Jeffrey L. Cummings’s research while affiliated with University of Nevada, Reno and other places

Background and objectives: Disturbances in brain catecholamine activity may be associated with symptoms after exposure to repetitive head impacts (RHIs) or related chronic traumatic encephalopathy (CTE). In this article, we studied CSF catecholamines in former professional and college American football players and examined the relationship with football proxies of RHI exposure, CTE probability, cognitive performance, neuropsychiatric symptoms, and parkinsonism. Methods: In this observational cross-sectional study, we examined male former American football players, professional ("PRO") or college ("COL") level, and asymptomatic unexposed male ("UE") individuals from the DIAGNOSE CTE Research Project. Catecholamines-norepinephrine (NE) and its metabolite, 3,4-dihydroxyphenylglycol (DHPG), and dopamine (DA) and its precursor, 3,4-dihydroxyphenylalanine (l-DOPA), and metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC)-were measured in CSF with high-performance liquid chromatography and compared across groups with analysis of covariance. Multivariable linear regression models tested the relationship between CSF catecholamines and proxies of RHI exposure (e.g., total years of playing American football), factor scores for cognition, and neurobehavioral dysregulation (explosivity, emotional dyscontrol, impulsivity, affective lability), as well as depressive/anxiety symptoms, measured with the Beck Depression/Anxiety Inventories. CTE probability and parkinsonism were assessed using the National Institute of Neurological Disorders and Stroke consensus diagnostic criteria for traumatic encephalopathy syndrome (TES), and biomarkers were compared among different diagnostic groups. Results: The cohort consisted of 120 former American football players (85 PRO players, 35 COL players) and 35 UE participants (age 45-75). Former players had significantly lower levels of NE (mean difference = -0.114, 95% CI -0.190 to -0.038), l-DOPA (-0.121, 95% CI -0.109 to -0.027), and DOPAC (-0.116, 95% CI -0.177 to -0.054) than UE participants. For NE and DOPAC, these overall group differences were primarily due to differences between the PRO and UE cohorts. No significant differences were found across TES-CTE probability subgroups or TES-parkinsonism diagnostic groups. Within the COL cohort, tested as post hoc analyses, higher CSF NE and l-DOPA were associated with higher neurobehavioral dysregulation factor scores, BAI total score, and worse executive functioning and processing speed. CSF DHPG and DOPAC were associated with impulsivity only in this subgroup. Discussion: We observed reduced CSF catecholamine concentrations in former elite American football players, although the relationship with degree of RHI exposure and the clinical impact needs further study.

Neurodegenerative disorders are characterized by complex neurobiological changes that are reflected in biomarker alterations detectable in blood, cerebrospinal fluid (CSF) and with brain imaging. As accessible proxies for processes that are difficult to measure, biomarkers are tools that hold increasingly important roles in drug development and clinical trial decision making. In the past few years, biomarkers have been the basis for accelerated approval of new therapies for Alzheimer disease and amyotrophic lateral sclerosis as surrogate end points reasonably likely to predict clinical benefit.Blood-based biomarkers are emerging for Alzheimer disease and other neurodegenerative disorders (for example, Parkinson disease, frontotemporal dementia), and some biomarkers may be informative across multiple disease states. Collection of CSF provides access to biomarkers not available in plasma, including markers of synaptic dysfunction and neuroinflammation. Molecular imaging is identifying an increasing array of targets, including amyloid plaques, neurofibrillary tangles, inflammation, mitochondrial dysfunction and synaptic density. In this Review, we consider how biomarkers can be implemented in clinical trials depending on their context of use, including providing information on disease risk and/or susceptibility, diagnosis, prognosis, pharmacodynamic outcomes, monitoring, prediction of response to therapy and safety. Informed choice of increasingly available biomarkers and rational deployment in clinical trials support drug development decision making and de-risk the drug development process for neurodegenerative disorders.

