Publications by authors named "James B Leverenz"

183 Publications

Mediterranean and Western diet effects on Alzheimer's disease biomarkers, cerebral perfusion, and cognition in mid-life: A randomized trial.

Alzheimers Dement 2021 Jul 26. Epub 2021 Jul 26.

Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

Introduction: Mid-life dietary patterns are associated with Alzheimer's disease (AD) risk, although few controlled trials have been conducted.

Methods: Eighty-seven participants (age range: 45 to 65) with normal cognition (NC, n = 56) or mild cognitive impairment (MCI, n = 31) received isocaloric diets high or low in saturated fat, glycemic index, and sodium (Western-like/West-diet vs. Mediterranean-like/Med-diet) for 4 weeks. Diet effects on cerebrospinal fluid (CSF) biomarkers, cognition, and cerebral perfusion were assessed to determine whether responses differed by cognitive status.

Results: CSF amyloid beta (Aβ) ratios increased following the Med-diet, and decreased after West-diet for NC adults, whereas the MCI group showed the reverse pattern. For the MCI group, the West-diet reduced and the Med-diet increased total tau (t-tau), whereas CSF Aβ /t-tau ratios increased following the West-diet and decreased following the Med-diet. For NC participants, the Med-diet increased and the West-diet decreased cerebral perfusion.

Discussion: Diet response during middle age may highlight early pathophysiological processes that increase AD risk.
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http://dx.doi.org/10.1002/alz.12421DOI Listing
July 2021

Temporal Ordering of Inflammatory Analytes sTNFR2 and sTREM2 in Relation to Alzheimer's Disease Biomarkers and Clinical Outcomes.

Front Aging Neurosci 2021 29;13:676744. Epub 2021 Jun 29.

Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, United States.

Inflammatory changes are among the key markers of Alzheimer's disease (AD) related pathological changes. Pro-inflammatory analytes have been related to cognitive decline while others have been related to attenuating neuronal death. Among them, changes in cerebrospinal fluid (CSF) levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2) and soluble tumor necrosis factor receptor 2 (sTNFR2) have been described as impacting favorable clinical outcomes in AD. We therefore evaluate the effect of CSF sTREM2 and sTNFR2 when taken together on AD biomarkers and longitudinal clinical decline to understand their relative role on impacting AD clinical biomarkers and subsequent clinical outcomes. This longitudinal observational cohort study included 168 amyloid-positive (A+) and p-tau-positive (T+) participants with mild cognitive impairment (MCI) or AD dementia from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with 109 of them having concomitant CSF sTREM2 and sTNFR2 data and 48 A+ T+ participants with MCI from a tertiary memory clinic cohort. An exploratory analysis was performed using data from 86 cognitively normal (CN) participants from ADNI with 72 of them having concomitant CSF AD biomarkers and CSF sTREM2 and sTNFR2 data. General linear models were used to evaluate the effect of sTREM2 and sTNFR2 levels on baseline CSF Aβ42, t-tau, and p-tau, and a linear mixed-effects model was used to assess longitudinal cognitive change after controlling for well-known covariates. Among ADNI A+ T+ MCI and AD dementia participants, CSF sTNFR2 had a stronger association, than CSF sTREM2, with CSF t-tau and p-tau. This was replicated among A+ T+ MCI participants from the memory clinic cohort. On the contrary, among A+ T+ CN participants, CSF sTREM2 explained significant variance in CSF t-tau and p-tau, while CSF sTNFR2 did not. When the effects of CSF sTNFR2 and t-tau on longitudinal cognitive change were taken into account, higher CSF sTREM2 predicted slower cognitive decline in A+ T+ AD dementia participants and faster decline in A+ T+ CN participants. Our results show that given the dynamic changes in sTREM2 and sTNFR2, the clinical impact of these distinct inflammation related biomarkers in tracking AD temporal progression across disease stages are likely to differ.
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http://dx.doi.org/10.3389/fnagi.2021.676744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279003PMC
June 2021

Lewy Body Dementia Association's Industry Advisory Council: proceedings of the second annual meeting.

Alzheimers Res Ther 2021 07 8;13(1):124. Epub 2021 Jul 8.

Lewy Body Dementia Association, S.W, Lilburn, GA, USA.

In 2019, the Lewy Body Dementia Association formed an Industry Advisory Council to bring together a collaborative group of stakeholders with the goal of accelerating clinical research into Lewy body dementia treatments. At the second annual meeting of the Industry Advisory Council, held virtually on June 18, 2020, the key members presented ongoing and planned efforts toward the council's goals. The meeting also featured a discussion about the effects of the COVID-19 pandemic on Lewy body dementia clinical research, lessons learned from that experience, and how those lessons can be applied to the design and conduct of future clinical trials. This report provides a brief summary of the meeting proceedings with a focus on efforts to improve and adapt future Lewy body dementia clinical research.
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http://dx.doi.org/10.1186/s13195-021-00868-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265285PMC
July 2021

Network medicine links SARS-CoV-2/COVID-19 infection to brain microvascular injury and neuroinflammation in dementia-like cognitive impairment.

Alzheimers Res Ther 2021 06 9;13(1):110. Epub 2021 Jun 9.

Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.

Background: Dementia-like cognitive impairment is an increasingly reported complication of SARS-CoV-2 infection. However, the underlying mechanisms responsible for this complication remain unclear. A better understanding of causative processes by which COVID-19 may lead to cognitive impairment is essential for developing preventive and therapeutic interventions.

Methods: In this study, we conducted a network-based, multimodal omics comparison of COVID-19 and neurologic complications. We constructed the SARS-CoV-2 virus-host interactome from protein-protein interaction assay and CRISPR-Cas9-based genetic assay results and compared network-based relationships therein with those of known neurological manifestations using network proximity measures. We also investigated the transcriptomic profiles (including single-cell/nuclei RNA-sequencing) of Alzheimer's disease (AD) marker genes from patients infected with COVID-19, as well as the prevalence of SARS-CoV-2 entry factors in the brains of AD patients not infected with SARS-CoV-2.

