal to Alzheimer's dementia [AD]) remain unexplored.

Objectives: To investigate influences of APOE ε2, ε4, BDNF Met and HF on cognition among participants across the cognitive spectrum.

Methods: Genetic association study using national databases (N = 7,166).

Results: APOE ε2 frequencies were similar across the cognitive spectrum among participants with HF. APOE ε4 frequency was lower among participants with HF and AD than non-HF participants with AD. BDNF Met frequencies did not differ across the spectrum. HF was associated with worse attention and language. In the HF subsample, ε4 was associated with worse memory.

Conclusion: Associations between APOE and cognition may differ in HF but need to be tested in a larger sample.
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http://dx.doi.org/10.1016/j.hrtlng.2020.06.014DOI Listing
April 2021

Harnessing peripheral DNA methylation differences in the Alzheimer's Disease Neuroimaging Initiative (ADNI) to reveal novel biomarkers of disease.

Clin Epigenetics 2020 06 15;12(1):84. Epub 2020 Jun 15.

Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.

Background: Alzheimer's disease (AD) is a chronic progressive neurodegenerative disease impacting an estimated 44 million adults worldwide. The causal pathology of AD (accumulation of amyloid-beta and tau), precedes hallmark symptoms of dementia by more than a decade, necessitating development of early diagnostic markers of disease onset, particularly for new drugs that aim to modify disease processes. To evaluate differentially methylated positions (DMPs) as novel blood-based biomarkers of AD, we used a subset of 653 individuals with peripheral blood (PB) samples in the Alzheimer's disease Neuroimaging Initiative (ADNI) consortium. The selected cohort of AD, mild cognitive impairment (MCI), and age-matched healthy controls (CN) all had imaging, genetics, transcriptomics, cerebrospinal protein markers, and comprehensive clinical records, providing a rich resource of concurrent multi-omics and phenotypic information on a well-phenotyped subset of ADNI participants.

Results: In this manuscript, we report cross-diagnosis differential peripheral DNA methylation in a cohort of AD, MCI, and age-matched CN individuals with longitudinal DNA methylation measurements. Epigenome-wide association studies (EWAS) were performed using a mixed model with repeated measures over time with a P value cutoff of 1 × 10 to test contrasts of pairwise differential peripheral methylation in AD vs CN, AD vs MCI, and MCI vs CN. The most highly significant differentially methylated loci also tracked with Mini Mental State Examination (MMSE) scores. Differentially methylated loci were enriched near brain and neurodegeneration-related genes (e.g., BDNF, BIN1, APOC1) validated using the genotype tissue expression project portal (GTex).

Conclusions: Our work shows that peripheral differential methylation between age-matched subjects with AD relative to healthy controls will provide opportunities to further investigate and validate differential methylation as a surrogate of disease. Given the inaccessibility of brain tissue, the PB-associated methylation marks may help identify the stage of disease and progression phenotype, information that would be central to bringing forward successful drugs for AD.
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http://dx.doi.org/10.1186/s13148-020-00864-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294637PMC
June 2020

Novel Markers of Angiogenesis in the Setting of Cognitive Impairment and Dementia.

J Alzheimers Dis 2020 ;75(3):959-969

Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN, USA.

Background: Aberrant angiogenesis may play a role in the development of Alzheimer's disease and related dementia.

Objective: To explore the relationship between angiogenesis activity and evidence of neurodegeneration among older adults.

Methods: Cross-sectional study of 49 older adults clinically characterized as cognitively normal, mild cognitive impairment, or early Alzheimer's disease. In addition to neuroimaging, we completed assays on peripheral blood, including: vascular endothelial growth factor, tumor necrosis factor, fibroblast growth factor, and amyloid-β peptide 40. We used advanced polychromatic flow cytometry to phenotype circulating mononuclear cells to assess angiogenesis activity.

Results: Although we documented differences in cognitive performance, structural changes on neuroimaging, and burden of amyloid and tau on positron emission tomography, angiogenesis activity did not vary by group. Interestingly, VEGF levels were shown to be increased among subjects with mild cognitive impairment. In ANCOVA models controlling for age, sex, intracranial volume, and monocyte subpopulations, angiogenesis activity was correlated with increased white matter hyperintensities.

