Publications by authors named "John C Morris"

758 Publications

The informed road map to prevention of Alzheimer Disease: A call to arms.

Mol Neurodegener 2021 Jul 21;16(1):49. Epub 2021 Jul 21.

Department of Neurology, Washington University in St Louis, 660 S. Euclid Avenue, Campus Box, St Louis, MO, 8111, USA.

Alzheimer disease (AD) prevention trials hold the promise to delay or prevent cognitive decline and dementia onset by intervening before significant neuronal damage occurs. In recent years, the first AD prevention trials have launched and are yielding important findings on the biology of targeting asymptomatic AD pathology. However, there are limitations that impact the design of these prevention trials, including the translation of animal models that recapitulate key stages and multiple pathological aspects of the human disease, missing target validation in asymptomatic disease, uncertain causality of the association of pathophysiologic changes with cognitive and clinical symptoms, and limited biomarker validation for novel targets. The field is accelerating advancements in key areas including the development of highly specific and quantitative biomarker measures for AD pathology, increasing our understanding of the course and relationship of amyloid and tau pathology in asymptomatic through symptomatic stages, and the development of powerful interventions that can slow or reverse AD amyloid pathology. We review the current status of prevention trials and propose key areas of needed research as a call to basic and translational scientists to accelerate AD prevention. Specifically, we review (1) sporadic and dominantly inherited primary and secondary AD prevention trials, (2) proposed targets, mechanisms, and drugs including the amyloid, tau, and inflammatory pathways and combination treatments, (3) the need for more appropriate prevention animal models and experiments, and (4) biomarkers and outcome measures needed to design human asymptomatic prevention trials. We conclude with actions needed to effectively move prevention targets and trials forward.
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http://dx.doi.org/10.1186/s13024-021-00467-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8293489PMC
July 2021

Medullary thyroid cancer: What is the optimal management of the lateral neck in a node negative patient at index operation?

Surgery 2021 Jul 18. Epub 2021 Jul 18.

Department of Surgery, Mayo Clinic, Rochester, MN. Electronic address:

Background: Medullary thyroid cancer is a neuroendocrine malignancy that can occur sporadically or as the result of genomic rearranged during transfection mutations. Medullary thyroid cancer has a higher rate of metastasis than well-differentiated thyroid cancer. Lateral neck dissection is often performed, and its prophylactic use is controversial.

Methods: Single-center, retrospective review (2000-2017) of patients undergoing primary surgical treatment for medullary thyroid cancer who had negative lateral neck imaging preoperatively. Demographics, genetic associations, clinical, and imaging findings were analyzed. Locoregional recurrence, overall recurrence, and overall survival were examined.

Results: A total of 110 patients were identified, of which 18 underwent prophylactic lateral neck dissection and 92 did not. Age, sex distribution, preoperative calcitonin levels, and follow-up were similar among groups. Overall recurrence was 20% for no prophylactic lateral neck dissection and 39% for prophylactic lateral neck dissection (P = .46). Most recurrences were locoregional recurrence, 7.6% for no prophylactic lateral neck dissection versus 22% for prophylactic lateral neck dissection (P = .08), half of it being to the lateral neck in both groups. A total of 7 patients from the no prophylactic lateral neck dissection group required treatment for recurrences versus 4 patients in prophylactic lateral neck dissection group (P = .57). Overall survival at 5 years was similar, 43% the no prophylactic lateral neck dissection group and 31% for prophylactic lateral neck dissection group (P = .52).

Conclusion: Lateral neck dissection has no effect in decreasing locoregional or overall recurrences in medullary thyroid cancer and has no effect in overall survival when performed prophylactically at index surgical intervention.
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http://dx.doi.org/10.1016/j.surg.2021.04.052DOI Listing
July 2021

Pattern and degree of individual brain atrophy predicts dementia onset in dominantly inherited Alzheimer's disease.

Alzheimers Dement (Amst) 2021 5;13(1):e12197. Epub 2021 Jul 5.

The Florey Institute University of Melbourne Parkville Victoria Australia.

Introduction: Asymptomatic and mildly symptomatic dominantly inherited Alzheimer's disease mutation carriers (DIAD-MC) are ideal candidates for preventative treatment trials aimed at delaying or preventing dementia onset. Brain atrophy is an early feature of DIAD-MC and could help predict risk for dementia during trial enrollment.

Methods: We created a dementia risk score by entering standardized gray-matter volumes from 231 DIAD-MC into a logistic regression to classify participants with and without dementia. The score's predictive utility was assessed using Cox models and receiver operating curves on a separate group of 65 DIAD-MC followed longitudinally.

Results: Our risk score separated asymptomatic versus demented DIAD-MC with 96.4% (standard error = 0.02) and predicted conversion to dementia at next visit (hazard ratio = 1.32, 95% confidence interval [CI: 1.15, 1.49]) and within 2 years (area under the curve = 90.3%, 95% CI [82.3%-98.2%]) and improved prediction beyond established methods based on familial age of onset.

Discussion: Individualized risk scores based on brain atrophy could be useful for establishing enrollment criteria and stratifying DIAD-MC participants for prevention trials.
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http://dx.doi.org/10.1002/dad2.12197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256623PMC
July 2021

Genomic atlas of the proteome from brain, CSF and plasma prioritizes proteins implicated in neurological disorders.

Nat Neurosci 2021 Jul 8. Epub 2021 Jul 8.

Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.

Understanding the tissue-specific genetic controls of protein levels is essential to uncover mechanisms of post-transcriptional gene regulation. In this study, we generated a genomic atlas of protein levels in three tissues relevant to neurological disorders (brain, cerebrospinal fluid and plasma) by profiling thousands of proteins from participants with and without Alzheimer's disease. We identified 274, 127 and 32 protein quantitative trait loci (pQTLs) for cerebrospinal fluid, plasma and brain, respectively. cis-pQTLs were more likely to be tissue shared, but trans-pQTLs tended to be tissue specific. Between 48.0% and 76.6% of pQTLs did not co-localize with expression, splicing, DNA methylation or histone acetylation QTLs. Using Mendelian randomization, we nominated proteins implicated in neurological diseases, including Alzheimer's disease, Parkinson's disease and stroke. This first multi-tissue study will be instrumental to map signals from genome-wide association studies onto functional genes, to discover pathways and to identify drug targets for neurological diseases.
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http://dx.doi.org/10.1038/s41593-021-00886-6DOI Listing
July 2021

A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer's disease.

Nat Med 2021 Jul 21;27(7):1187-1196. Epub 2021 Jun 21.

University of Alabama at Birmingham School of Medicine, Birmingham, AL, USA.