Results: We found significant network-based relationships between COVID-19 and neuroinflammation and brain microvascular injury pathways and processes which are implicated in AD. We also detected aberrant expression of AD biomarkers in the cerebrospinal fluid and blood of patients with COVID-19. While transcriptomic analyses showed relatively low expression of SARS-CoV-2 entry factors in human brain, neuroinflammatory changes were pronounced. In addition, single-nucleus transcriptomic analyses showed that expression of SARS-CoV-2 host factors (BSG and FURIN) and antiviral defense genes (LY6E, IFITM2, IFITM3, and IFNAR1) was elevated in brain endothelial cells of AD patients and healthy controls relative to neurons and other cell types, suggesting a possible role for brain microvascular injury in COVID-19-mediated cognitive impairment. Overall, individuals with the AD risk allele APOE E4/E4 displayed reduced expression of antiviral defense genes compared to APOE E3/E3 individuals.

Conclusion: Our results suggest significant mechanistic overlap between AD and COVID-19, centered on neuroinflammation and microvascular injury. These results help improve our understanding of COVID-19-associated neurological manifestations and provide guidance for future development of preventive or treatment interventions, although causal relationship and mechanistic pathways between COVID-19 and AD need future investigations.
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http://dx.doi.org/10.1186/s13195-021-00850-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189279PMC
June 2021

High resolution structural and functional MRI of the hippocampus in young adults with Down syndrome.

Brain Commun 2021 19;3(2):fcab088. Epub 2021 Apr 19.

Department of Pediatrics, Case Western Reserve University, Cleveland, OH 44106, USA.

Down syndrome is the phenotypic consequence of trisomy 21, with clinical presentation including both neurodevelopmental and neurodegenerative components. Although the intellectual disability typically displayed by individuals with Down syndrome is generally global, it also involves disproportionate deficits in hippocampally-mediated cognitive processes. Hippocampal dysfunction may also relate to Alzheimer's disease-type pathology, which can appear in as early as the first decade of life and becomes universal by age 40. Using 7-tesla MRI of the brain, we present an assessment of the structure and function of the hippocampus in 34 individuals with Down syndrome (mean age 24.5 years ± 6.5) and 27 age- and sex-matched typically developing healthy controls. In addition to increased whole-brain mean cortical thickness and lateral ventricle volumes (<1.0 × 10), individuals with Down syndrome showed selective volume reductions in bilateral hippocampal subfields cornu Ammonis field 1, dentate gyrus, and tail (<0.005). In the group with Down syndrome, bilateral hippocampi showed widespread reductions in the strength of functional connectivity, predominately to frontal regions (<0.02). Age was not related to hippocampal volumes or functional connectivity measures in either group, but both groups showed similar relationships of age to whole-brain volume measures (<0.05). Finally, we performed an exploratory analysis of a subgroup of individuals with Down syndrome with both imaging and neuropsychological assessments. This analysis indicated that measures of spatial memory were related to mean cortical thickness, total grey matter volume and right hemisphere hippocampal subfield volumes ( < 0.02). This work provides a first demonstration of the usefulness of high-field MRI to detect subtle differences in structure and function of the hippocampus in individuals with Down syndrome, and suggests the potential for development of MRI-derived measures as surrogate markers of drug efficacy in pharmacological studies designed to investigate enhancement of cognitive function.
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http://dx.doi.org/10.1093/braincomms/fcab088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100000PMC
April 2021

The Application of Zonisamide to Patients Suffering from Dementia with Lewy Bodies: Emerging Clinical Data.

Drug Des Devel Ther 2021 3;15:1811-1817. Epub 2021 May 3.

Lou Ruvo Center for Brain Health, Cleveland Clinic, Cleveland, OH, USA.

Zonisamide is an anti-epileptic medication with multiple mechanisms of action and a favorable safety profile. Zonisamide may interact with Lewy body dementia pathophysiology through a mechanism unrelated to its original indication. Zonisamide has shown efficacy as adjunct therapy for the management of motor symptoms in patients with Parkinson's disease (PD). Given that dementia with Lewy bodies (DLB) and PD are considered subtypes of a Lewy body disease spectrum, zonisamide was investigated for the treatment of parkinsonism in DLB. Phase II and phase III clinical trials were conducted in patients with DLB in Japan. In both studies, participants were randomized to receive 12 weeks of zonisamide 25 or 50 mg/day or placebo. Zonisamide significantly improved the Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) without affecting the Mini-Mental State Examination (MMSE) or Neuropsychiatry Inventory-10 (NPI-10) scores at week 12. In 2018, zonisamide received Japanese regulatory approval for the additional indication of parkinsonism in DLB. This review discusses the emerging clinical data on zonisamide in the field of DLB.
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http://dx.doi.org/10.2147/DDDT.S240865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106402PMC
May 2021

Hypertension and Hypercholesterolemia Modify Dementia Risk in Relation to APOEɛ4 Status.

J Alzheimers Dis 2021 ;81(4):1493-1504

Lou Ruvo Center for Brain Health, Cleveland Clinic, Cleveland, OH, USA.

Background: There is significant interest in understanding the role of modifiable vascular risk factors contributing to dementia risk across age groups.

Objective: Risk of dementia onset was assessed in relation to vascular risk factors of hypertension and hypercholesterolemia among cognitively normal APOEɛ4 carriers and non-carriers.

Methods: In a sample of prospectively characterized longitudinal cohort from the National Alzheimer's Coordinating Center database, 9,349 participants met criteria for normal cognition at baseline, had a CDR-Global (CDR-G) score of zero, and had concomitant data on APOEɛ4 status and medical co-morbidities including histories of hypertension and hypercholesterolemia. Multivariable Cox proportional hazards models adjusted for well-known potential confounders were used to compare dementia onset among APOEɛ4 carriers and non-carriers by young (≤65 years) and old (> 65 year) age groups.

Results: 519 participants converted to dementia within an average follow up of 5.97 years. Among older APOEɛ4 carriers, hypercholesterolemia was related to lower risk of dementia (HR (95% CI), 0.68 (0.49-0.94), p = 0.02). Among older APOEɛ4 non-carriers, hypertension was related to higher risk of dementia (HR (95% CI), 1.44 (1.13-1.82), p = 0.003). These results were corroborated among a subset with autopsy data characterizing underlying neuropathology. Among younger participants, vascular risk factors did not impact dementia risk, likely from a lower frequency of vascular and Alzheimer's as etiologies of dementia among this cohort.