The minimum clinically important difference (MCID) is a measure of the minimal clinically relevant change. The MCID represents the smallest difference in score on the measure or domain of interest which patients or clinicians perceive as beneficial or as meaningful decline. The MCID is not an alternative clinical trial outcome; it does not apply to group measures and is used as a means of determining whether an individual patient has reached a threshold of change. MCIDs have been derived for symptomatic treatments and for disease targeted therapies. MCIDs have been derived for nearly all clinical trial instruments used in AD therapeutic research. Application of the MCID to patients on disease‐targeted therapies requires awareness of the expected increasing treatment‐no treatment difference exhibited by these agents. The MCID complements other strategies for assessing the meaningfulness of interventions including effect size, number needed to treat, responder analyses, time saved, quality of life, and quality‐adjusted life years. MCID is not a required measure for regulatory approval of a therapeutic since it is applicable to individual patients and not to group outcomes or mean differences used to determine treatment benefit in clinical trials. Highlights MCID is a key measure of within‐person change in cognition, function, or behavior when it is applied to metrics of Alzheimer's disease progression. In Alzheimer's disease, MCID or minimum within person change (MWPC) can function as useful means of determining if a patient has progressed to thresholds of detectable change. In Alzheimer's disease, MCID/MWPC can be used to determine the number or percent of individuals who have progressed to detectable levels of within‐person change, with differences anticipated in active treatment and placebo groups. MCID/MWPC are not measures that are appropriately applied to group outcomes of clinical trials.

Background Alzheimer’s disease (AD) is the main cause of dementia with few effective therapies. We aimed to identify potential plasma biomarkers or drug targets for AD by investigating the causal association between plasma proteins and AD by integrating comprehensive Mendelian randomization (MR) and multi-omics data. Methods Using two-sample MR, cis protein quantitative trait loci (cis-pQTLs) for 1,916 plasma proteins were used as an exposure to infer their causal effect on AD liability in individuals of European ancestry, with two large-scale AD genome-wide association study (GWAS) datasets as the outcome for discovery and replication. Significant causal relationships were validated by sensitivity analyses, reverse MR analysis, and Bayesian colocalization analysis. Additionally, we investigated the causal associations at the transcriptional level with cis gene expression quantitative trait loci (cis-eQTLs) data across brain tissues and blood in European ancestry populations, as well as causal plasma proteins in African ancestry populations. Results In those of European ancestry, the genetically predicted levels of five plasma proteins (BLNK, CD2AP, GRN, PILRA, and PILRB) were causally associated with AD. Among these five proteins, GRN was protective against AD, while the rest were risk factors. Consistent causal effects were found in the brain for cis-eQTLs of GRN, BLNK, and CD2AP, while the same was true for PILRA in the blood. None of the plasma proteins were significantly associated with AD in persons of African ancestry. Conclusions Comprehensive MR analyses with multi-omics data identified five plasma proteins that had causal effects on AD, highlighting potential biomarkers or drug targets for better diagnosis and treatment for AD.

A European Task Force has recently developed and published the concept and protocols for the setup of the innovative health offer of Brain Health Services for the secondary prevention of dementia and cognitive impairment (dBHS). dBHS are outpatient health care facilities where adult persons can find an assessment of their risk of developing cognitive impairment and dementia, have their risk level and contributing factors communicated using appropriate language supported by adequate communication tools, can decide to participate to programs for personalized risk reduction if at higher risk, and benefit from cognitive enhancement interventions. This health offer is distinct from that of currently active memory clinics. The ultimate aim of dBHS is to extend healthy life, free from cognitive impairment. Here, we (i) discuss the pertinent opportunities and challenges for those persons who want to benefit from dBHS, professionals, and wider society, (ii) describe the concepts, protocols, organizational features, and patient journeys of some currently active dBHS in Europe, and (iii) argue in favor of the business case for dBHS in Europe.

Anti-amyloid monoclonal antibodies (MABs) have introduced a new era of Alzheimer's disease (AD) therapeutics with disease-targeted drugs. Three agents --- aducanumab, lecanemab, donanemab --- have been approved and others are in development. These agents are administered intravenously, once in the brain they activate microglia to engulf amyloid-beta protein fibrillar plaques. Each approved agent has a specific profile of administration, titration, amyloid target, and adverse events. In 18 month trials of participants with early AD (defined as mild cognitive impairment due to AD or mild AD dementia), anti-amyloid MABs slow cognitive and functional decline by approximately 30 %. Amyloid positron emission tomography reveals marked reductions in amyloid plaque burden; reductions below a threshold of 15–25 Centiloids are associated with clinical benefit. The magnitude, scope, and trajectory of clinical end points provide the basis for interpretations of clinical meaningfulness. Occurrence of amyloid-related imaging abnormalities with intracerebral edema, microhemorrhages, or superficial siderosis must be monitored and managed to prevent serious or rare catastrophic consequences. Infusion reactions occur and anticipatory management is required. Development of subcutaneous formulations and use of blood-based biomarkers for diagnosis and monitoring promises to increase the accessibility and decrease the demands on health care systems associated with these agents. Anti-amyloid MABs provide the foundation for further advances in developing a repertoire of disease-targeted therapies for AD.