Conclusion: We demonstrate a significant association between angiogenesis activity and cerebrovascular disease. To better understand the potential of angiogenesis as an intervention target, longitudinal studies are needed.
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http://dx.doi.org/10.3233/JAD-191293DOI Listing
May 2021

Visual contrast sensitivity is associated with the presence of cerebral amyloid and tau deposition.

Brain Commun 2020 26;2(1):fcaa019. Epub 2020 Feb 26.

Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.

Visual deficits are common in neurodegenerative diseases including Alzheimer's disease. We sought to determine the association between visual contrast sensitivity and neuroimaging measures of Alzheimer's disease-related pathophysiology, including cerebral amyloid and tau deposition and neurodegeneration. A total of 74 participants (7 Alzheimer's disease, 16 mild cognitive impairment, 20 subjective cognitive decline, 31 cognitively normal older adults) underwent the frequency doubling technology 24-2 examination, a structural MRI scan and amyloid PET imaging for the assessment of visual contrast sensitivity. Of these participants, 46 participants (2 Alzheimer's disease, 9 mild cognitive impairment, 12 subjective cognitive decline, 23 cognitively normal older adults) also underwent tau PET imaging with [F]flortaucipir. The relationships between visual contrast sensitivity and cerebral amyloid and tau, as well as neurodegeneration, were assessed using partial Pearson correlations, covaried for age, sex and race and ethnicity. Voxel-wise associations were also evaluated for amyloid and tau. The ability of visual contrast sensitivity to predict amyloid and tau positivity were assessed using forward conditional logistic regression and receiver operating curve analysis. All analyses first were done in the full sample and then in the non-demented at-risk individuals (subjective cognitive decline and mild cognitive impairment) only. Significant associations between visual contrast sensitivity and regional amyloid and tau deposition were observed across the full sample and within subjective cognitive decline and mild cognitive impairment only. Voxel-wise analysis demonstrated strong associations of visual contrast sensitivity with amyloid and tau, primarily in temporal, parietal and occipital brain regions. Finally, visual contrast sensitivity accurately predicted amyloid and tau positivity. Alterations in visual contrast sensitivity were related to cerebral deposition of amyloid and tau, suggesting that this measure may be a good biomarker for detecting Alzheimer's disease-related pathophysiology. Future studies in larger patient samples are needed, but these findings support the power of these measures of visual contrast sensitivity as a potential novel, inexpensive and easy-to-administer biomarker for Alzheimer's disease-related pathology in older adults at risk for cognitive decline.
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http://dx.doi.org/10.1093/braincomms/fcaa019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7151662PMC
February 2020

Association of Hypercholesterolemia with Alzheimer's Disease Pathology and Cerebral Amyloid Angiopathy.

J Alzheimers Dis 2020 ;73(4):1305-1311

Department of Biostatistics, Indiana University School of Medicine and Fairbanks School of Public Health, Indianapolis, IN, USA.

Background: Animal studies have shown that diet-induced hypercholesterolemia (HC) increases amyloid-β (Aβ) accumulation and accelerates Alzheimer's disease (AD) pathology. However, the association of HC with AD in human studies has not been consistently established.

Objective: We aimed to investigate the relationship between HC and risk of AD neuropathology in a large national sample with autopsies.

Methods: This study used neuropathological and clinical data from 3,508 subjects from the National Alzheimer's Coordinating Center (NACC) who underwent autopsies from 2005 to 2017. Demographic and clinical characteristics, as well as neuropathological outcomes were compared between subjects with and without HC. Associations between HC and AD neuropathology were examined by multivariate ordinal logistic regressions adjusting for potential confounders.

Results: HC was not associated with any AD neuropathology in a model only adjusting for demographic variables. However, HC was significantly associated with higher CERAD neuritic and diffuse plaque burden, higher Braak stage, and more severe cerebral amyloid angiopathy when analyzed in a multivariate model controlling for comorbidities. Additional adjusting for cerebrovascular conditions did not diminish these associations. The association between HC and increased risk of neuritic plaques weakened but remained significant even after controlling for ApoE genotype.