Conclusion: A history of hypercholesterolemia related to a lower risk of dementia among older APOEɛ4 carriers, while hypertension related to a higher risk of dementia among older APOEɛ4 non-carriers.
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http://dx.doi.org/10.3233/JAD-201609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239808PMC
January 2021

Unique Sleep and Circadian Rhythm Dysfunction Neuroinflammatory and Immune Profiles in Alzheimer's Disease with Mild Cognitive Impairment.

J Alzheimers Dis 2021 ;81(2):487-492

Sleep Disorders Center, Neurologic Institute, Cleveland Clinic, Cleveland, OH, USA.

Sleep dysfunction has been identified in the pathophysiology of Alzheimer's disease (AD); however, the role and mechanism of circadian rhythm dysfunction is less well understood. In a well-characterized cohort of patients with AD at the mild cognitive impairment stage (MCI-AD), we identify that circadian rhythm irregularities were accompanied by altered humoral immune responses detected in both the cerebrospinal fluid and plasma as well as alterations of cerebrospinal fluid biomarkers of neurodegeneration. On the other hand, sleep disruption was more so associated with abnormalities in circulating markers of immunity and inflammation and decrements in cognition.
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http://dx.doi.org/10.3233/JAD-201573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8179975PMC
January 2021

Network medicine links SARS-CoV-2/COVID-19 infection to brain microvascular injury and neuroinflammation in dementia-like cognitive impairment.

bioRxiv 2021 Mar 22. Epub 2021 Mar 22.

Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

Background: Dementia-like cognitive impairment is an increasingly reported complication of SARS-CoV-2 infection. However, the underlying mechanisms responsible for this complication remain unclear. A better understanding of causative processes by which COVID-19 may lead to cognitive impairment is essential for developing preventive interventions.

Methods: In this study, we conducted a network-based, multimodal genomics comparison of COVID-19 and neurologic complications. We constructed the SARS-CoV-2 virus-host interactome from protein-protein interaction assay and CRISPR-Cas9 based genetic assay results, and compared network-based relationships therein with those of known neurological manifestations using network proximity measures. We also investigated the transcriptomic profiles (including single-cell/nuclei RNA-sequencing) of Alzheimer's disease (AD) marker genes from patients infected with COVID-19, as well as the prevalence of SARS-CoV-2 entry factors in the brains of AD patients not infected with SARS-CoV-2.

Results: We found significant network-based relationships between COVID-19 and neuroinflammation and brain microvascular injury pathways and processes which are implicated in AD. We also detected aberrant expression of AD biomarkers in the cerebrospinal fluid and blood of patients with COVID-19. While transcriptomic analyses showed relatively low expression of SARS-CoV-2 entry factors in human brain, neuroinflammatory changes were pronounced. In addition, single-nucleus transcriptomic analyses showed that expression of SARS-CoV-2 host factors ( and ) and antiviral defense genes ( , , , and ) was significantly elevated in brain endothelial cells of AD patients and healthy controls relative to neurons and other cell types, suggesting a possible role for brain microvascular injury in COVID-19-mediated cognitive impairment. Notably, individuals with the AD risk allele E4/E4 displayed reduced levels of antiviral defense genes compared to E3/E3 individuals.

Conclusion: Our results suggest significant mechanistic overlap between AD and COVID-19, strongly centered on neuroinflammation and microvascular injury. These results help improve our understanding of COVID-19-associated neurological manifestations and provide guidance for future development of preventive or treatment interventions.
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http://dx.doi.org/10.1101/2021.03.15.435423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010732PMC
March 2021

Gene Variants and Related Soluble TNFR2 Levels Impact Resilience in Alzheimer's Disease.

Front Aging Neurosci 2021 25;13:638922. Epub 2021 Feb 25.

Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, United States.

Tumor necrosis factor receptor 2 (TNFR2) promotes neuronal survival downstream. This longitudinal study evaluated whether the gene encoding TNFR2 and levels of its soluble form (sTNFR2) affect Alzheimer disease (AD) biomarkers and clinical outcomes. Data analyzed included 188 patients in the Alzheimer's Disease Neuroimaging Initiative (ADNI) who had mild cognitive impairment (MCI) and AD dementia. Further, a replication study was performed in 48 patients with MCI with positive AD biomarkers who were treated at a memory clinic. Cerebrospinal fluid (CSF) sTNFR2 levels along with two related gene single nucleotide polymorphisms (SNPs) rs976881 and rs1061622 were assessed. General linear models were used to evaluate the effect of CSF sTNFR2 levels and each SNP in relationship to CSF t-tau and p-tau, cognitive domains, MRI brain measures, and longitudinal cognitive changes after adjustments were made for covariates such as ε status. In the ADNI cohort, a significant interaction between rs976881 and CSF sTNFR2 modulates CSF t-tau and p-tau levels; hippocampal and whole brain volumes; and Digit Span Forwards subtest scores. In the replication cohort, a significant interaction between rs976881 and CSF sTNFR2 modulates CSF p-tau. A significant interaction between rs976881 and CSF sTNFR2 also impacts Clinical Dementia Rating Sum of Boxes scores over 12 months in the ADNI cohort. The interaction between variant rs976881 and CSF sTNFR2 levels was noted to modulate multiple AD-associated severity markers and cognitive domains. This interaction impacts resilience-related clinical outcomes in AD and lends support to sTNFR2 as a promising candidate for therapeutic targeting to improve clinical outcomes of interest.
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http://dx.doi.org/10.3389/fnagi.2021.638922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947258PMC
February 2021

Rasagiline effects on glucose metabolism, cognition, and tau in Alzheimer's dementia.

Alzheimers Dement (N Y) 2021 14;7(1):e12106. Epub 2021 Feb 14.

Cleveland Clinic Lou Ruvo Center for Brain Health Las Vegas Nevada USA.

Background: A Phase II proof of concept (POC) randomized clinical trial was conducted to evaluate the effects of rasagiline, a monoamine oxidase B (MAO-B) inhibitor approved for Parkinson disease, in mild to moderate Alzheimer's disease (AD). The primary objective was to determine if 1 mg of rasagiline daily for 24 weeks is associated with improved regional brain metabolism (fluorodeoxyglucose-positron emission tomography [FDG-PET]) compared to placebo. Secondary objectives included measurement of effects on tau PET and evaluation of directional consistency of clinical end points.