Dominantly inherited Alzheimer's disease (DIAD) causes predictable biological changes decades before the onset of clinical symptoms, enabling testing of interventions in the asymptomatic and symptomatic stages to delay or slow disease progression. We conducted a randomized, placebo-controlled, multi-arm trial of gantenerumab or solanezumab in participants with DIAD across asymptomatic and symptomatic disease stages. Mutation carriers were assigned 3:1 to either drug or placebo and received treatment for 4-7 years. The primary outcome was a cognitive end point; secondary outcomes included clinical, cognitive, imaging and fluid biomarker measures. Fifty-two participants carrying a mutation were assigned to receive gantenerumab, 52 solanezumab and 40 placebo. Both drugs engaged their Aβ targets but neither demonstrated a beneficial effect on cognitive measures compared to controls. The solanezumab-treated group showed a greater cognitive decline on some measures and did not show benefits on downstream biomarkers. Gantenerumab significantly reduced amyloid plaques, cerebrospinal fluid total tau, and phospho-tau181 and attenuated increases of neurofilament light chain. Amyloid-related imaging abnormalities edema was observed in 19.2% (3 out of 11 were mildly symptomatic) of the gantenerumab group, 2.5% of the placebo group and 0% of the solanezumab group. Gantenerumab and solanezumab did not slow cognitive decline in symptomatic DIAD. The asymptomatic groups showed no cognitive decline; symptomatic participants had declined before reaching the target doses.
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http://dx.doi.org/10.1038/s41591-021-01369-8DOI Listing
July 2021

GPS driving: a digital biomarker for preclinical Alzheimer disease.

Alzheimers Res Ther 2021 06 14;13(1):115. Epub 2021 Jun 14.

Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA.

Background: Alzheimer disease (AD) is the most common cause of dementia. Preclinical AD is the period during which early AD brain changes are present but cognitive symptoms have not yet manifest. The presence of AD brain changes can be ascertained by molecular biomarkers obtained via imaging and lumbar puncture. However, the use of these methods is limited by cost, acceptability, and availability. The preclinical stage of AD may have a subtle functional signature, which can impact complex behaviours such as driving. The objective of the present study was to evaluate the ability of in-vehicle GPS data loggers to distinguish cognitively normal older drivers with preclinical AD from those without preclinical AD using machine learning methods.

Methods: We followed naturalistic driving in cognitively normal older drivers for 1 year with a commercial in-vehicle GPS data logger. The cohort included n = 64 individuals with and n = 75 without preclinical AD, as determined by cerebrospinal fluid biomarkers. Four Random Forest (RF) models were trained to detect preclinical AD. RF Gini index was used to identify the strongest predictors of preclinical AD.

Results: The F1 score of the RF models for identifying preclinical AD was 0.85 using APOE ε4 status and age only, 0.82 using GPS-based driving indicators only, 0.88 using age and driving indicators, and 0.91 using age, APOE ε4 status, and driving. The area under the receiver operating curve for the final model was 0.96.

Conclusion: The findings suggest that GPS driving may serve as an effective and accurate digital biomarker for identifying preclinical AD among older adults.
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http://dx.doi.org/10.1186/s13195-021-00852-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204509PMC
June 2021

Blocking the Thyrotropin Receptor with K1-70 in a Patient with Follicular Thyroid Cancer, Graves' Disease, and Graves' Ophthalmopathy.

Thyroid 2021 Jul 8. Epub 2021 Jul 8.

AV7 Limited, FIRS Laboratories, Cardiff, United Kingdom.

We report the therapeutic use of K1-70™, a thyrotropin receptor (TSHR) antagonist monoclonal antibody, in a patient with follicular thyroid cancer (FTC), Graves' disease (GD), and Graves' ophthalmopathy (GO). A 51-year-old female patient, who smoked, presented in October 2014 with FTC complicated by GD, high levels of TSHR autoantibodies with high thyroid stimulating antibody (TSAb) activity, and severe GO. K1-70 was administered at 3 weekly intervals with the dose adjusted to block TSAb activity. Her cancer was managed with lenvatinib and radioiodine therapy. Following initiation of K1-70 therapy, TSAb activity measured in serum decreased and GO (proptosis and inflammation) improved. On K1-70 monotherapy during the pause in lenvatinib, several metastatic lesions stabilized while others showed progression attenuation compared with that before lenvatinib therapy. These observations suggest that blocking TSHR stimulation with K1-70 can be an effective treatment for GO and may also benefit select patients with FTC and GD.
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http://dx.doi.org/10.1089/thy.2021.0053DOI Listing
July 2021

Dynamic Amyloid PET: Relationships to Flortaucipir Tau PET Measures.

J Nucl Med 2021 May 28. Epub 2021 May 28.

University of Alabama at Birmingham (UAB), United States.

Measuring amyloid and predicting tau status using a single amyloid positron emission tomography (PET) study would be valuable for assessing brain AD pathophysiology. We hypothesized that early-frame amyloid PET (efAP) correlates with the presence of tau pathology because the initial regional brain concentrations of radioactivity are primarily determined by blood flow, which is expected to be decreased in the setting of tau pathology. 120 participants (63 amyloid-positive/57 amyloid-negative) with dynamic F-florbetapir-PET and static F-flortaucipir-PET scans obtained within 6 months of each other were included. These subjects were predominantly cognitively intact in both the amyloid positive (63%) and amyloid negative (93%) groups. Parameters for efAP quantification were optimized for stratification of tau PET positivity, assessed by either a tauopathy score or Braak regions. The ability of efAP to stratify tau positivity was measured using receiver operating characteristics (ROC) analysis of area under the curve (AUC). Pearson's r and Spearman's ρ were used for parametric and non-parametric comparisons between efAP and tau PET, respectively. Standardized net benefit was used to evaluate improvement in utilizing efAP as an additional co-predictor over hippocampal volumes in predicting tau PET positivity. Measuring efAP within the hippocampus and summing the first 3 minutes of brain activity post-injection showed the strongest discriminative ability to stratify for tau positivity (AUC 0.67-0.89 across tau PET Braak regions) in amyloid positive individuals. Hippocampal efAP correlated significantly with a global tau-PET tauopathy score in amyloid-positive participants (r = -0.57, < 0.0001). Compared to hippocampal volumes, hippocampal efAP showed stronger association with tau PET Braak stage (ρ = -0.58 vs. -0.37) and superior stratification of tau PET tauopathy score (AUC: 0.86 vs. 0.66, = 0.002). Hippocampal efAP can provide additional information to conventional amyloid-PET, including estimation of the likelihood of tau positivity in amyloid-positive individuals.
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http://dx.doi.org/10.2967/jnumed.120.254490DOI Listing
May 2021

Undetected Neurodegenerative Disease Biases Estimates of Cognitive Change in Older Adults.

Psychol Sci 2021 Jun 27;32(6):849-860. Epub 2021 May 27.

Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University in St. Louis.

Neurodegenerative disease is highly prevalent among older adults and, if undetected, may obscure estimates of cognitive change among aging samples. Our aim in this study was to determine the nature and magnitude of cognitive change in the absence of common neuropathologic markers of neurodegenerative disease. Cognitively normal older adults (ages 65-89 years, = 199) were classified as normal or abnormal using neuroimaging and cerebrospinal-fluid biomarkers of β-amyloid, tau, and neurodegeneration. When cognitive change was modeled without accounting for biomarker status, significant decline was evident for semantic memory, processing speed, and working memory. However, after adjusting for biomarker status, we found that the rate of change was attenuated and that the biomarker-normal group demonstrated no decline for any cognitive domain. These results indicate that estimates of cognitive change in otherwise healthy older adults will be biased toward decline when the presence of early neurodegenerative disease is not accounted for.
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http://dx.doi.org/10.1177/0956797620985518DOI Listing
June 2021

Network dysfunction in cognitively normal APOE ε4 carriers is related to subclinical tau.