Conclusion: This study suggested that HC was associated with increased severity of AD pathology, which could only be partially accounted for by ApoE genotype. The associations were not mediated by cerebrovascular conditions.
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http://dx.doi.org/10.3233/JAD-191023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489304PMC
May 2021

Neurodegenerative Patterns of Cognitive Clusters of Early-Onset Alzheimer's Disease Subjects: Evidence for Disease Heterogeneity.

Dement Geriatr Cogn Disord 2019 3;48(3-4):131-142. Epub 2020 Jan 3.

Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana, USA.

Background/aims: Alzheimer's disease (AD) with onset before 65 (early-onset AD [EOAD]) occurs in approximately 6% of cases and can affect nonmemory domains. Here, we analyze patterns of impairment in amnestic EOAD individuals using data-driven statistical analyses.

Methods: Cognitive data of 146 EOAD subjects were Z-normalized to 395 cognitively normal (CN) individuals. Domain-averaged Z-scores were adjusted for age, sex, and education followed by Wald cluster analysis of residuals. Magnetic resonance imaging and positron emission tomography comparisons of EOAD clusters to age-matched CN were done using Statistic Parametric Mapping 8. Cluster-level-family-wise error (p < 0.05) correction was applied. Mixed-effect models were used to compute longitudinal change across clusters.

Results: Scree plot using the pseudo-T-squared suggested a 4-cluster solution. Cluster 1 (memory-predominant impairment) showed atrophy/hypometabolism in medial/lateral temporal, lateral parietal, and posterior cingulate regions. Cluster 2 (memory/visuospatial-predominant) showed atrophy/hypometabolism of medial temporal, temporoparietal, and frontal cortices. Cluster 3 (memory, language, and executive function) and Cluster 4 (globally impaired) manifested atrophy and hypometabolism throughout the brain. Longitudinally between-cluster differences in the visuospatial and language/executive domains were significant, suggesting phenotypic variation.

Conclusion: We observed significant heterogeneity in cognitive presentation among amnestic EOAD subjects and patterns of atrophy/hypometabolism in each cluster in agreement with the observed cognitive phenotype.
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http://dx.doi.org/10.1159/000504341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031037PMC
June 2020

Association of brain amyloidosis with the incidence and frequency of neuropsychiatric symptoms in ADNI: a multisite observational cohort study.

BMJ Open 2019 12 18;9(12):e031947. Epub 2019 Dec 18.

Neurology, Indiana University School of Medicine, Indianapolis, Indiana, USA

Objective: To investigate the relationship between amyloid burden and frequency of existing and incidence of new neuropsychiatric symptoms (NPS) in elderly with and without cognitive decline.

Methods: 275 cognitively normal controls (NC), 100 subjective memory complaint (SMC), 559 mild cognitive impairment (MCI) and 143 Alzheimer's disease dementia subjects from the Alzheimer's Disease Neuroimaging Initiative received (F)-florbetapir positron emission tomography (PET) scans. Yearly neuropsychiatric inventory (Neuropsychiatric Inventory (NPI)/NPI-Questionnaire) data were collected from the study partners at each visit. Mean standard uptake volume ratios (SUVR) normalised to whole cerebellum were obtained. Positive amyloid PET scan was defined as mean SUVR ≥1.17. Fisher's exact test was used to compare frequency and incidence between amyloid positive and amyloid negative subjects. Survival analyses were used to estimate of neuropsychiatric symptoms (NPS) between amyloid positive and amyloid negative subjects. Survival analyses were used to estimate hazard ratios for developing the most common NPS by amyloid status.

Results: No differences in NPS frequency were seen between amyloid positive and amyloid negative NC, SMC, MCI or dementia groups. MCI subjects with amyloid pathology however tended to have greater frequency x severity (FxS) of anxiety, hallucinations, delusions, apathy, disinhibition, irritability, aberrant motor behavior, and appetite, but not agitation, depression, night-time disturbances, or elation. MCI subjects with amyloid pathology were at greater risk for developing apathy, anxiety and agitation over time. Baseline presence of agitation and apathy and new onset agitation, irritability and apathy predicted faster conversion to dementia among MCI subjects.