Methods: This was a double-blind, parallel group, placebo-controlled, community-based, three-site trial of 50 participants randomized 1:1 to receive oral rasagiline or placebo (NCT02359552). FDG-PET was analyzed for the presence of an AD-like pattern as an inclusion criterion and as a longitudinal outcome using prespecified regions of interest and voxel-based analyses. Tau PET was evaluated at baseline and longitudinally. Clinical outcomes were analyzed using an intention-to-treat (ITT) model.

Results: Fifty patients were randomized and 43 completed treatment. The study met its primary end point, demonstrating favorable change in FDG-PET differences in rasagiline versus placebo in middle frontal ( < 0.025), anterior cingulate ( < 0.041), and striatal ( < 0.023) regions. Clinical measures showed benefit in quality of life ( < 0.04). Digit Span, verbal fluency, and Neuropsychiatric Inventory (NPI) showed non-significant directional favoring of rasagiline; no effects were observed in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) or activities of daily living. Rasagiline was generally well tolerated with low rates of adverse events and notably fewer neuropsychiatric symptoms in the active treatment group.

Discussion: These outcomes illustrate the potential benefits of rasagiline on clinical and neuroimaging measures in patients with mild to moderate AD. Rasagiline appears to affect neuronal activity in frontostriatal pathways, with associated clinical benefit potential warranting a more fully powered trial. This study illustrated the potential benefit of therapeutic repurposing and an experimental medicine proof-of-concept design with biomarkers to characterize patient and detect treatment response.
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http://dx.doi.org/10.1002/trc2.12106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882538PMC
February 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

Impact of APOE ε4 genotype on initial cognitive symptoms differs for Alzheimer's and Lewy body neuropathology.

Alzheimers Res Ther 2021 01 23;13(1):31. Epub 2021 Jan 23.

Department of Neurology, Lou Ruvo Center for Brain Health, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, 9500 Euclid Ave / U10, Cleveland, OH, 44195, USA.

Background: APOE ε4 carrier status is known to increase odds of amnestic presentations with Alzheimer's pathology. It is unknown how APOE ε4 carrier status impacts odds of specific initial cognitive symptoms in the presence of Lewy body pathology. Here we evaluate the impact of APOE ε4 genotype on initial cognitive symptoms among those with Alzheimer's disease pathology (ADP) and Lewy-related pathology (LRP).

Methods: A retrospective cohort study of 2288 participants with neuropathology confirmed ADP or LRP in the National Alzheimer's Coordinating Center database, who had initial cognitive symptoms documented and had a Clinical Dementia Rating-Global (CDR-G) score ≤ 1 (cognitively normal, MCI, or early dementia). Unadjusted and adjusted logistic regression models taking into account age at evaluation, sex, and education examined the relationship between APOE ε4 genotype and initial symptoms (memory, executive, language visuospatial) among ADP with LRP and ADP-LRP groups.

Results: One thousand three hundred three participants met criteria for ADP alone, 90 for LRP alone, and 895 for co-existing ADP and LRP (ADP-LRP). Younger age increased odds of non-amnestic symptoms across all three groups. In the adjusted model among ADP, APOE ε4 carriers had higher odds of amnestic initial symptoms 1.5 [95% CI, 1.7-2.14, p = 0.003] and lower odds of initial language symptoms 0.67 [95% CI, 0.47-0.96, p = 0.03] than non-carriers. The odds for these two symptoms were not different between ADP and mixed ADP-LRP groups. Female sex and higher education increased odds of initial language symptoms in the ADP group in the adjusted model. In the unadjusted model, APOE ε4 carriers with LRP had a higher odds of visuospatial initial symptoms 21.96 [95% CI, 4.02-110.62, p < 0.0001], while no difference was noted for initial executive/attention symptoms. Among LRP, the odds of APOE ε4 on amnestic symptom was not significant; however, the interaction effect evaluating the difference in odds ratios of amnestic symptom between ADP and LRP groups also did not reach statistical significance.

Conclusions: The odds of specific initial cognitive symptoms differed between ADP and LRP among APOE ε4 carriers compared to non-carriers. The odds of initial amnestic symptom was higher among ADP APOE ε4 carriers and the odds of visuospatial initial symptom was higher with LRP APOE ε4 carriers. This supports the hypothesis that APOE ε4 differentially impacts initial cognitive symptoms together with underlying neuropathology.
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http://dx.doi.org/10.1186/s13195-021-00771-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825215PMC
January 2021

Amyloid Precursor Protein Variant, E665D, Associated With Unique Clinical and Biomarker Phenotype.

Am J Alzheimers Dis Other Demen 2021 Jan-Dec;36:1533317520981225

Lou Ruvo Center for Brain Health, Neurological Institute, 2569Cleveland Clinic, Cleveland, OH, USA.

We describe a clinical, imaging and biomarker phenotype associated with an amyloid precursor gene variant in a 45-year-old man with progressive cognitive and behavioral dysfunction. Brain MRI showed bilateral, confluent T2 hyperintensities predominantly in the anterior white matter. Amyloid imaging and CSF testing were consistent with amyloid deposition. 7 Tesla MRI revealed cerebral microhemorrhages suggestive of cerebral amyloid angiopathy (CAA). Contrary to previous reports, this case raises the possibility that the genetic change may be pathogenic, particularly given the abnormal Alzheimer's disease biomarkers observed in the cerebrospinal fluid, positive amyloid imaging and imaging evidence for CAA in a relatively young patient with progressive cognitive decline.
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http://dx.doi.org/10.1177/1533317520981225DOI Listing
April 2021

AlzGPS: a genome-wide positioning systems platform to catalyze multi-omics for Alzheimer's drug discovery.

Alzheimers Res Ther 2021 01 13;13(1):24. Epub 2021 Jan 13.

Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA.

Background: Recent DNA/RNA sequencing and other multi-omics technologies have advanced the understanding of the biology and pathophysiology of AD, yet there is still a lack of disease-modifying treatments for AD. A new approach to integration of the genome, transcriptome, proteome, and human interactome in the drug discovery and development process is essential for this endeavor.