Alzheimers Dement 2021 May 18. Epub 2021 May 18.

Department of Neurology, Washington University in Saint Louis, Saint Louis, Missouri, USA.

Introduction: Apolipoprotein E (APOE) ε4 allele status is associated with amyloid and tau-related pathological changes related to Alzheimer's disease (AD). However, it is unknown whether brain network changes are related to amyloid beta (Aβ) and/or tau-related pathology in cognitively normal APOE ε4 carriers with subthreshold Aβ accumulation.

Methods: Resting state functional connectivity measures of network integrity were evaluated in cognitively normal individuals (n = 121, mean age 76.6 ± 7.8 years, 15% APOE ε4 carriers, 65% female) with minimal Aβ per cerebrospinal fluid (CSF) or amyloid positron emission tomography.

Results: APOE ε4 carriers had increased lateralized connections relative to callosal connections within the default-mode, memory, and salience networks (P = .02), with significant weighting on linear regression toward CSF total tau (P = .03) and CSF phosphorylated tau at codon 181 (P = .03), but not CSF Aβ .

Discussion: Cognitively normal APOE ε4 carriers with subthreshold amyloid accumulation may have network reorganization associated with tau.
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http://dx.doi.org/10.1002/alz.12375DOI Listing
May 2021

Temporal Correlation of CSF and Neuroimaging in the Amyloid-Tau-Neurodegeneration Model of Alzheimer Disease.

Neurology 2021 07 30;97(1):e76-e87. Epub 2021 Apr 30.

From the Departments of Neurology (A.H.B., J.K.W., O.H.B., S.E.S., C.S., A.M.F., J.C.M., B.M.A.) and Radiology (C.D.C., B.A.G., S.F., A.D., T.L.S.B.), Washington University in St. Louis, MO.

Objective: To evaluate temporal correlations between CSF and neuroimaging (PET and MRI) measures of amyloid, tau, and neurodegeneration in relation to Alzheimer disease (AD) progression.

Methods: A total of 371 cognitively unimpaired and impaired participants enrolled in longitudinal studies of AD had both CSF (β-amyloid [Aβ], phosphorylated tau, total tau, and neurofilament light chain) and neuroimaging (Pittsburgh compound B [PiB] PET, flortaucipir PET, and structural MRI) measures. The pairwise time interval between CSF and neuroimaging measures was binned into 2-year periods. Spearman correlations identified the time bin when CSF and neuroimaging measures most strongly correlated. CSF and neuroimaging measures were then binarized as biomarker-positive or biomarker-negative using Gaussian mixture modeling. Cohen kappa coefficient identified the time bin when CSF measures best agreed with corresponding neuroimaging measures when determining amyloid, tau, and neurodegeneration biomarker positivity.

Results: CSF Aβ and PiB PET showed maximal correlation when collected within 6 years of each other ( ≈ -0.5). CSF phosphorylated tau and flortaucipir PET showed maximal correlation when CSF was collected 4 to 8 years prior to PET ( ≈ 0.4). CSF neurofilament light chain and cortical thickness showed low correlation, regardless of time interval ( ≈ -0.3). Similarly, CSF total tau and cortical thickness had low correlation, regardless of time interval ( < -0.2).

Conclusions: CSF Aβ and PiB PET best agree when acquired in close temporal proximity, whereas CSF phosphorylated tau precedes flortaucipir PET by 4 to 8 years. CSF and neuroimaging measures of neurodegeneration have low correspondence and are not interchangeable at any time interval.
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http://dx.doi.org/10.1212/WNL.0000000000012123DOI Listing
July 2021

African Americans Have Differences in CSF Soluble TREM2 and Associated Genetic Variants.

Neurol Genet 2021 Apr 4;7(2):e571. Epub 2021 Mar 4.

Department of Neurology (S.E.S., A.J., R.L.H., R.J.M., L.P., J.J.L.-G., K.L.M., A.M.F., D.M.H., J.C.M.), Department of Psychiatry (C.C., F.H.G.F.), and Division of Biostatistics (L.M., C.X.), Washington University School of Medicine, St. Louis, MO; Office of Health Equity and Department of Medicine (C.H.W.), Division of Geriatrics, Vanderbilt University Medical Center, Nashville, TN; Department of Internal Medicine (C.H.W.), Meharry Medical College, Nashville, TN; Alzheimers Disease Research Center (Y.D.), University of Wisconsin School of Medicine and Public Health, Madison; Brain and Mind Centre (L.P.), University of Sydney, NSW, Australia; and Mallinckrodt Institute of Radiology (B.M.A., T.L.S.B.), Washington University School of Medicine, St. Louis, MO.

Objective: To evaluate for racial differences in triggering receptor expressed on myeloid cells 2 (TREM2), a key immune mediator in Alzheimer disease, the levels of CSF soluble TREM2 (sTREM2), and the frequency of associated genetic variants were compared in groups of individuals who self-reported their race as African American (AA) or non-Hispanic White (NHW).

Methods: Community-dwelling older research participants underwent measurement of CSF sTREM2 concentrations and genetic analyses.

Results: The primary cohort included 91 AAs and 868 NHWs. CSF sTREM2 levels were lower in the AA compared with the NHW group (1,336 ± 470 vs 1,856 ± 624 pg/mL, < 0.0001). AAs were more likely to carry coding variants (15% vs 3%, < 0.0001), which were associated with lower CSF sTREM2. AAs were less likely to carry the rs1582763 minor allele (8% vs 37%, < 0.0001), located near , which was associated with higher CSF sTREM2. These findings were replicated in an independent cohort of 23 AAs and 917 NHWs: CSF sTREM2 levels were lower in the AA group ( = 0.03), AAs were more likely to carry coding variants (22% vs 4%, = 0.002), and AAs were less likely to carry the rs1582763 minor allele (16% vs 37%, = 0.003).

Conclusions: On average, AAs had lower CSF sTREM2 levels compared with NHWs, potentially because AAs are more likely to carry genetic variants associated with lower CSF sTREM2 levels. Importantly, CSF sTREM2 reflects TREM2-mediated microglial activity, a critical step in the immune response to amyloid plaques. These findings suggest that race may be associated with risk for genetic variants that influence Alzheimer disease-related inflammation.
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http://dx.doi.org/10.1212/NXG.0000000000000571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054965PMC
April 2021

Plasma Amyloid-Beta Levels in a Pre-Symptomatic Dutch-Type Hereditary Cerebral Amyloid Angiopathy Pedigree: A Cross-Sectional and Longitudinal Investigation.

Int J Mol Sci 2021 Mar 13;22(6). Epub 2021 Mar 13.

Department of Biomedical Sciences, Macquarie University, North Ryde, NSW 2109, Australia.