Conclusions: Amyloid pathology is associated with greater rate of development of new NPS in MCI. Anxiety and delusions are significant predictors of amyloid pathology. Agitation, irritability and apathy are significant predictors for conversion from MCI to dementia.
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http://dx.doi.org/10.1136/bmjopen-2019-031947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937083PMC
December 2019

Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group.

Mol Psychiatry 2019 Dec 6. Epub 2019 Dec 6.

University Medical Centre Hamburg-Eppendorf, House W34, 3.OG, Martinistr. 52, 20246, Hamburg, Germany.

DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc)-three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.
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http://dx.doi.org/10.1038/s41380-019-0605-zDOI Listing
December 2019

Blood-based biomarkers for Alzheimer's disease and related dementias: Keys to success and things to consider.

Alzheimers Dement (Amst) 2019 Dec 14;11:784-786. Epub 2019 Nov 14.

Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI, USA.

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http://dx.doi.org/10.1016/j.dadm.2019.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872805PMC
December 2019

The Functional Ability of MCI and Alzheimer's Patients Predicts Caregiver Burden.

GeroPsych (Bern) 2019 Mar 5;32(1):31-39. Epub 2019 Mar 5.

Department of Psychology, California State University, Northridge.

Sixty patients and their caregivers participated in this study. Patients completed activities of daily living tasks and several neuropsychological tests assessing memory, abstract reasoning, and language. Caregivers completed self-report measures assessing caregiver burden and psychological distress. Results revealed that the mAD caregivers endorsed greater physical burden and feelings of missing out on life compared to MCI caregivers. The mAD caregivers indicated greater depression and anxiety relative to MCI caregivers. Stepwise regression found that fewer patient neuropsychological scores predicted caregiver burden, as compared to patients' daily functioning. Overall, mAD displayed more severe types of burden and psychological distress relative to MCI caregivers and patients' daily functional abilities better predicated caregivers' burden and psychological distress than patients' neuropsychological functioning.
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http://dx.doi.org/10.1024/1662-9647/a000200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785829PMC
March 2019

Cognitive Correlates of Hippocampal Atrophy and Ventricular Enlargement in Adults with or without Mild Cognitive Impairment.

Dement Geriatr Cogn Dis Extra 2019 May-Aug;9(2):281-293. Epub 2019 Aug 13.

Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana, USA.

We analyzed structural magnetic resonance imaging data from 58 cognitively normal and 101 mild cognitive impairment subjects. We used a general linear regression model to study the association between cognitive performance with hippocampal atrophy and ventricular enlargement using the radial distance method. Bilateral hippocampal atrophy was associated with baseline and longitudinal memory performance. Left hippocampal atrophy predicted longitudinal decline in visuospatial function. The multidomain ventricular analysis did not reveal any significant predictors.
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http://dx.doi.org/10.1159/000490044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6751474PMC
August 2019

White matter alterations in early-stage Alzheimer's disease: A tract-specific study.

Alzheimers Dement (Amst) 2019 Dec 21;11:576-587. Epub 2019 Aug 21.

Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.

Introduction: Diffusion magnetic resonance imaging may allow for microscopic characterization of white matter degeneration in early stages of Alzheimer's disease.

Methods: Multishell Diffusion magnetic resonance imaging data were acquired from 100 participants (40 cognitively normal, 38 with subjective cognitive decline, and 22 with mild cognitive impairment [MCI]). White matter microscopic degeneration in 27 major tracts of interest was assessed using diffusion tensor imaging (DTI), neurite orientation dispersion and density imaging, and q-space imaging.

Results: Lower DTI fractional anisotropy and higher radial diffusivity were observed in the cingulum, thalamic radiation, and forceps major of participants with MCI. These tracts of interest also had the highest predictive power to discriminate groups. Diffusion metrics were associated with cognitive performance, particularly Rey Auditory Verbal Learning Test immediate recall, with the highest association observed in participants with MCI.