Methods: In this study, we developed AlzGPS (Genome-wide Positioning Systems platform for Alzheimer's Drug Discovery, https://alzgps.lerner.ccf.org ), a comprehensive systems biology tool to enable searching, visualizing, and analyzing multi-omics, various types of heterogeneous biological networks, and clinical databases for target identification and development of effective prevention and treatment for AD.

Results: Via AlzGPS: (1) we curated more than 100 AD multi-omics data sets capturing DNA, RNA, protein, and small molecule profiles underlying AD pathogenesis (e.g., early vs. late stage and tau or amyloid endophenotype); (2) we constructed endophenotype disease modules by incorporating multi-omics findings and human protein-protein interactome networks; (3) we provided possible treatment information from ~ 3000 FDA approved/investigational drugs for AD using state-of-the-art network proximity analyses; (4) we curated nearly 300 literature references for high-confidence drug candidates; (5) we included information from over 1000 AD clinical trials noting drug's mechanisms-of-action and primary drug targets, and linking them to our integrated multi-omics view for targets and network analysis results for the drugs; (6) we implemented a highly interactive web interface for database browsing and network visualization.

Conclusions: Network visualization enabled by AlzGPS includes brain-specific neighborhood networks for genes-of-interest, endophenotype disease module networks for omics-of-interest, and mechanism-of-action networks for drugs targeting disease modules. By virtue of combining systems pharmacology and network-based integrative analysis of multi-omics data, AlzGPS offers actionable systems biology tools for accelerating therapeutic development in AD.
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http://dx.doi.org/10.1186/s13195-020-00760-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804907PMC
January 2021

Novel Alzheimer Disease Risk Loci and Pathways in African American Individuals Using the African Genome Resources Panel: A Meta-analysis.

JAMA Neurol 2021 01;78(1):102-113

Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York.

Importance: Compared with non-Hispanic White individuals, African American individuals from the same community are approximately twice as likely to develop Alzheimer disease. Despite this disparity, the largest Alzheimer disease genome-wide association studies to date have been conducted in non-Hispanic White individuals. In the largest association analyses of Alzheimer disease in African American individuals, ABCA7, TREM2, and an intergenic locus at 5q35 were previously implicated.

Objective: To identify additional risk loci in African American individuals by increasing the sample size and using the African Genome Resource panel.

Design, Setting, And Participants: This genome-wide association meta-analysis used case-control and family-based data sets from the Alzheimer Disease Genetics Consortium. There were multiple recruitment sites throughout the United States that included individuals with Alzheimer disease and controls of African American ancestry. Analysis began October 2018 and ended September 2019.

Main Outcomes And Measures: Diagnosis of Alzheimer disease.

Results: A total of 2784 individuals with Alzheimer disease (1944 female [69.8%]) and 5222 controls (3743 female [71.7%]) were analyzed (mean [SD] age at last evaluation, 74.2 [13.6] years). Associations with 4 novel common loci centered near the intracellular glycoprotein trafficking gene EDEM1 (3p26; P = 8.9 × 10-7), near the immune response gene ALCAM (3q13; P = 9.3 × 10-7), within GPC6 (13q31; P = 4.1 × 10-7), a gene critical for recruitment of glutamatergic receptors to the neuronal membrane, and within VRK3 (19q13.33; P = 3.5 × 10-7), a gene involved in glutamate neurotoxicity, were identified. In addition, several loci associated with rare variants, including a genome-wide significant intergenic locus near IGF1R at 15q26 (P = 1.7 × 10-9) and 6 additional loci with suggestive significance (P ≤ 5 × 10-7) such as API5 at 11p12 (P = 8.8 × 10-8) and RBFOX1 at 16p13 (P = 5.4 × 10-7) were identified. Gene expression data from brain tissue demonstrate association of ALCAM, ARAP1, GPC6, and RBFOX1 with brain β-amyloid load. Of 25 known loci associated with Alzheimer disease in non-Hispanic White individuals, only APOE, ABCA7, TREM2, BIN1, CD2AP, FERMT2, and WWOX were implicated at a nominal significance level or stronger in African American individuals. Pathway analyses strongly support the notion that immunity, lipid processing, and intracellular trafficking pathways underlying Alzheimer disease in African American individuals overlap with those observed in non-Hispanic White individuals. A new pathway emerging from these analyses is the kidney system, suggesting a novel mechanism for Alzheimer disease that needs further exploration.

Conclusions And Relevance: While the major pathways involved in Alzheimer disease etiology in African American individuals are similar to those in non-Hispanic White individuals, the disease-associated loci within these pathways differ.
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http://dx.doi.org/10.1001/jamaneurol.2020.3536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573798PMC
January 2021

High-resolution functional connectivity of the default mode network in young adults with down syndrome.

Brain Imaging Behav 2020 Oct 18. Epub 2020 Oct 18.

Lou Ruvo Center for Brain Health, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA.

Studies of resting-state functional connectivity MRI in Alzheimer's disease suggest that disease stage plays a role in functional changes of the default mode network. Individuals with the genetic disorder Down syndrome show an increased incidence of early-onset Alzheimer's-type dementia, along with early and nearly universal neuropathologic changes of Alzheimer's disease. The present study examined high-resolution functional connectivity of the default mode network in 11 young adults with Down syndrome that showed no measurable symptoms of dementia and 11 age- and sex-matched neurotypical controls. We focused on within-network connectivity of the default mode network, measured from both anterior and posterior aspects of the cingulate cortex. Sixty-eight percent of connections to the posterior cingulate and 26% to the anterior cingulate showed reduced strength in the group with Down syndrome (p < 0.01). The Down syndrome group showed increased connectivity strength from the anterior cingulate to the bilateral inferior frontal gyri and right putamen (p < 0.005). In an exploratory analysis, connectivity in the group with Down syndrome showed regional relationships to plasma measures of inflammatory markers and t-tau. In non-demented adults with Down syndrome, functional connectivity within the default mode network may be analogous to changes reported in preclinical Alzheimer's disease, and warrants further investigation as a measure of dementia risk.
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http://dx.doi.org/10.1007/s11682-020-00399-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053201PMC
October 2020

Biomarker Use for Dementia With Lewy Body Diagnosis: Survey of US Experts.

Alzheimer Dis Assoc Disord 2021 Jan-Mar 01;35(1):55-61

Department of Neurology, Comprehensive Center for Brain Health, University of Miami Miller School of Medicine, Miami, FL.