Plasma amyloid-beta (Aβ) has long been investigated as a blood biomarker candidate for Cerebral Amyloid Angiopathy (CAA), however previous findings have been inconsistent which could be attributed to the use of less sensitive assays. This study investigates plasma Aβ alterations between pre-symptomatic Dutch-type hereditary CAA (D-CAA) mutation-carriers (MC) and non-carriers (NC) using two Aβ measurement platforms. Seventeen pre-symptomatic members of a D-CAA pedigree were assembled and followed up 3-4 years later (NC = 8; MC = 9). Plasma Aβ1-40 and Aβ1-42 were cross-sectionally and longitudinally analysed at baseline (T1) and follow-up (T2) and were found to be lower in MCs compared to NCs, cross-sectionally after adjusting for covariates, at both T1(Aβ1-40: = 0.001; Aβ1-42: = 0.0004) and T2 (Aβ1-40: = 0.001; Aβ1-42: = 0.016) employing the Single Molecule Array (Simoa) platform, however no significant differences were observed using the xMAP platform. Further, pairwise longitudinal analyses of plasma Aβ1-40 revealed decreased levels in MCs using data from the Simoa platform ( = 0.041) and pairwise longitudinal analyses of plasma Aβ1-42 revealed decreased levels in MCs using data from the xMAP platform ( = 0.041). Findings from the Simoa platform suggest that plasma Aβ may add value to a panel of biomarkers for the diagnosis of pre-symptomatic CAA, however, further validation studies in larger sample sets are required.
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http://dx.doi.org/10.3390/ijms22062931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000178PMC
March 2021

Prospective Quantification of CSF Biomarkers in Antibody-Mediated Encephalitis.

Neurology 2021 05 1;96(20):e2546-e2557. Epub 2021 Apr 1.

From the Department of Neurology (G.S.D., A.S.L.-C., N.R.G.-R.), Mayo Clinic, Jacksonville, FL; Departments of Pathology and Immunology (M.Y.Y., E.M.H., J.H.L.) and Neurology (R.C.B., R.L.H., E.M.H., J.H.L., J.C.M., A.F.) and The Charles F. and Joanne Knight Alzheimer Disease Research Center (R.L.H., J.C.M., A.F.), Washington University School of Medicine, St. Louis, MO; Department of Neurology (P.M.D.K.), University of Magdeburg; Department of Neurology and Experimental Neurology (P.M.D.K., H.P.) Charité, Universitätmedizin Berlin, Germany; Department of Medicine (M.J.F.), Cumming School of Medicine, University of Calgary; Department of Medicine (W.M., D.F.T.-W., J.H.), Division of Neurology, University of Toronto, Canada; and NYU Langone Comprehensive Epilepsy Center (C.S.), NYU Langone Health, New York, NY.

Objective: To determine whether neuronal and neuroaxonal injury, neuroinflammation, and synaptic dysfunction associate with clinical course and outcomes in antibody-mediated encephalitis (AME), we measured biomarkers of these processes in CSF from patients presenting with AME and cognitively normal individuals.

Methods: Biomarkers of neuronal (total tau, VILIP-1) and neuroaxonal damage (neurofilament light chain [NfL]), inflammation (YKL-40), and synaptic function (neurogranin, SNAP-25) were measured in CSF obtained from 45 patients at the time of diagnosis of NMDA receptor (n = 34) or / (n = 11) AME and 39 age- and sex-similar cognitively normal individuals. The association between biomarkers and modified Rankin Scale (mRS) scores were evaluated in a subset (n = 20) of longitudinally followed patients.

Results: Biomarkers of neuroaxonal injury (NfL) and neuroinflammation (YKL-40) were elevated in AME cases at presentation, whereas markers of neuronal injury and synaptic function were stable (total tau) or decreased (VILIP-1, SNAP-25, neurogranin). The log-transformed ratio of YKL-40/SNAP-25 optimally discriminated patients from cognitively normal individuals (area under the receiver operating characteristic curve 0.99; 95% confidence interval 0.97, >0.99). Younger age (ρ = -0.56; = 0.01), lower VILIP-1 (ρ = -0.60; < 0.01) and SNAP-25 (ρ = -0.54; = 0.01), and higher log(YKL-40/SNAP-25) (ρ = 0.48; = 0.04) associated with greater disease severity (higher mRS score) in prospectively followed patients. Higher YKL-40 (ρ = 0.60; = 0.02) and neurogranin (ρ = 0.55; = 0.03) at presentation were associated with higher mRS scores 12 months following hospital discharge.

Conclusions: CSF biomarkers suggest that neuronal integrity is acutely maintained in AME, despite neuroaxonal compromise. Low levels of biomarkers of synaptic function may reflect antibody-mediated internalization of cell surface receptors and may represent an acute correlate of antibody-mediated synaptic dysfunction, with the potential to inform disease severity and outcomes.
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http://dx.doi.org/10.1212/WNL.0000000000011937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205475PMC
May 2021

Cognitively normal APOE ε4 carriers have specific elevation of CSF SNAP-25.

Neurobiol Aging 2021 Jun 11;102:64-72. Epub 2021 Feb 11.

Department of Neurology, Washington University, Saint Louis, MO, USA; Knight Alzheimer Disease Research Center, Washington University, St. Louis, MO, USA. Electronic address:

Cerebrospinal fluid (CSF) synaptosomal-associated protein 25 (SNAP-25) and neurogranin (Ng) are recently described biomarkers for pre- and postsynaptic integrity known to be elevated in symptomatic Alzheimer disease (AD). Their relationship with Apolipoprotein E (APOE) ε4 carrier status, the major genetic risk factor for AD, remains unclear. In this study, CSF SNAP-25 and Ng were compared in cognitively normal APOE ε4 carriers and noncarriers (n = 274, mean age 65 ± 9.0 years, 39% APOE ε4 carriers, 58% female). CSF SNAP-25, not CSF Ng, was specifically elevated in APOE ε4 carriers versus noncarriers (5.95 ± 1.72 pg/mL, 4.44 ± 1.40 pg/mL, p < 0.0001), even after adjusting for age, sex, years of education, and amyloid status (p < 0.0001). CSF total tau (t-tau), phosphorylated-tau-181 (ptau181), and neurofilament light chain (NfL) also did not vary by APOE ε4 status. Our findings suggest APOE ε4 carriers have amyloid-related and amyloid-independent presynaptic disruption as reflected by elevated CSF SNAP-25 levels. In contrast, postsynaptic disruption as reflected by elevations in CSF neurogranin is related to amyloid status.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.02.008DOI Listing
June 2021

Segregation of functional networks is associated with cognitive resilience in Alzheimer's disease.

Brain 2021 Mar 16. Epub 2021 Mar 16.

Dementia Research Centre, University College London, Queen Square, London, UK.