Discussion: While DTI was the most sensitive, neurite orientation dispersion and density imaging and q-space imaging complementarily characterized reduced axonal density accompanied with dispersed and less restricted white matter microstructures.
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http://dx.doi.org/10.1016/j.dadm.2019.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713788PMC
December 2019

Plasma amyloid beta levels are associated with cerebral amyloid and tau deposition.

Alzheimers Dement (Amst) 2019 Dec 26;11:510-519. Epub 2019 Jul 26.

Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana University School of Medicine, Indianapolis, IN, USA.

Introduction: We investigated the relationship of plasma amyloid beta (Aβ) with cerebral deposition of Aβ and tau on positron emission tomography (PET).

Methods: Forty-four participants (18 cognitively normal older adults [CN], 10 mild cognitive impairment, 16 Alzheimer's disease [AD]) underwent amyloid PET and a blood draw. Free and total plasma Aβ40 and Aβ42 were assessed using a validated assay. Thirty-seven participants (17 CN, 8 mild cognitive impairment, 12 AD) also underwent a [F]flortaucipir scan. Scans were preprocessed by standard techniques, and mean global and regional amyloid and tau values were extracted. Free Aβ42/Aβ40 (Aβ F42:F40) and total Aβ42/Aβ40 (Aβ T42:T40) were evaluated for differences by diagnosis and relation to PET Aβ positivity. Relationships between these measures and cerebral Aβ and tau on both regional and voxel-wise basis were also evaluated.

Results: Lower Aβ T42:T40 was associated with diagnosis and PET Aβ positivity. Lower plasma Aβ T42:T40 ratios predicted cerebral Aβ positivity, both across the full sample and in CN only. Finally, lower plasma Aβ T42:T40 ratios were associated with increased cortical Aβ and tau in AD-related regions on both regional and voxel-wise analyses.

Discussion: Plasma Aβ measures may be useful biomarkers for predicting cerebral Aβ and tau. Additional studies in larger samples are warranted.
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http://dx.doi.org/10.1016/j.dadm.2019.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6661419PMC
December 2019

Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.

Nat Genet 2019 03 28;51(3):414-430. Epub 2019 Feb 28.

Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades-Universitat Internacional de Catalunya, Barcelona, Spain.

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.
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http://dx.doi.org/10.1038/s41588-019-0358-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463297PMC
March 2019

Resting state network modularity along the prodromal late onset Alzheimer's disease continuum.

Neuroimage Clin 2019 22;22:101687. Epub 2019 Jan 22.

Department of Radiology and Imaging Sciences, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA; Indiana Alzheimer Disease Center, IUSM, Indianapolis, IN, USA; Indiana University Network Science Institute, Bloomington, IN, USA; School of Informatics, Computing and Engineering, Indiana University, Bloomington, IN, USA; Program in Medical Neuroscience, Paul and Carole Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA; Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA. Electronic address:

Alzheimer's disease is considered a disconnection syndrome, motivating the use of brain network measures to detect changes in whole-brain resting state functional connectivity (FC). We investigated changes in FC within and among resting state networks (RSN) across four different stages in the Alzheimer's disease continuum. FC changes were examined in two independent cohorts of individuals (84 and 58 individuals, respectively) each comprising control, subjective cognitive decline, mild cognitive impairment and Alzheimer's dementia groups. For each participant, FC was computed as a matrix of Pearson correlations between pairs of time series from 278 gray matter brain regions. We determined significant differences in FC modular organization with two distinct approaches, network contingency analysis and multiresolution consensus clustering. Network contingency analysis identified RSN sub-blocks that differed significantly across clinical groups. Multiresolution consensus clustering identified differences in the stability of modules across multiple spatial scales. Significant modules were further tested for statistical association with memory and executive function cognitive domain scores. Across both analytic approaches and in both participant cohorts, the findings converged on a pattern of FC that varied systematically with diagnosis within the frontoparietal network (FP) and between the FP network and default mode network (DMN). Disturbances of modular organization were manifest as greater internal coherence of the FP network and stronger coupling between FP and DMN, resulting in less segregation of these two networks. Our findings suggest that the pattern of interactions within and between specific RSNs offers new insight into the functional disruption that occurs across the Alzheimer's disease spectrum.
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http://dx.doi.org/10.1016/j.nicl.2019.101687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357852PMC
January 2020

Automated and manual hippocampal segmentation techniques: Comparison of results, reproducibility and clinical applicability.