Background: Dementia with Lewy body (DLB) diagnostic criteria define "indicative" and "supportive" biomarkers, but clinical practice patterns are unknown.

Methods: An anonymous survey querying clinical use of diagnostic tests/biomarkers was sent to 38 center of excellence investigators. The survey included "indicative" biomarkers (dopamine transporter scan, myocardial scintigraphy, polysomnography), "supportive" biomarkers [magnetic resonance imaging (MRI)], positron emission tomography, or single-photon emission computed tomography perfusion/metabolism scans, quantitative electroencephalography), and other diagnostic tests (neuropsychological testing, cerebrospinal fluid analysis, genetics). Responses were analyzed descriptively.

Results: Of the 22 respondents (58%), all reported the capability to perform neuropsychological testing, MRI, polysomnography, dopamine transporter scans, positron emission tomography/single-photon emission computed tomography scans, and cerebrospinal fluid analysis; 96% could order genetic testing. Neuropsychological testing and MRI were the most commonly ordered tests. Diagnostic testing beyond MRI and neuropsychological testing was most helpful in the context of "possible" DLB and mild cognitive impairment and to assist with differential diagnosis. Myocardial scintigraphy and electroencephalograpy use were rare.

Conclusions And Relevance: Neuropsychological testing and MRI remain the most widely used diagnostic tests by DLB specialists. Other tests-particularly indicative biomarkers-are used only selectively. Research is needed to validate existing potential DLB biomarkers, develop new biomarkers, and investigate mechanisms to improve DLB diagnosis.
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http://dx.doi.org/10.1097/WAD.0000000000000414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904569PMC
June 2020

Correlation between brain volume and retinal photoreceptor outer segment volume in normal aging and neurodegenerative diseases.

PLoS One 2020 3;15(9):e0237078. Epub 2020 Sep 3.

The Tony and Leona Campane Center for Excellence in Image-guided Surgery and Advanced Imaging Research, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.

Purpose: To investigate the association between outer retinal layer metrics, including photoreceptor outer segment volume, on spectral-domain optical coherence tomography (OCT) and brain volume on MRI in normal aging, Alzheimer's disease and Parkinson's disease.

Methods: This was an exploratory analysis of a cross-sectional cohort study that was approved by the Cleveland Clinic Institutional Review Board to evaluate neurodegenerative disorders. Subjects aged ≥ 50 were recruited. A comprehensive neurological exam, brain MRI with volumetric evaluation, and OCT were performed for each subject. Outer retinal layer parameters, including ellipsoid zone (EZ) to retinal pigment epithelium (RPE) volume (i.e., surrogate for panmacular photoreceptor outer segment volume), were evaluated with a novel OCT analysis platform.

Results: Of 85 subjects, 64 eyes of 64 subjects met MRI and OCT quality control criteria. Total brain volume (%ICV) significantly correlated with EZ-RPE volume in the normal cognition control group (n = 31, Pearson correlation coefficient 0.514, P < .01), the Parkinson's disease group (n = 19, Pearson correlation coefficient 0.482, P = .04), and the Alzheimer's dementia group (n = 14, Pearson correlation coefficient 0.526, P = .05). Multiple linear regression analysis revealed that photoreceptor outer segment (i.e., EZ-RPE) volume was an independent, influential factor on total brain volume in all study subjects (Coefficient 15.2, 95% confidence interval 7.8-22.6, P < .001).

Conclusion: Outer retinal parameters on OCT may serve as a novel biomarker related to brain volume. This correlation was noted in control subjects suggesting a possible developmental link between retina and brain volume. This relationship was also maintained with atrophic neurodegenerative disorders. Further research is needed to explore possible threshold differences for underlying neurodegenerative disorders.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237078PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470418PMC
October 2020

Emerging blood-based biomarkers for Alzheimer disease.

Cleve Clin J Med 2020 Aug 31;87(9):537-539. Epub 2020 Aug 31.

Director, Cleveland Lou Ruvo Center for Brain Health, Neurological Institute, and Joseph Hahn, MD, Endowed Chair of the Cleveland Clinic Neurological Institute, Cleveland Clinic.

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http://dx.doi.org/10.3949/ccjm.87a.20133DOI Listing
August 2020

Harnessing endophenotypes and network medicine for Alzheimer's drug repurposing.

Med Res Rev 2020 11 13;40(6):2386-2426. Epub 2020 Jul 13.

Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.

Following two decades of more than 400 clinical trials centered on the "one drug, one target, one disease" paradigm, there is still no effective disease-modifying therapy for Alzheimer's disease (AD). The inherent complexity of AD may challenge this reductionist strategy. Recent observations and advances in network medicine further indicate that AD likely shares common underlying mechanisms and intermediate pathophenotypes, or endophenotypes, with other diseases. In this review, we consider AD pathobiology, disease comorbidity, pleiotropy, and therapeutic development, and construct relevant endophenotype networks to guide future therapeutic development. Specifically, we discuss six main endophenotype hypotheses in AD: amyloidosis, tauopathy, neuroinflammation, mitochondrial dysfunction, vascular dysfunction, and lysosomal dysfunction. We further consider how this endophenotype network framework can provide advances in computational and experimental strategies for drug-repurposing and identification of new candidate therapeutic strategies for patients suffering from or at risk for AD. We highlight new opportunities for endophenotype-informed, drug discovery in AD, by exploiting multi-omics data. Integration of genomics, transcriptomics, radiomics, pharmacogenomics, and interactomics (protein-protein interactions) are essential for successful drug discovery. We describe experimental technologies for AD drug discovery including human induced pluripotent stem cells, transgenic mouse/rat models, and population-based retrospective case-control studies that may be integrated with multi-omics in a network medicine methodology. In summary, endophenotype-based network medicine methodologies will promote AD therapeutic development that will optimize the usefulness of available data and support deep phenotyping of the patient heterogeneity for personalized medicine in AD.
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http://dx.doi.org/10.1002/med.21709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561446PMC
November 2020

Inflammatory pathway analytes predicting rapid cognitive decline in MCI stage of Alzheimer's disease.

Ann Clin Transl Neurol 2020 07 7;7(7):1225-1239. Epub 2020 Jul 7.

Lou Ruvo Center for Brain Health, Cleveland Clinic, Cleveland, Ohio, 44195.