Repurposed drugs provide a rich source of potential therapies for Alzheimer's disease (AD) and other neurodegenerative disorders (NDD). Repurposed drugs have information from non-clinical studies, phase 1 dosing, and safety and tolerability data collected with the original indication. Computational approaches, "omic" studies, drug databases, and electronic medical records help identify candidate therapies. Generic repurposed agents lack intellectual property protection and are rarely advanced to late-stage trials for AD/NDD. In this review we define repurposing, describe the advantages and challenges of repurposing, offer strategies for overcoming the obstacles, and describe the key contributions of repurposing to the drug development ecosystem. The prevalence of Alzheimer's disease (AD) is growing rapidly. The global population of individuals with AD dementia is anticipated to increase from the current 57 million to 153 million by 2050 1. There will be a disproportionate growth of AD and other dementias in low-and middle-income countries (LMICs); by 2050 71% of patients with dementia will live in these regions 2. In addition to those with the dementia of AD, many more have mild cognitive impairment (MCI) or preclinical AD 3. Other neurodegenerative disorders (NDDs) that are growing with the aging of the global population include Par-kinson's disease and related disorders such as dementia with Lewy bodies, frontotemporal dementia and associated conditions such as progressive supranuclear palsy and corticobasal degeneration, and amyotrophic lateral sclerosis (ALS) 4. Approval of anti-amyloid monoclonal antibodies represents an important advance in the treatment of AD but applies to an early form of the disease and rely on diagnostic and therapeutic technologies with limited availability 5. There are many non-amyloid processes in the patho-physiology of AD that comprise important targets for new therapeutic development 6-8. There is an urgent need to develop new therapies that will prevent or delay the onset of the pathology or symptoms of AD/ NDDs, slow the progression of the diseases, or improve cognition, behavior, function, and other neurological abnormalities. Development of new treatments for AD/NDDs is complex, requires a development program that averages 13 years to complete, and frequently results in failure 9. Approaches to drug development that are more likely to succeed and require more limited time and financial investment could accelerate the emergence of new therapies. Repurposed drugs approved for a non-AD/non-NDD indication are a promising source of new therapies. We describe the potential for repurposing therapeutics for AD/ NDDs and note the benefits of developing a second use of an approved medicine whose pharmacokinetics, safety toxicity, and manufacturing are known. We note the role of repurposed drugs in the current AD pipeline and describe the emergence of new technologies for the identification of candidate repurposable agents. We note the advantages of repurposing as a development strategy. We describe the challenges associated with advancing repurposed drugs, particularly the limited availability of funding and sponsors for late-stage trials if the agents are generic. We suggest possible solutions for the challenges faced by repurposing and issue a call to action for legislative changes that would incentivize programs to develop repurposable

Biomarkers are vital to Alzheimer's disease (AD) drug development and clinical trials, and will have an increasing role in clinical care. In this narrative review, we demonstrate the use of the National Institutes on Aging/Alzheimer's Association (NIA/AA) Common Alzheimer's Disease Research Ontology (CADRO) system for the categorization of biomarkers based on the primary mechanism on which they report. We show that biomarkers are available (in various levels of validation) for all CADRO processes. Application of the CADRO system demonstrates gaps in the field where novel biomarkers are needed for specific aspects of the disease, and assays to detect and measure biological changes, in individuals with symptomatic or preclinical AD. We demonstrate the CADRO system as a means of categorizing established and candidate AD biomarkers, showing the feasibility and practicality of the system. CADRO can assist with biomarker selection for AD clinical trials and drug development, and may eventually be applied to implementing biomarkers in patient care. Highlights The Common Alzheimer's Disease Research Ontology (CADRO) system can be used to categorize biomarkers for drug development. We demonstrate the use of CADRO with Alzheimer's disease (AD) biomarkers. We identified AD biomarkers in each of the CADRO categories. CADRO can be incorporated into current AD drug development and clinical trial systems.