2020 SPEAKERS

Ranjan Duara, MD, FAAN

Organizer

Ranjan Duara, MD, FAAN, is the Medical Director and Dennis C. Cole Family Chair in Alzheimer’s Disease Research at the Wien Center for Alzheimer’s Disease and Memory Disorders at Mount Sinai Medical Center in Miami Beach. He is a Professor of Neurology at the Herbert Wertheim College of Medicine (Department of Neurology) at Florida International University and Courtesy Professor of Neurology, University of Florida College of Medicine. He completed internal medicine and neurology residencies in India, the United Kingdom and at Thomas Jefferson University Hospital in Philadelphia. He also completed a fellowship in neuroscience and neuroimaging at NIH.

Dr. Duara’s research has focused primarily on early diagnosis of Alzheimer’s disease and other dementias, neuroimaging, genetic epidemiology and the methodology for staging the transition from normal cognitive aging to dementia. He has contributed to over 200 articles in peer-review scientific journals as well many book chapters.

He is the Principal Investigator for the State of Florida Alzheimer’s Disease Initiative Brain Bank and Associate Director of the 1FLORIDA Alzheimer’s Disease Research Center. He has also been an investigator in numerous clinical trials of novel agents for the treatment of Alzheimer’s Disease.

Treating Dementia with Lewy Bodies: Beyond Medications

Melissa Armstrong
University of Florida, Gainesville, FL, USA

Lewy body dementia includes dementia with Lewy bodies (DLB) and Parkinson disease (PD) dementia, both of which can be associated with prodromal mild cognitive impairment (MCI) forms. Parkinson disease – mild cognitive impairment (PD-MCI) is present in 20-40% of individuals with PD at the time of PD diagnosis. The point prevalence of MCI in PD is 25-50%. PD is typically associated with non-amnestic MCI. As is the case with MCI in general, the presence of MCI confers a higher risk of dementia in individuals with PD. It is estimated that 40-60% of individuals with PD-MCI will progress to PD dementia over 4-5 years. While some individuals characterized as PD-MCI revert to normal, it is likely that most individuals with PD-MCI will progress to dementia, as 50% of individuals with PD for 10 years meet criteria for PD dementia.  In individuals with PD for 20 years, 83% have dementia. DLB-MCI remains less well defined than PD-MCI.

DLB-MCI is one of three proposed prodromal forms of DLB, but its prevalence is uncertain. Individuals with non-amnestic MCI are 10 times more likely to develop clinically probable DLB than clinically probable Alzheimer disease dementia, with an annual transition rate to DLB of 20%. Individuals progressing from MCI to probable DLB commonly have attention and visuospatial deficits, REM sleep behavior disorder, fluctuations, and subtle parkinsonism.

There currently are no pharmacologic strategies that are effective for MCI in the context of Lewy body diseases. Non-pharmacologic approaches to quality care start with giving the diagnosis. This validates that something is wrong, allows individuals to plan for the future, and is care in keeping with MCI quality measures. The second non-pharmacologic approach to DLB-MCI is to counsel individuals with what to expect, both for DLB-MCI and for eventual DLB. The third non-pharmacologic approach is to connect individuals with DLB-MCI to longitudinal/biomarker and therapeutic clinical research. Additional approaches include encouraging therapy/exercise, connecting individuals to support services, and preparing individuals for events such as hospitalization. Finally, quality care of individuals with DLB-MCI requires shared decision making. Specific examples of these approaches will be discussed.

Sex and Neuropathology of Dementia

Zoe Arvanitakis
Rush University Medical Center, Chicago, IL, USA

Biologic factors influence the development of disease and the clinical expression of disease. In the past decade, the scientific community and funding agencies including the National Institutes of Health, have increasingly recognized the importance of studying the biologic factor of sex, and of elucidating potential “sex differences” in diseases. Increased understanding about such differences, if present, will move science and clinical care toward a more precision-based model, ultimately allowing for more effective healthcare for all. In the realm of cognitive impairment and dementia, some data suggest the presence of sex differences among women and men. We will present data on sex and neuropathology of dementia, leveraging data from several large, prospective, clinical-pathologic cohort studies from the Rush Alzheimer’s Disease Center.