Cognitive resilience is an important modulating factor of cognitive decline in Alzheimer's disease, but the functional brain mechanisms that support cognitive resilience remain elusive. Given previous findings in normal aging, we tested the hypothesis that higher segregation of the brain's connectome into distinct functional networks represents a functional mechanism underlying cognitive resilience in Alzheimer's disease. Using resting-state functional MRI, we assessed both resting-state-fMRI global system segregation, i.e. the balance of between-network to within-network connectivity, and the alternate index of modularity Q as predictors of cognitive resilience. We performed all analyses in two independent samples for validation: First, we included 108 individuals with autosomal dominantly inherited Alzheimer's disease and 71 non-carrier controls. Second, we included 156 amyloid-PET positive subjects across the spectrum of sporadic Alzheimer's disease as well as 184 amyloid-negative controls. In the autosomal dominant Alzheimer's disease sample, disease severity was assessed by estimated years from symptom onset. In the sporadic Alzheimer's sample, disease stage was assessed by temporal-lobe tau-PET (i.e. composite across Braak stage I & III regions). In both samples, we tested whether the effect of disease severity on cognition was attenuated at higher levels of functional network segregation. For autosomal dominant Alzheimer's disease, we found higher fMRI-assessed system segregation to be associated with an attenuated effect of estimated years from symptom onset on global cognition (p = 0.007). Similarly, for sporadic Alzheimer's disease patients, higher fMRI-assessed system segregation was associated with less decrement in global cognition (p = 0.001) and episodic memory (p = 0.004) per unit increase of temporal lobe tau-PET. Confirmatory analyses using the alternate index of modularity Q revealed consistent results. In conclusion, higher segregation of functional connections into distinct large-scale networks supports cognitive resilience in Alzheimer's disease.
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http://dx.doi.org/10.1093/brain/awab112DOI Listing
March 2021

Comparison of single-channel EEG, actigraphy, and sleep diary in cognitively normal and mildly impaired older adults.

Sleep Adv 2020 24;1(1):zpaa006. Epub 2020 Oct 24.

Department of Neurology, Washington University School of Medicine, St Louis, MO.

Study Objectives: Multiple methods for monitoring sleep-wake activity have identified sleep disturbances as risk factors for Alzheimer disease (AD). In order to identify the level of agreement between different methods, we compared sleep parameters derived from single-channel EEG (scEEG), actigraphy, and sleep diaries in cognitively normal and mildly impaired older adults.

Methods: Two hundred ninety-three participants were monitored at home for up to six nights with scEEG, actigraphy, and sleep diaries. Total sleep time (TST), sleep efficiency (SE), sleep onset latency (SOL), and wake after sleep onset (WASO) were calculated using each of these methods. In 109 of the 293 participants, the ratio of cerebrospinal fluid concentrations of phosphorylated tau (p-tau) and amyloid-β-42 (Aβ42) was used as a biomarker for AD pathology.

Results: Agreement was highest for TST across instruments, especially in cognitively normal older adults. Overall, scEEG and actigraphy appeared to have greater agreement for multiple sleep parameters than for scEEG and diary or actigraphy and diary. Levels of agreement between scEEG and actigraphy overall decreased in mildly impaired participants and those with biomarker evidence of AD pathology, especially for measurements of TST.

Conclusions: Caution should be exercised when comparing scEEG and actigraphy in individuals with mild cognitive impairment or with AD pathology. Sleep diaries may capture different aspects of sleep compared to scEEG and actigraphy. Additional studies comparing different methods of measuring sleep-wake activity in older adults are necessary to allow for comparison between studies using different methods.
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http://dx.doi.org/10.1093/sleepadvances/zpaa006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898727PMC
October 2020

Spatially constrained kinetic modeling with dual reference tissues improves F-flortaucipir PET in studies of Alzheimer disease.

Eur J Nucl Med Mol Imaging 2021 Feb 18. Epub 2021 Feb 18.

Mallinckrodt Institute of Radiology, Washington University School of Medicine, Campus Box 8225, 510 S. Kingshighway Blvd, St Louis, MO, 63110, USA.

Purpose: Recent studies have shown that standard compartmental models using plasma input or the cerebellum reference tissue input are generally not reliable for quantifying tau burden in dynamic F-flortaucipir PET studies of Alzheimer disease. So far, the optimal reference region for estimating F-flortaucipir delivery and specific tau binding has yet to be determined. The objective of the study is to improve F-flortaucipir brain tau PET quantification using a spatially constrained kinetic model with dual reference tissues.

Methods: Participants were classified as either cognitively normal (CN) or cognitively impaired (CI) based on clinical assessment. T1-weighted structural MRI and 105-min dynamic F-flortaucipir PET scans were acquired for each participant. Using both a simplified reference tissue model (SRTM2) and Logan plot with either cerebellum gray matter or centrum semiovale (CS) white matter as the reference tissue, we estimated distribution volume ratios (DVRs) and the relative transport rate constant R for region of interest-based (ROI) and voxelwise-based analyses. Conventional linear regression (LR) and LR with spatially constrained (LRSC) parametric imaging algorithms were then evaluated. Noise-induced bias in the parametric images was compared to estimates from ROI time activity curve-based kinetic modeling. We finally evaluated standardized uptake value ratios at early phase (SUVR, 0.7-2.9 min) and late phase (SUVR, 80-105 min) to approximate R and DVR, respectively.

Results: The percent coefficients of variation of R and DVR estimates from SRTM2 with spatially constrained modeling were comparable to those from the Logan plot and SUVRs. The SRTM2 using CS reference tissue with LRSC reduced noise-induced underestimation in the LR generated DVR images to negligible levels (< 1%). Inconsistent overestimation of DVR in the SUVR only occurred using the cerebellum reference tissue-based measurements. The CS reference tissue-based DVR and SUVR, and cerebellum-based SUVR and R provided higher Cohen's effect size d to detect increased tau deposition and reduced relative tracer transport rate in CI individuals.

Conclusion: Using a spatially constrained kinetic model with dual reference tissues significantly improved quantification of relative perfusion and tau binding. Cerebellum and CS are the suggested reference tissues to estimate R and DVR, respectively, for dynamic F-flortaucipir PET studies. Cerebellum-based SUVR and CS-based SUVR may be used to simplify F-flortaucipir PET study.
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http://dx.doi.org/10.1007/s00259-020-05134-wDOI Listing
February 2021

Lack of evidence supporting a role for DPP6 sequence variants in Alzheimer's disease in the European American population.

Acta Neuropathol 2021 04 16;141(4):623-624. Epub 2021 Feb 16.

Department Psychiatry, Washington University School of Medicine (WUSM), 660 S. Euclid Ave. B8134, St. Louis, MO, 63110, USA.

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http://dx.doi.org/10.1007/s00401-021-02271-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952336PMC
April 2021

Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture.

Nat Genet 2021 03 15;53(3):294-303. Epub 2021 Feb 15.

Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, University College London, London, UK.

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.
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http://dx.doi.org/10.1038/s41588-021-00785-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946812PMC
March 2021

The ideological divide in confidence in science and participation in medical research.

Sci Rep 2021 Feb 4;11(1):3120. Epub 2021 Feb 4.

Washington University in St. Louis, St. Louis, USA.

In the United States, the wide ideological divergence in public confidence in science poses a potentially significant problem for the scientific enterprise. We examine the behavioral consequences of this ideological divide for Americans' contributions to medical research. Based on a mass survey of American adults, we find that engagement in a wide range of medical research activities is a function of a latent propensity to participate. The propensity is systematically higher among liberals than among conservatives. A substantial part of this ideological divide is due to conservative Americans' lower confidence in science. These findings raise important issues for the recruitment of subjects for medical studies and the generalizability of results from such studies.
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http://dx.doi.org/10.1038/s41598-021-82516-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862386PMC
February 2021

Lack of association between acute stroke, post-stroke dementia, race, and β-amyloid status.