Neuroimage Clin 2019 14;21:101574. Epub 2018 Oct 14.

Department of Neurology, Indiana University, Indianapolis, IN, USA; Department of Radiological Sciences, Indiana University, Indianapolis, IN, USA; Department of Medical and Molecular Genetics, Indiana University, Indianapolis, IN, USA. Electronic address:

Background: Imaging techniques used to measure hippocampal atrophy are key to understanding the clinical progression of Alzheimer's disease (AD). Various semi-automated hippocampal segmentation techniques are available and require human expert input to learn how to accurately segment new data. Our goal was to compare 1) the performance of our automated hippocampal segmentation technique relative to manual segmentations, and 2) the performance of our automated technique when provided with a training set from two different raters. We also explored the ability of hippocampal volumes obtained using manual and automated hippocampal segmentations to predict conversion from MCI to AD.

Methods: We analyzed 161 1.5 T T1-weighted brain magnetic resonance images (MRI) from the ADCS Donepezil/Vitamin E clinical study. All subjects carried a diagnosis of mild cognitive impairment (MCI). Three different segmentation outputs (one produced by manual tracing and two produced by a semi-automated algorithm trained with training sets developed by two raters) were compared using single measure intraclass correlation statistics (smICC). The radial distance method was used to assess each segmentation technique's ability to detect hippocampal atrophy in 3D. We then compared how well each segmentation method detected baseline hippocampal differences between MCI subjects who remained stable (MCInc) and those who converted to AD (MCIc) during the trial. Our statistical maps were corrected for multiple comparisons using permutation-based statistics with a threshold of p < .01.

Results: Our smICC analyses showed significant agreement between the manual and automated hippocampal segmentations from rater 1 [right smICC = 0.78 (95%CI 0.72-0.84); left smICC = 0.79 (95%CI 0.72-0.85)], the manual segmentations from rater 1 versus the automated segmentations from rater 2 [right smICC = 0.78 (95%CI 0.7-0.84); left smICC = 0.78 (95%CI 0.71-0.84)], and the automated segmentations of rater 1 versus rater 2 [right smICC = 0.97 (95%CI 0.96-0.98); left smICC = 0.97 (95%CI 0.96-0.98)]. All three segmentation methods detected significant CA1 and subicular atrophy in MCIc compared to MCInc at baseline (manual: right p = 0.0112, left p = 0.0006; automated rater 1: right p = 0.0318, left p = 0.0302; automated rater 2: right p = 0.0029, left p = 0.0166).

Conclusions: The hippocampal volumes obtained with a fast semi-automated segmentation method were highly comparable to the ones obtained with the labor-intensive manual segmentation method. The AdaBoost automated hippocampal segmentation technique is highly reliable allowing the efficient analysis of large data sets.
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http://dx.doi.org/10.1016/j.nicl.2018.10.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413347PMC
December 2019

Detection of tau in Gerstmann-Sträussler-Scheinker disease (PRNP F198S) by [F]Flortaucipir PET.

Acta Neuropathol Commun 2018 10 29;6(1):114. Epub 2018 Oct 29.

Department of Radiology and Imaging Sciences, Indiana University School of Medicine, 355 West 16th Street, Suite 4100, Indianapolis, IN, 46202, USA.