Objective: To determine the inflammatory analytes that predict clinical progression and evaluate their performance against biomarkers of neurodegeneration.

Methods: A longitudinal study of MCI-AD patients in a Discovery cohort over 15 months, with replication in the Alzheimer's Disease Neuroimaging Initiative (ADNI) MCI cohort over 36 months. Fifty-three inflammatory analytes were measured in the CSF and plasma with a RBM multiplex analyte platform. Inflammatory analytes that predict clinical progression on Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) and Mini Mental State Exam scores were assessed in multivariate regression models. To provide context, key analyte results in ADNI were compared against biomarkers of neurodegeneration, hippocampal volume, and CSF neurofilament light (NfL), in receiver operating characteristic (ROC) analyses evaluating highest quartile of CDR-SB change over two years (≥3 points).

Results: Cerebrospinal fluid inflammatory analytes in relation to cognitive decline were best described by gene ontology terms, natural killer cell chemotaxis, and endothelial cell apoptotic process and in plasma, extracellular matrix organization, blood coagulation, and fibrin clot formation described the analytes. CSF CCL2 was most robust in predicting rate of cognitive change and analytes that correlated to CCL2 suggest IL-10 pathway dysregulation. The ROC curves for ≥3 points change in CDR-SB over 2 years when comparing baseline hippocampal volume, CSF NfL, and CCL2 were not significantly different.

Interpretation: Baseline levels of immune cell chemotactic cytokine CCL2 in the CSF and IL-10 pathway dysregulation impact longitudinal cognitive and functional decline in MCI-AD. CCL2's utility appears comparable to biomarkers of neurodegeneration in predicting rapid decline.
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http://dx.doi.org/10.1002/acn3.51109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359114PMC
July 2020

Cognitive tests aid in clinical differentiation of Alzheimer's disease versus Alzheimer's disease with Lewy body disease: Evidence from a pathological study.

Alzheimers Dement 2020 08 19;16(8):1173-1181. Epub 2020 Jun 19.

Cognitive Neuroscience Division, Department of Neurology, Gertrude H. Sergievsky Center, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, New York, USA.

Introduction: Clinical differentiation between Alzheimer's disease (AD) and AD with Lewy body disease (LBD) is relatively imprecise. The current study examined pathologically confirmed group differences in neuropsychological functioning, and the classification ability of specific tests.

Methods: Fifty-one participants with postmortem diagnoses of AD (n = 34) and AD plus LBD (n = 17) were drawn from the Predictors Study. One-way analyses of variance (ANOVAs) and χ analyses examined group differences in neuropsychological performance. Binary logistic regressions examined predictive utility of specific tests for pathological diagnosis.

Results: Individuals with AD had better visuoconstruction (P = .006), phonemic fluency (P = .08), and processing speed than AD plus LBD (P = .013). No differences were found in memory, naming, semantic fluency, or set-switching. Processing speed and visuoconstruction predicted pathologic group (P = .03).

Discussion: Processing speed and visuoconstruction predicted postmortem diagnosis of AD versus AD plus LBD. Current results offer guidance in the selection and interpretation of neuropsychological tests to be used in the differential diagnosis of early dementia.
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http://dx.doi.org/10.1002/alz.12120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880164PMC
August 2020

Research criteria for the diagnosis of prodromal dementia with Lewy bodies.

Neurology 2020 04 2;94(17):743-755. Epub 2020 Apr 2.

From the Newcastle University (I.G.M., A.J.T., P.D., J.P.T.); Mayo Clinic (T.J.F.), Jacksonville; University of Strasbourg (F.B.); Mayo Clinic (B.F.B., K.K.), Rochester; Nagoya University (H.F.), Kawasaki Memorial Hospital; Istituto Neurologico "Carlo Besta" (C.M., P.T.), Milan; Cambridge University (F.M.S.); McGill University (R.B.P.); King's College London and Stavanger University Hospital (D.A.); University of Exeter (C.B.); University of Chieti-Pescara (L.B.); Istanbul Faculty of Medicine (M.E.); University of Miami Miller School of Medicine (J.E.G.); University of California (D.G., D.P.S.), San Diego; Feinberg School of Medicine (J.G.G.); Massachusetts General Hospital (S.N.G.); Columbia University Irving Medical Center (L.S.H., K.S.M.); Osaka University (M.I.); Lou Ruvo Center of Brain Health (J.B.L.), Cleveland Clinic; University of Sydney (S.J.G.L.); Sunnybrook Health Sciences Centre (M.M.), University of Toronto; VA Puget Sound & University of Washington (D.W.T.); University College London (Z.W.).

The prodromal phase of dementia with Lewy bodies (DLB) includes (1) mild cognitive impairment (MCI), (2) delirium-onset, and (3) psychiatric-onset presentations. The purpose of our review is to determine whether there is sufficient information yet available to justify development of diagnostic criteria for each of these. Our goal is to achieve evidence-based recommendations for the recognition of DLB at a predementia, symptomatic stage. We propose operationalized diagnostic criteria for probable and possible mild cognitive impairment with Lewy bodies, which are intended for use in research settings pending validation for use in clinical practice. They are compatible with current criteria for other prodromal neurodegenerative disorders including Alzheimer and Parkinson disease. Although there is still insufficient evidence to propose formal criteria for delirium-onset and psychiatric-onset presentations of DLB, we feel that it is important to characterize them, raising the index of diagnostic suspicion and prioritizing them for further investigation.
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http://dx.doi.org/10.1212/WNL.0000000000009323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274845PMC
April 2020

An Altered Relationship between Soluble TREM2 and Inflammatory Markers in Young Adults with Down Syndrome: A Preliminary Report.

J Immunol 2020 03 20;204(5):1111-1118. Epub 2020 Jan 20.

Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH 44195;

Individuals with Down syndrome (DS) develop Alzheimer's disease (AD)-related neuropathology, characterized by amyloid plaques with amyloid β (Aβ) and neurofibrillary tangles with tau accumulation. Peripheral inflammation and the innate immune response are elevated in DS. Triggering receptor expressed in myeloid cells 2 () genetic variants are risk factors for AD and other neurodegenerative diseases. Soluble TREM2 (sTREM2), a soluble cleavage product of TREM2, is elevated in AD cerebrospinal fluid and positively correlates with cognitive decline. There is relatively little information about TREM2 in DS. Our objective was to examine the relationship between sTREM2 and inflammatory markers in young adults with DS, prior to the development of dementia symptoms. Because TREM2 plays a role in the innate immune response and has been associated with dementia, the hypothesis of this exploratory study was that young adults with DS predementia ( = 15, mean age = 29.5 y) would exhibit a different relationship between sTREM2 and inflammatory markers in plasma, compared with neurotypical, age-matched controls ( = 16, mean age = 29.6 y). Indeed, young adults with DS had significantly elevated plasma sTREM2 and inflammatory markers. Additionally, in young adults with DS, sTREM2 correlated positively with 24 of the measured cytokines, whereas there were no significant correlations in the control group. Hierarchical clustering of sTREM2 and cytokine concentrations also differed between the groups, supporting the hypothesis that its function is altered in people with DS predementia. This preliminary report of human plasma provides a basis for future studies investigating the relationship between TREM2 and the broader immune response predementia.
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http://dx.doi.org/10.4049/jimmunol.1901166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033027PMC
March 2020

Longitudinal change in regional brain volumes with exposure to repetitive head impacts.

Neurology 2020 01 23;94(3):e232-e240. Epub 2019 Dec 23.

From the Cleveland Clinic (C.B., V.R.M.), Las Vegas; University of Nevada (G.S.), Las Vegas; Sahlgrenska Academy (H.Z., K.B.), University of Gothenburg, Sweden; University of California (S.B.), San Diego; and Cleveland Clinic (L.B., J.B.L.), OH.

Objective: This study tests the hypothesis that certain MRI-based regional brain volumes will show reductions over time in a cohort exposed to repetitive head impacts (RHI).

Methods: Participants were drawn from the Professional Fighters Brain Health Study, a longitudinal observational study of professional fighters and controls. Participants underwent annual 3T brain MRI, computerized cognitive testing, and blood sampling for determination of neurofilament light (NfL) and tau levels. Yearly change in regional brain volume was calculated for several predetermined cortical and subcortical brain volumes and the relationship with NfL and tau levels determined.

Results: A total of 204 participants who had at least 2 assessments were included in the analyses. Compared to controls, the active boxers had an average yearly rate of decline in volumes of the left thalamus (102.3 mm/y [ = 0.0004], mid anterior corpus callosum (10.2 mm/y [ = 0.018]), and central corpus callosum (16.5 mm/y [ = <0.0001]). Retired boxers showed the most significant volumetric declines compared to controls in left (32.1 mm/y [ = 0.002]) and right (30.6 mm/y [ = 0.008]) amygdala and right hippocampus (33.5 mm/y [ = 0.01]). Higher baseline NfL levels were associated with greater volumetric decline in left hippocampus and mid anterior corpus callosum.

Conclusion: Volumetric loss in different brain regions may reflect different pathologic processes at different times among individuals exposed to RHI.
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http://dx.doi.org/10.1212/WNL.0000000000008817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108810PMC
January 2020

Clinical and Imaging Characteristics Associated with Color Vision Impairment in Lewy Body Disease.

J Alzheimers Dis 2019 ;72(4):1233-1240

Lou Ruvo Center for Brain Health, Cleveland Clinic, Cleveland, OH, USA.

Background: Color vision impairment (CVI) has been reported in dementia with Lewy bodies (DLB) and prodromal Lewy body disease (pro-LBD).

Objective: In order to better characterize the diagnostic value of CVI testing, we compared the prevalence of CVI in patients with with Lewy body disease compared to Alzheimer's disease (AD), and we examined clinical and imaging characteristics associated with CVI in patients with DLB and suspected pro-LBD.

Methods: We retrospectively reviewed medical records, dopamine transporter (DaT-SPECT) imaging, and volumetric MRI from patients with AD, DLB, and suspected pro-LBD who underwent an online Farnsworth D-15 color vision test.

Results: 111 patients (62 DLB, 25 pro-LBD, and 24 AD) were included with a median age of 75 years. Newly diagnosed CVI was present in 67% of patients with DLB, 44% of patients with pro-LBD, and 18% of patients with AD. In patients with DLB, CVI was associated with lower Montreal Cognitive Assessment (MoCA) scores and lower sub-scores in visuospatial/executive function, naming, and language. In a multivariable logistic regression model, a diagnosis of DLB or pro-LBD compared to AD, and a lower composite MoCA score in visuospatial/executive function, naming, and language were associated with CVI controlling for age and gender. Among 17 DLB patients who underwent volumetric MRI, patients with CVI (n = 9) demonstrated lower normative volumetric percentiles in the right transverse superior temporal lobe.

Conclusion: We provide further evidence that CVI can help differentiate DLB from AD, and we suggest that CVI may be an indicator of cognitive decline and disease progression in DLB.
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http://dx.doi.org/10.3233/JAD-190727DOI Listing
December 2020

Clinical drug development for dementia with Lewy bodies: past and present.

Expert Opin Investig Drugs 2019 Nov 28;28(11):951-965. Epub 2019 Oct 28.

Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA.

: Dementia with Lewy bodies (DLB) is an under-researched area despite being the second most common type of degenerative dementia after Alzheimer's disease. It is an area of unmet need with no approved symptomatic or disease-modifying therapies. The pharmacological management of DLB is complex and challenging because early trials of drugs for DLB have resulted in no demonstrable efficacy. Randomized controlled trials (RCTs) in the DLB population have only recently been initiated. Understanding results from previous and current clinical trials in DLB can provide insights for future research and development.: We provide an overview of the DLB drug development landscape and the current treatment strategies. We reviewed ClinicalTrials.gov to identify all clinical trials for the treatment of DLB.: DLB drug development has significantly improved in recent years with eight agents now in clinical trials. However, more rigorous RCTs are urgently needed. Diagnostic criteria must be optimized to accurately diagnose patients for clinical trials and care. New biomarker strategies are necessary to improve diagnostic capabilities and trial designs, and novel drug targets should be identified to develop DLB specific disease-modifying therapies. Evaluating the current drug development landscape can provide insight into how best to optimize development practices.
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http://dx.doi.org/10.1080/13543784.2019.1681398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823159PMC
November 2019
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