The ATN Framework: The Good, the Bad, and the Ugly

David Bennett
Rush University Medical Center, Chicago, IL, USA

The Good

Alzheimer’s disease, like all common chronic conditions of aging, begins with a stage of disease in which the pathology develops but it is clinically asymptomatic. We finally have separate terms, Alzheimer’s disease (AD) and Alzheimer’s dementia, to refer to the pathology/biomarkers and the clinical expression, or presumed clinical expression, of the pathology. We had an opportunity to do this with the 2011 criteria but failed to achieve a consensus and let the opportunity slip away. The A and T mirror pathologic criteria that have been used for decades.

The Bad

AD is now much more common than before. However, pathologic AD, is actually less common as a direct cause of dementia. In older persons, which represents the majority of persons with dementia, the attributable risk of Alzheimer’s dementia from pathologic AD is about 33%. About 67% of dementia is due to other conditions.

The Ugly

What are the other conditions? It’s TDP-43, hippocampal sclerosis, cortical Lewy bodies, amyloid angiopathy (OK, so maybe that should go along with AD – but not necessarily ATN so it’s here), macroscopic infarcts and atherosclerosis. About 33% of Alzheimer’s dementia are attributable to those additional pathologic indices. That leaves another third explained by some other pathologies, e.g., watershed microinfarcts, white matter microstructure, soluble amyloid (OK, so maybe that should go along with AD – but not necessarily ATN so it’s here). But there are other factors associated with Alzheimer’s dementia that do not have a pathologic footprint.

Application of the ATN Framework in African Americans and Caucasians

Tammie Benzinger
Washington University in St. Louis

The A-T-N framework gives us a classification system for risk of preclinical Alzheimer disease which moves as away from a cannonical disease staging and into a realm where there can be multiple pathways towards development of AD dementia. However, the cohorts upon which this criteria were developed were largely Caucasian American and European. How this criteria will work in other cohorts is largely untested. Here, we examine the A-T-N in the context of largely cognitively normal adults, who enrolled in studies of memory and aging at the Knight Alzheimer Disease Research Center (ADRC) at Washington University, as well as in the context of autosomal dominant Alzheimer disease as part of the Dominantly Inherited Alzheimer Network (DIAN). In addition to memory and cognition, analyses will explore the impact of comorbid cardiovascular risk including hypertension, diabetes, and stroke.

Cognitive Predictors of Disease Progression in Normal and At-risk States

Rosie Curiel Cid
University of Miami Miller School of Medicine, Miami, FL, USA

Clinical outcome measures that can detect preclinical and prodromal changes, and that have the ability to predict clinical outcome over time are ever more necessary to emerging prevention trials. Intrusion errors made on memory tests may be among the earliest behavioral markers of elevated Alzheimer’s disease (AD) brain pathology; however, few studies have examined whether these cognitive errors predict progression of cognitive impairment in at-risk populations. Novel data will be presented examining whether a novel index, the percentage of semantic intrusion errors (PIE) could predict clinical/cognitive outcomes in different at-risk groups. 

A Novel Method for Assessing and Training Everyday Functional Skills

Sara J. Czaja¹, Philip D. Harvey², Peter Kallestrup³

¹Weill Cornell Medicine;²University of Miami Miller School of Medicine;³i-Function

Older adults, especially those with cognitive impairments often experience difficulty performing everyday tasks critical to independence such as money or medication management. Thus, there is an increasing interest in developing tools to detect the earliest manifestations of cognitive and functional decline and to develop efficacious treatment approaches for those who are experiencing or at risk for cognitive problems. There exists an array of standard neuropsychological measures, which are used to assess and characterize changes or deficits in cognition. These measures fail to capture the complexity of everyday activities. In terms of remediation strategies, a variety of cognitive remediation training (CRT) programs have emerged, many of which are computer-based, aimed at preventing or remediating cognitive decline. Although, findings indicate that these programs can be effective in improving cognitive abilities, there is limited evidence that suggest these programs result in performance gains in everyday tasks. This presentation will discuss an innovative computer -based functional skills assessment and training (CFSAT) program. The program includes ecologically valid simulations of everyday tasks. Data will be presented from a trial evaluating the battery with non-cognitively impaired older adults and those with aMCI. The task performance data include real time measures of accuracy, response time and efficiency.