This study aimed to determine the pattern of [F]flortaucipir uptake in individuals affected by Gerstmann-Sträussler-Scheinker disease (GSS) associated with the PRNP F198S mutation. The aims were to: 1) determine the pattern of [F]flortaucipir uptake in two GSS patients; 2) compare tau distribution by [F]flortaucipir PET imaging among three groups: two GSS patients, two early onset Alzheimer's disease patients (EOAD), two cognitively normal older adults (CN); 3) validate the PET imaging by comparing the pattern of [F]flortaucipir uptake, in vivo, with that of tau neuropathology, post-mortem. Scans were processed to generate standardized uptake value ratio (SUVR) images. Regional [F]flortaucipir SUVR was extracted and compared between GSS patients, EOADs, and CNs. Neuropathology and tau immunohistochemistry were carried out post-mortem on a GSS patient who died 9 months after the [F]flortaucipir scan. The GSS patients were at different stages of disease progression. Patient A was mildly to moderately affected, suffering from cognitive, psychiatric, and ataxia symptoms. Patient B was moderately to severely affected, suffering from ataxia and parkinsonism accompanied by psychiatric and cognitive symptoms. The [F]flortaucipir scans showed uptake in frontal, cingulate, and insular cortices, as well as in the striatum and thalamus. Uptake was greater in Patient B than in Patient A. Both GSS patients showed greater uptake in the striatum and thalamus than the EOADs and greater uptake in all evaluated regions than the CNs. Thioflavin S fluorescence and immunohistochemistry revealed that the anatomical distribution of tau pathology is consistent with that of [F]flortaucipir uptake. In GSS patients, the neuroanatomical localization of pathologic tau, as detected by [F]flortaucipir, suggests correlation with the psychiatric, motor, and cognitive symptoms. The topography of uptake in PRNP F198S GSS is strikingly different from that seen in AD. Further studies of the sensitivity, specificity, and anatomical patterns of tau PET in diseases with tau pathology are warranted.
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http://dx.doi.org/10.1186/s40478-018-0608-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205777PMC
October 2018

Neuronal pentraxin 1: A synaptic-derived plasma biomarker in Alzheimer's disease.

Neurobiol Dis 2018 06 6;114:120-128. Epub 2018 Mar 6.

Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, United States; Veterans Affairs Greater Los Angeles Healthcare System, United States. Electronic address:

Synaptic neurodegeneration is thought to be an early event initiated by soluble β-amyloid (Aβ) aggregates that closely correlates with cognitive decline in Alzheimer disease (AD). Apolipoprotein ε4 (APOE4) is the most common genetic risk factor for both familial AD (FAD) and sporadic AD; it accelerates Aβ aggregation and selectively impairs glutamate receptor function and synaptic plasticity. However, its molecular mechanisms remain elusive and these synaptic deficits are difficult to monitor. AD- and APOE4-dependent plasma biomarkers have been proposed, but synapse-related plasma biomarkers are lacking. We evaluated neuronal pentraxin 1 (NP1), a potential CNS-derived plasma biomarker of excitatory synaptic pathology. NP1 is preferentially expressed in brain and involved in glutamate receptor internalization. NP1 is secreted presynaptically induced by Aβ oligomers, and implicated in excitatory synaptic and mitochondrial deficits. Levels of NP1 and its fragments were increased in a correlated fashion in both brain and plasma of 7-8 month-old E4FAD mice relative to E3FAD mice. NP1 was also found in exosome preparations and reduced by dietary DHA supplementation. Plasma NP1 was higher in E4FAD+ (APOE4/FAD) relative to E4FAD- (non-carrier; APOE4/FAD) mice, suggesting NP1 is modulated by Aβ expression. Finally, relative to normal elderly, plasma NP1 was also elevated in patients with mild cognitive impairment (MCI) and elevated further in the subset who progressed to early-stage AD. In those patients, there was a trend towards increased NP1 levels in APOE4 carriers relative to non-carriers. These findings indicate that NP1 may represent a potential synapse-derived plasma biomarker relevant to early alterations in excitatory synapses in MCI and early-stage AD.
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http://dx.doi.org/10.1016/j.nbd.2018.02.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092920PMC
June 2018

Associations of the Top 20 Alzheimer Disease Risk Variants With Brain Amyloidosis.

JAMA Neurol 2018 03;75(3):328-341

Department of Radiology and Imaging Sciences, Center for Neuroimaging, School of Medicine, Indiana University, Indianapolis.