Neuroimage Clin 2021 5;29:102553. Epub 2021 Jan 5.

Department of Neurology, Washington University School of Medicine, St. Louis, MO USA. Electronic address:

Introduction: Stroke and Alzheimer disease share risk factors and often co-occur, and both have been reported to have a higher prevalence in African Americans as compared to non-Hispanic whites. However, their interaction has not been established. The objective of this study was to determine if preclinical Alzheimer disease is a risk factor for stroke and post-stroke dementia and whether racial differences moderate this relationship.

Methods: This case-control study was analyzed in 2019 using retrospective data from 2007 to 2013. Participants were adults age 65 and older with and without acute ischemic stroke. Recruitment included word of mouth and referrals in Saint Louis, MO, with stroke participants recruited from acutely hospitalized patients and non-stroke participants from community living older adults who were research volunteers. Our assessment included radiologic reads of infarcts, microbleeds, and white matter hyperintensitites (WMH); a Pittsburgh Compound B PET measure of cortical β-amyloid binding; quantitative measures of hippocampal and WMH volume; longitudinal Mini Mental State Examination (MMSE) scores; and Clinical Dementia Rating (CDR) 1 year post-stroke.

Results: A total of 243 participants were enrolled, 81 of which had a recent ischemic stroke. Participants had a mean age of 75, 57% were women, and 52% were African American. Cortical amyloid did not differ significantly by race, stroke status, or CDR post-stroke. There were racial differences in MMSE scores at baseline (mean 26.8 for African Americans, 27.9 for non-Hispanic whites, p = 0.03), but not longitudinally. African Americans were more likely to have microbleeds (32.8% vs 22.6%, p = 0.04), and within the acute stroke group, African Americans were more likely to have small infarcts (75.6% vs 56.8%, p = 0.049).

Conclusion: Preclinical Alzheimer disease did not show evidence of being a risk factor for stroke nor predictive of post-stroke dementia. We did not observe racial differences in β-amyloid levels. However, even after controlling for several vascular risk factors, African Americans with clinical stroke presentations had greater levels of vascular pathology on MRI.
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http://dx.doi.org/10.1016/j.nicl.2020.102553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848631PMC
June 2021

Longitudinal Accumulation of Cerebral Microhemorrhages in Dominantly Inherited Alzheimer Disease.

Neurology 2021 03 25;96(12):e1632-e1645. Epub 2021 Jan 25.

From the Departments of Radiology (N.J.-M., T.M.B., B.A.G., G.C., P.M., R.C.H., T.L.S.B.), Neurology (E.M., J.H., B.M.A., R.J.P., J.C.M., R.J.B.), Psychological and Brain Sciences (J.H.), Psychiatry (C.C., C.M.K.), and Pathology and Immunology (R.J.P.) and Division of Biostatistics (G.W., C.X.), Washington University School of Medicine, St. Louis, MO; Banner Alzheimers Institute (Y.S.), Phoenix, AZ; Department of Cognitive Neurology and Neuropsychology (R.F.A.), Instituto de Investigaciones Neurológicas Fleni, Buenos Aires, Argentina; Departments of Neurology and Clinical and Translational Science (S.B.B.), University of Pittsburgh School of Medicine, PA; Department of Neurology (A.M.B.), Taub Institute for Research on Alzheimers Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY; Neuroscience Research Australia (W.S.B., P.R.S.); School of Medical Sciences (P.R.S.), University of New South Wales (W.S.B.), Sydney, Australia; Dementia Research Centre and UK Dementia Research Institute (D.M.C., N.C.F., A.O.), UCL Queen Square Institute of Neurology, London, UK; Departments of Neurology (J.P.C., K.A.J.) and Radiology (K.A.J.), Massachusetts General Hospital, Boston; Department of Neurology (H.C.C., J.M.R.), Keck School of Medicine of USC, Los Angeles, CA; Department of Psychiatry and Human Behavior (S.C., A.K.W.L., S.S.), Memory and Aging Program, Butler Hospital, Brown University Alpert Medical School, Providence, RI; Center for Neuroimaging, Department of Radiology and Imaging Science (M.R.F., A.J.S.), Department of Pathology and Laboratory Medicine (B.G.), and Indiana Alzheimers Disease Research Center (A.J.S.), Indiana University School of Medicine, Indianapolis; Departments of Molecular Imaging and Neurology (M.F.), Royal Prince Alfred Hospital, University of Sydney, Australia; Department of Neurology (N.R.G.-R.), Mayo Clinic, Jacksonville, FL; German Center for Neurodegenerative Diseases (DZNE) (C.L., J.L., I.Y.); Section for Dementia Research, Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy (C.L.), University of Tübingen; Department of Neurology (J.L., I.Y.), Ludwig-Maximilians-Universität München; Munich Cluster for Systems Neurology (SyNergy) (J.L., I.Y.), Germany; Florey Institute and The University of Melbourne (C.L.M.), Australia; Department of Neurology (J.M.N.), Columbia University Irving Medical Center, New York, NY; Department of Radiology (K.K., C.R.J., G.M.P.), Mayo Clinic, Rochester, MN; Department of Molecular Imaging and Therapy (C.C.R., V.L.V.), Austin Health, University of Melbourne, Heidelberg, Australia; Clinical Research Center for Dementia (H.S.), Osaka City University; Department of Neurology (M.S.), Hirosaki University Graduate School of Medicine; and Department of Neurology (K.S.), The University of Tokyo, Japan.

Objective: To investigate the inherent clinical risks associated with the presence of cerebral microhemorrhages (CMHs) or cerebral microbleeds and characterize individuals at high risk for developing hemorrhagic amyloid-related imaging abnormality (ARIA-H), we longitudinally evaluated families with dominantly inherited Alzheimer disease (DIAD).

Methods: Mutation carriers (n = 310) and noncarriers (n = 201) underwent neuroimaging, including gradient echo MRI sequences to detect CMHs, and neuropsychological and clinical assessments. Cross-sectional and longitudinal analyses evaluated relationships between CMHs and neuroimaging and clinical markers of disease.

Results: Three percent of noncarriers and 8% of carriers developed CMHs primarily located in lobar areas. Carriers with CMHs were older, had higher diastolic blood pressure and Hachinski ischemic scores, and more clinical, cognitive, and motor impairments than those without CMHs. ε4 status was not associated with the prevalence or incidence of CMHs. Prevalent or incident CMHs predicted faster change in Clinical Dementia Rating although not composite cognitive measure, cortical thickness, hippocampal volume, or white matter lesions. Critically, the presence of 2 or more CMHs was associated with a significant risk for development of additional CMHs over time (8.95 ± 10.04 per year).

Conclusion: Our study highlights factors associated with the development of CMHs in individuals with DIAD. CMHs are a part of the underlying disease process in DIAD and are significantly associated with dementia. This highlights that in participants in treatment trials exposed to drugs, which carry the risk of ARIA-H as a complication, it may be challenging to separate natural incidence of CMHs from drug-related CMHs.
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http://dx.doi.org/10.1212/WNL.0000000000011542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032370PMC
March 2021

Clinical and Paraclinical Measures Associated with Outcome in Cerebral Amyloid Angiopathy with Related Inflammation.