Overall the data indicate that the assessment and training protocols were feasible for and highly acceptable to both non-impaired and MCI older adults; both groups demonstrated improvements in performance across all tasks; the non-impaired participants proceeded through the training fairly rapidly; and the MCI participants required more training sessions for completion. These results indicate that the CFSAT program is a feasible and useful tool for assessing and training functional performance in a variety of populations.

Steven DeKosky, MD

University of Florida, Gainesville, FL, USA

Steven DeKosky, MD, is the Aerts-Cosper Professor of Alzheimer’s Research at the University of Florida College of Medicine and is Deputy Director of the McKnight Brain Institute. His basic research centers on structural and neurochemical changes in human brain in aging and dementia and effects of traumatic brain injury (TBI).

Beginning trauma studies as a Principal Investigator in the University of Pittsburgh Brain Trauma Research Center in 1992, he studied similarities in the injury cascades of TBI and AD. Dr. DeKosky has served on and led numerous NIH review and advisory committees, and taught and mentored in clinical research training programs sponsored by the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS).

Dr. DeKosky was a member of the national Board of Directors of the Alzheimer’s Association from 1994 to 2002 (Board Vice Chair in 2001-2002), and again from 2003 to 2010. He served as Chair of the Section on Geriatrics of the American Academy of Neurology (AAN) and chaired the AAN Practice Parameters Committee for Early Detection, Diagnosis and Management of Dementia. He is the founding Chair of the Advisory Council of ISTAART, the International Society to Advance Alzheimer’s Disease Research and Treatment. He has testified multiple times before U.S. Senate Committees for greater research funding for Alzheimer’s disease, and has met with government officials in other countries as a consultant and advocate for programs and support for people with dementia.

Alan Evans, PhD

McGill University

Alan Evans, PhD, is a James McGill Professor of Neurology and Neurosurgery, Psychiatry and Biomedical Engineering at McGill University since 2009, and a researcher in the McConnell Brain Imaging Centre (BIC) of the Montreal Neurological Institute.  He is co-director of the Ludmer Centre for Neuroinformatics and Mental Health and is Principal Investigator of CBRAIN, a pan-Canadian project to integrate Canadian brain research with the Compute Canada high-performance computing grid. He is the sole Canadian participant in the $1.1 billion European Human Brain Project and is a co-principal investigator of the Big Brain project. He is Scientific Director of McGill’s $84 million CFREF project, “Healthy Brains for Healthy Lives.”

Dr. Evans heads the Data Coordinating Center for a large NIH multi-centre MRI study of normal pediatric development. This provides a web-accessible reference database of neuroanatomical and behavioral maturation. Dr. Evans was principal investigator in the Montreal Consortium for Brain Imaging Research (MCBIR), which was founded in 2000 with a $35 million award from the Canada Foundation for Innovation. He was a co-founder of the International Consortium for Brain Mapping (ICBM), a multinational effort funded by the U.S. Human Brain Project to create a computational atlas of the adult human brain. He was one of the founders of the Organization for Human Brain Mapping (OHBM), serving in numerous positions on the OHBM Council since 1995.

Dr. Evans’ research interests include cognitive neuroimaging, neuroanatomical variability, and image-processing methodologies for PET and MRI. He pioneered the technique of multi-modal 3D brain imaging with PET and MRI, which provides detailed 3D images of brain anatomy.

As BIC Coordinator from 1992 to 2000, Dr. Evans fostered the development of brain “activation” studies in which specific brain regions show subtle changes in blood flow in response to cognitive and sensorimotor stimuli. This so-called brain-mapping technique is widely used to map human brain functions. Dr. Evans extended these techniques to large-scale studies of brain anatomy. This work has spun off a new company, Biospective Inc., which performs fully automated analysis of neuroimaging databases collected as part of pharmaceutical clinical trials.

Dr. Evans has published over 550 peer-reviewed papers, and is a member of numerous international advisory boards, review panels and research collaborations. He was acknowledged as a Thompson-Reuters Highly Cited Scientist for 2014 and 2015 (top 1% in Neuroscience and Behaviour).