Importance: Late-onset Alzheimer disease (AD) is highly heritable. Genome-wide association studies have identified more than 20 AD risk genes. The precise mechanism through which many of these genes are associated with AD remains unknown.

Objective: To investigate the association of the top 20 AD risk variants with brain amyloidosis.

Design, Setting, And Participants: This study analyzed the genetic and florbetapir F 18 data from 322 cognitively normal control individuals, 496 individuals with mild cognitive impairment, and 159 individuals with AD dementia who had genome-wide association studies and 18F-florbetapir positron emission tomographic data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), a prospective, observational, multisite tertiary center clinical and biomarker study. This ongoing study began in 2005.

Main Outcomes And Measures: The study tested the association of AD risk allele carrier status (exposure) with florbetapir mean standard uptake value ratio (outcome) using stepwise multivariable linear regression while controlling for age, sex, and apolipoprotein E ε4 genotype. The study also reports on an exploratory 3-dimensional stepwise regression model using an unbiased voxelwise approach in Statistical Parametric Mapping 8 with cluster and significance thresholds at 50 voxels and uncorrected P < .01.

Results: This study included 977 participants (mean [SD] age, 74 [7.5] years; 535 [54.8%] male and 442 [45.2%] female) from the ADNI-1, ADNI-2, and ADNI-Grand Opportunity. The adenosine triphosphate-binding cassette subfamily A member 7 (ABCA7) gene had the strongest association with amyloid deposition (χ2 = 8.38, false discovery rate-corrected P < .001), after apolioprotein E ε4. Significant associations were found between ABCA7 in the asymptomatic and early symptomatic disease stages, suggesting an association with rapid amyloid accumulation. The fermitin family homolog 2 (FERMT2) gene had a stage-dependent association with brain amyloidosis (FERMT2 × diagnosis χ2 = 3.53, false discovery rate-corrected P = .05), which was most pronounced in the mild cognitive impairment stage.

Conclusions And Relevance: This study found an association of several AD risk variants with brain amyloidosis. The data also suggest that AD genes might differentially regulate AD pathologic findings across the disease stages.
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http://dx.doi.org/10.1001/jamaneurol.2017.4198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885860PMC
March 2018

Volumetric comparison of hippocampal subfields extracted from 4-minute accelerated vs. 8-minute high-resolution T2-weighted 3T MRI scans.

Brain Imaging Behav 2018 Dec;12(6):1583-1595

Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, 355 West 16th Street Suite 4100, Indianapolis, IN, 46202, USA.

The hippocampus has been widely studied using neuroimaging, as it plays an important role in memory and learning. However, hippocampal subfield information is difficult to capture by standard magnetic resonance imaging (MRI) techniques. To facilitate morphometric study of hippocampal subfields, ADNI introduced a high resolution (0.4 mm in plane) T2-weighted turbo spin-echo sequence that requires 8 min. With acceleration, the protocol can be acquired in 4 min. We performed a comparative study of hippocampal subfield volumes using standard and accelerated protocols on a Siemens Prisma 3T MRI in an independent sample of older adults that included 10 cognitively normal controls, 9 individuals with subjective cognitive decline, 10 with mild cognitive impairment, and 6 with a clinical diagnosis of Alzheimer's disease (AD). The Automatic Segmentation of Hippocampal Subfields (ASHS) software was used to segment 9 primary labeled regions including hippocampal subfields and neighboring cortical regions. Intraclass correlation coefficients were computed for reliability tests between 4 and 8 min scans within and across the four groups. Pairwise group analyses were performed, covaried for age, sex and total intracranial volume, to determine whether the patterns of group differences were similar using 4 vs. 8 min scans. The 4 and 8 min protocols, analyzed by ASHS segmentation, yielded similar volumetric estimates for hippocampal subfields as well as comparable patterns of differences between study groups. The accelerated protocol can provide reliable imaging data for investigation of hippocampal subfields in AD-related MRI studies and the decreased scan time may result in less vulnerability to motion.
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http://dx.doi.org/10.1007/s11682-017-9819-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033688PMC
December 2018