J Alzheimers Dis 2021 ;80(1):133-142

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

Background: Cerebral amyloid angiopathy with related inflammation (CAA-ri) is a rare age-associated disorder characterized by an inflammatory response to amyloid in cerebral blood vessels. CAA-ri is often treated with corticosteroids, but response to treatment is variable.

Objective: To assess the relationship between clinical and paraclinical measures and outcomes in patients with CAA-ri treated with high doses of methylprednisolone.

Methods: Longitudinal clinical course, and results from serum and cerebrospinal fluid (CSF) testing, electroencephalography, and neuroimaging were reviewed from 11 prospectively-accrued CAA-ri patients diagnosed, treated, and followed at Barnes Jewish Hospital (St. Louis, MO, USA). Magnetic resonance imaging (MRI) changes were quantified using a scoring system validated in cases of amyloid related imaging abnormality (ARIA-E). Clinical outcomes were assessed as change in modified Rankin Scale (ΔmRS) from baseline to final assessment (median 175 days from treatment with high doses of methylprednisolone; range, 31-513).

Results: Worse outcomes following methylprednisolone treatment were associated with requirement for intensive care unit admission (median ΔmRS, 5 versus 1.5; p = 0.048), CSF pleocytosis (median ΔmRS 4.5 versus 1; p = 0.04), or lower CSF Aβ40 at presentation (rho = -0.83; p = 0.02), and diffusion restriction (median ΔmRS 4 versus 1.5; p = 0.03) or higher late ARIA-E scores (rho = 0.70; p = 0.02) on MRI, but not preexisting cognitive decline (median ΔmRS 2 versus 2; p = 0.66).

Conclusion: Clinical and paraclinical measures associated with outcomes may inform clinical counseling and treatment decisions in patients with CAA-ri. Baseline cognitive status was not associated with treatment responsiveness.
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http://dx.doi.org/10.3233/JAD-201299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7965250PMC
January 2021

Early neuroinflammation is associated with lower amyloid and tau levels in cognitively normal older adults.

Brain Behav Immun 2021 05 22;94:299-307. Epub 2021 Jan 22.

Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, United States; Alzheimer Disease Research Center, Department of Neurology, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, United States. Electronic address:

CNS inflammation is a key factor in Alzheimer's Disease (AD), but its relation to pathological Aβ, tau, and APOE4 is poorly understood, particularly prior to the onset of cognitive symptoms. To better characterize early relationships between inflammation, APOE4, and AD pathology, we assessed correlations between cerebrospinal fluid (CSF) inflammatory markers and brain levels of Aβ and tau in cognitively normal older adults. Each participant received a lumbar puncture to collect and quantify CSF levels of TNFα, IL-6, IL-8, and IL-10, a T1-weighted MRI, and PET scanning with [F]flortaucipir (FTP; n = 57), which binds to tau tangles and/or [F]florbetapir (FBP; n = 58), which binds to Aβ. Parallel voxelwise regressions assessed relationships between each CSF inflammatory marker and FTP and FBP SUVR, as well as APOE4*CSF inflammation interactions. Unexpectedly, we detected significant negative associations between regional Aβ and tau PET uptake and CSF inflammatory markers. For Aβ PET, we detected negative associations with CSF IL-6 and IL-8 in regions known to show early accumulation of Aβ (i.e. lateral and medial frontal lobes). For tau PET, negative relationships were observed with CSF TNFα and IL-8, predominantly in regions known to exhibit early tau accumulation (i.e. medial temporal lobe). In subsequent analyses, significant interactions between APOE4 status and IL-8 on Aβ and tau PET levels were observed in spatially distinct regions from those showing CSF-Aβ/tau relationships. Results from the current cross-sectional study support previous findings that neuroinflammation may be protective against AD pathology at a given stage of the disease, and extend these findings to a cognitively normal aging population. This study provides new insight into a dynamic relationship between neuroinflammation and AD pathology and may have implications for whom and when neuroinflammatory therapies may be appropriate.
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http://dx.doi.org/10.1016/j.bbi.2021.01.010DOI Listing
May 2021

Modeling autosomal dominant Alzheimer's disease with machine learning.

Alzheimers Dement 2021 06 21;17(6):1005-1016. Epub 2021 Jan 21.

German Center for Neurodegenerative Diseases, Munich, Germany.

Introduction: Machine learning models were used to discover novel disease trajectories for autosomal dominant Alzheimer's disease.

Methods: Longitudinal structural magnetic resonance imaging, amyloid positron emission tomography (PET), and fluorodeoxyglucose PET were acquired in 131 mutation carriers and 74 non-carriers from the Dominantly Inherited Alzheimer Network; the groups were matched for age, education, sex, and apolipoprotein ε4 (APOE ε4). A deep neural network was trained to predict disease progression for each modality. Relief algorithms identified the strongest predictors of mutation status.

Results: The Relief algorithm identified the caudate, cingulate, and precuneus as the strongest predictors among all modalities. The model yielded accurate results for predicting future Pittsburgh compound B (R  = 0.95), fluorodeoxyglucose (R  = 0.93), and atrophy (R  = 0.95) in mutation carriers compared to non-carriers.

Discussion: Results suggest a sigmoidal trajectory for amyloid, a biphasic response for metabolism, and a gradual decrease in volume, with disease progression primarily in subcortical, middle frontal, and posterior parietal regions.
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http://dx.doi.org/10.1002/alz.12259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195816PMC
June 2021

Drivers of the Decision to Biopsy and Follow-Up of Small Suspicious Thyroid Nodules.

Endocr Pract 2020 Aug;26(8):857-868

From the Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, Minnesota. Electronic address:

Objective: In 2015, the updated American Thyroid Association (ATA) guidelines recommended observation for suspicious subcentimeter thyroid nodules, based on their indolent course. We aimed to evaluate the frequency of biopsy in suspicious thyroid nodules since the introduction of these guidelines, including factors contributing to clinical decision-making in a tertiary care center.

Methods: We conducted a retrospective study of patients in the Mayo Clinic, Rochester, Minnesota, with new, subcentimeter suspicious thyroid nodules (by report or by sonographic features) between March, 2015, and November, 2017, not previously biopsied.

Results: We identified 141 nodules in 129 patients: mean age 58.1±14.1 years, 74% female, 87% Caucasian. The frequency of biopsy in suspicious thyroid nodules was 39%. Ultrasound features that were the strongest predictors for biopsy on multivariate analysis included: nodule volume (odds ratio [OR] 37.3 [7.5-188.7]), radiology recommendation for biopsy (OR 2.6 [1.8-3.9]) and radiology report of the nodule as "suspicious" (OR 2.1 [1.4-3.2]). Patient's age and degree of comorbidities did not change the likelihood for biopsy, nor did it vary by clinician type or how the nodule was initially found (incidentally or not incidentally). Among 86 nodules that were not biopsied, 41% had no specific follow-up recommendations.