Screening and Clinical Diagnosis of Lewy Body Disease

James Galvin
University of Miami Miller School of Medicine, Miami, FL, USA

Lewy body dementia (LBD) is an umbrella term that covers two closely related diagnoses, Dementia with Lewy Bodies (DLB) and Parkinson’s disease dementia (PDD). LBD is the second most common cause of dementia after Alzheimer’s disease (AD) affecting approximately 1.4 million Americans. The point prevalence of dementia in PD is close to 30% and the incidence rate is increased at 4-6 times relative to controls. Prevalence estimates of DLB range from 0% to 5% in the general population and from 0% to 30.5% of all dementia cases. The incidence rates for DLB are 0.1% in the general population, and 3% for all new dementia cases. LBD is a challenge to diagnose, particularly outside of expert centers with long delays in diagnosis leading to significant burden to patients and caregivers. The clinical dementia picture of LBD revolves around a constellation of cognitive deficits (visuospatial, executive, attention) together with evidence of parkinsonism, cognitive fluctuations, visual hallucinations, and rapid eye movement sleep behavioral disorder (RBD). While consensus criteria have excellent specificity, there is no standardized way to assess symptoms reducing their utility in clinical practice. To address these concerns, screening tools have been developed such as the Lewy Body Composite Risk Score (LBCRS) and DIAMOND-LEWY Assessment Toolkit for Lewy Body Dementia. The use of tools such the LBCRS and the LBD Assessment Toolkit increases diagnostic probability that Lewy body pathology is contributing to the dementia syndrome. Combined with emerging biomarkers, these screening tools should improve clinical detection, diagnosis and treatment, as well as case ascertainment to enhance enrollment for clinical trials.

Risk Factors and Progression Rates of MCI

Mary Ganguli
University of Pittsburgh, Pittsburgh, PA, USA

MCI is a heterogeneous entity with multiple potential causes. The distributions of the underlying causes vary across settings, e.g. Alzheimer disease research centers, geriatrics clinics, primary care, and the population at large. The neuropathology of MCI and dementia has been shown to vary between clinical and community settings. The likelihood of progression from MCI to dementia will depend on the underlying etiology, and therefore on the setting as well. In memory disorders clinics, studies have shown that the vast majority of patients progress from MCI to dementia within a few years. In population studies, the vast majority remain at the MCI level, i.e. stably impaired; while a minority of MCI cases progress to dementia and another minority reverts to normal.

This presentation will share data from the Monongahela Valley of southwestern Pennsylvania, an area of relatively low socioeconomic status following the collapse of the steel industry in the 1970s. Findings will be shown about the proportions and characteristics of study participants with MCI who have different outcomes (stability, progression, and reversion), and the apparent risk and protective factors for MCI progression and the rate of cognitive decline.

Biomarkers for LBD

David Irwin
University of Pennsylvania, Philadelphia, PA, USA

Significant advances have been made in the diagnosis of Lewy body disorders (i.e. Parkinson’s disease PD, PD with dementia PDD and Dementia with Lewy bodies DLB) with modern clinical criteria aimed at identifying individuals with underlying alpha-synuclein (aSYN) pathology and differentiating them from clinically similar neurodegenerative disorders. Modern DLB criteria incorporates biomarkers that detect clinical features indicative of aSYN-mediated neurodegeneration to improve diagnostic sensitivity and these biomarkers may have relevance for PD diagnosis as well. These biomarkers include sleep polysomnogram for REM sleep behavior disorder, dopamine transport imaging for striatonigral degeneration and cardiac scintigraphy for cardiac sympathetic denervation. Indeed, efforts to identify prodromal LBD incorporate these markers with other clinical features (e.g. autonomic instability, anosmia) in patients with mild cognitive impairment or neurologically normal individuals at risk of progression to DLB. Nonetheless, a biomarker modality to more directly visualize aSYN pathology is urgently needed. Moreover, there is considerable clinical and pathological overlap between PD/PDD and DLB along with significant clinical heterogeneity within these clinical syndromes that is poorly understood. Emerging postmortem work suggests Alzheimer’s disease (AD) plaque and tangle pathology is common (~50% of all LBD have sufficient AD neuropathologic change sufficient for a secondary neuropathological diagnosis of medium/high AD) and has a strong influence on clinical features in both PD/PDD and DLB, including earlier dementia and worse survival. Recent work suggests AD biomarkers (e.g. CSF, PET molecular imaging) in clinical and autopsy-confirmed LBD patients have important prognostic implications and reflect the deposition of these pathologies in vivo. Thus, natural history studies and clinical trials for LBD should consider AD biomarker profiles to stratify LBD into more biologically meaningful groups (i.e. LBD with AD co-pathology vs LBD without AD co-pathology) than classic LBD clinical syndromes alone (i.e. PD, PDD and DLB).