Conclusion: One third of suspicious thyroid nodules underwent biopsy since the release of updated ATA guidelines. Factors driving thyroid biopsy seem to be associated with nodule characteristics but not with patient factors including age and comorbidities. Further studies and development of decision aides may be helpful in providing individualized approaches for suspicious thyroid nodules.

Abbreviations: ATA = American Thyroid Association; OR = odds ratio.
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http://dx.doi.org/10.4158/EP-2019-0590DOI Listing
August 2020

Obesity and White Matter Neuroinflammation Related Edema in Alzheimer's Disease Dementia Biomarker Negative Cognitively Normal Individuals.

J Alzheimers Dis 2021 ;79(4):1801-1811

Mallinckrodt Institute of Radiology, Division of Neuroradiology, Washington University in St. Louis, St. Louis, MO, USA.

Background: Obesity is related to quantitative neuroimaging abnormalities including reduced gray matter volumes and impaired white matter microstructural integrity, although the underlying mechanisms are not well understood.

Objective: We assessed influence of obesity on neuroinflammation imaging that may mediate brain morphometric changes. Establishing the role of neuroinflammation in obesity will enhance understanding of this modifiable disorder as a risk factor for Alzheimer's disease (AD) dementia.

Methods: We analyzed brain MRIs from 104 cognitively normal participants (CDR = 0) and biomarker negativity for CSF amyloid or tau. We classified body mass index (BMI) as normal (BMI <25, N = 62) or overweight and obese (BMI ≥25, N = 42). Blood pressure was measured. BMI and blood pressure classifications were related to neuroinflammation imaging (NII) derived edema fraction in 17 white matter tracts. This metric was also correlated to hippocampal volumes and CSF biomarkers of inflammation and neurodegeneration: YKL-40, SNAP25, VILIP, tau, and NFL.

Results: Participants with BMI <25 had lower NII-derived edema fraction, with protective effects of normal blood pressure. Statistically significant white matter tracts included the internal capsule, external capsule, and corona radiata, FDR correc-ted for multiple comparisons to alpha = 0.05. Higher NII-derived edema fractions in the internal capsule, corpus callosum, gyrus, and superior fronto-occipital fasciculus were related with smaller hippocampal volumes only in individuals with BMI ≥25. There were no statistically significant correlations between NII-derived edema fraction and CSF biomarkers.

Conclusion: We demonstrate statistically significant relationships between neuroinflammation, elevated BMI, and hippocampal volume, raising implications for neuroinflammation mechanisms of obesity-related brain dysfunction in cognitively normal elderly.
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http://dx.doi.org/10.3233/JAD-201242DOI Listing
January 2021

Resting-State Functional Connectivity Disruption as a Pathological Biomarker in Autosomal Dominant Alzheimer Disease.

Brain Connect 2021 Apr 31;11(3):239-249. Epub 2021 Mar 31.

Department of Neurology, Washington University in Saint Louis, St. Louis, Missouri, USA.

Identify a global resting-state functional connectivity (gFC) signature in mutation carriers (MC) from the Dominantly Inherited Alzheimer Network (DIAN). Assess the gFC with regard to amyloid (A), tau (T), and neurodegeneration (N) biomarkers, and estimated years to symptom onset (EYO). Cross-sectional measures were assessed in MC ( = 171) and mutation noncarrier (NC) ( = 70) participants. A functional connectivity (FC) matrix that encompassed multiple resting-state networks was computed for each participant. A global FC was compiled as a single index indicating FC strength. The gFC signature was modeled as a nonlinear function of EYO. The gFC was linearly associated with other biomarkers used for assessing the AT(N) framework, including cerebrospinal fluid (CSF), positron emission tomography (PET) molecular biomarkers, and structural magnetic resonance imaging. The gFC was reduced in MC compared with NC participants. When MC participants were differentiated by clinical dementia rating (CDR), the gFC was significantly decreased in MC CDR >0 (demented) compared with either MC CDR 0 (cognitively normal) or NC participants. The gFC varied nonlinearly with EYO and initially decreased at EYO = -24 years, followed by a stable period followed by a further decline near EYO = 0 years. Irrespective of EYO, a lower gFC associated with values of amyloid PET, CSF Aβ, CSF p-tau, CSF t-tau, 18F-fluorodeoxyglucose, and hippocampal volume. The gFC correlated with biomarkers used for defining the AT(N) framework. A biphasic change in the gFC suggested early changes associated with CSF amyloid and later changes associated with hippocampal volume.
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http://dx.doi.org/10.1089/brain.2020.0808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8182476PMC
April 2021

Comparing cortical signatures of atrophy between late-onset and autosomal dominant Alzheimer disease.

Neuroimage Clin 2020 5;28:102491. Epub 2020 Nov 5.

Department of Radiology, Department of Neurology, Department of Psychiatry, Department of Pathology and Immunology, Division of Biostatistics, Washington University School of Medicine, Saint Louis, MO, USA.

Defining a signature of cortical regions of interest preferentially affected by Alzheimer disease (AD) pathology may offer improved sensitivity to early AD compared to hippocampal volume or mesial temporal lobe alone. Since late-onset Alzheimer disease (LOAD) participants tend to have age-related comorbidities, the younger-onset age in autosomal dominant AD (ADAD) may provide a more idealized model of cortical thinning in AD. To test this, the goals of this study were to compare the degree of overlap between the ADAD and LOAD cortical thinning maps and to evaluate the ability of the ADAD cortical signature regions to predict early pathological changes in cognitively normal individuals. We defined and analyzed the LOAD cortical maps of cortical thickness in 588 participants from the Knight Alzheimer Disease Research Center (Knight ADRC) and the ADAD cortical maps in 269 participants from the Dominantly Inherited Alzheimer Network (DIAN) observational study. Both cohorts were divided into three groups: cognitively normal controls (n = 381; n = 145), preclinical (n = 153; n = 76), and cognitively impaired (n = 54; n = 48). Both cohorts underwent clinical assessments, 3T MRI, and amyloid PET imaging with either C-Pittsburgh compound B or F-florbetapir. To generate cortical signature maps of cortical thickness, we performed a vertex-wise analysis between the cognitively normal controls and impaired groups within each cohort using six increasingly conservative statistical thresholds to determine significance. The optimal cortical map among the six statistical thresholds was determined from a receiver operating characteristic analysis testing the performance of each map in discriminating between the cognitively normal controls and preclinical groups. We then performed within-cohort and cross-cohort (e.g. ADAD maps evaluated in the Knight ADRC cohort) analyses to examine the sensitivity of the optimal cortical signature maps to the amyloid levels using only the cognitively normal individuals (cognitively normal controls and preclinical groups) in comparison to hippocampal volume. We found the optimal cortical signature maps were sensitive to early increases in amyloid for the asymptomatic individuals within their respective cohorts and were significant beyond the inclusion of hippocampus volume, but the cortical signature maps performed poorly when analyzing across cohorts. These results suggest the cortical signature maps are a useful MRI biomarker of early AD-related neurodegeneration in preclinical individuals and the pattern of decline differs between LOAD and ADAD.
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http://dx.doi.org/10.1016/j.nicl.2020.102491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689410PMC
June 2021
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