TDP43 Pathology – Effect of Demographic Factors

Gregory Jicha
University of Kentucky, Lexington, KY, USA

The presence of pathologic TDP-43 inclusions that can contribute to MCI can be seen in a wide range of degenerative disease states ranging from FTLD to LATE-NC and is a common pathological finding in a host of mixed disease states including AD, DLB, CTE and others. Given the lack of an antemortem biomarker for TDP-43 pathology, it is not until autopsy that a diagnosis of a TDP-43 related disorder can be established. As such, an understanding of the influence of potential TDP-43 pathology on MCI due to a mixed pathological state is problematic, and yet insights can be derived from prospectively followed subjects transitioning through MCI that are found to eventually have TDP-43 predominant pathology. Demographically, such disease states can be distinguished as those related to FTLD and those related to LATE-NC, albeit overlap between such states remains hotly debated in the field. In FTLD, TDP-43 pathology can be the predominant pathology manifesting as the behavioral or semantic variant of FTD, most often affecting a younger population, and can often be seen in conjunction with signs of motor neuron disease. TDP-43 positive inclusions are found throughout limbic and front-temporal neocortical regions sub serving behavioral and language function as well as in subcortical and even spinal regions related to motor involvement. Concomitant hippocampal sclerosis is frequently found in FTLD related to mutations in GRN encoding the progranulin gene product, leading to an amnestic presentation. TDP-43 inclusions also predominate in many cases of dementia in the oldest-old, frequently associated with hippocampal sclerosis and presenting as an almost pure amnestic syndrome, that is a common Alzheimer mimic (~20% of late-life dementia). Understanding the subtleties of the demographic, clinical, and genetic features of FTLD and LATE-NC may hopefully shed light on the many shared and potentially distinct phenotypes, molecular pathways, and early presentation of MCI due to TDP-43 pathology.

Assessment of the Aging Brain using Computing Technology

Jeffrey Kaye, MD
Oregon Health & Science University, Portland, OR, USA

Conventional clinical assessments including clinical trials are limited by brief, episodic examinations relying on surrogate markers and much subjective data as outcomes. An alternative to this paradigm is to harness the power of pervasive computing, remote sensing, and wireless technologies. The high dimensional, objective,  person-specific and continuous data generated by these technologies provides more real-time, unbiased and ecologically valid data that can be more effective in assessing a range of real-world cognitive and functional outcomes, as well as detect precipitants of change. In addition, these technologies at the same time can be employed to deliver timely, accountable interventions. This keynote will provide an overview of the field, including both successes, as well as challenge points. Progress and pitfalls will be illustrated through the recently established NIH-VA Collaborative Aging Research using Technology (CART) system, an integrated, home-based pervasive computing platform deployed to hundreds of homes, and designed be shared widely to improve clinical aging research by capturing objective, holistic, 24/7, and ecologically valid data.

Biomedical Informatics and eHealth Core (BMI-EH), 1FLORIDA ADRC

Demetrius Maraganore, MD
University of Florida, Gainesville, FL, USA

The 1Florida Alzheimer’s Disease Research Center (ADRC) and the OneFlorida Clinical Research Consortium have combined efforts to create a biomedical informatics and e-Health core (BMI-eH). The BMI-eH will leverage the OneFlorida Data Trust of the OneFlorida Clinical Research Consortium, and expertise in electronic medical record (EMR) research to achieve the following aims: 1. Provide 1Florida ADRC and other ADRC investigators access to a large statewide repository of linked EMR, claims and social determinants of health (SDoH) data to generate and test hypotheses for Alzheimer’s disease and related disorders (ADRD). 2. Provide 1Florida ADRC and other ADRC investigators with informatics tools that support study feasibility determination, cohort discovery, clinical trials, and population health initiatives in ADRD. 3. Facilitate use of the OneFlorida Data Trust as a registry to access existing data and/or collect new data from special populations and their matched controls. 4. Create linkages with other 1Florida ADRC cores, other ADRCs, and other stakeholder organizations such as the NIA and the Alzheimer’s Association. The OneFlorida statewide repository includes data from 15.1 million patients, including 2.3 million adults ages 65+. The repository combines information from 4,100 providers, 1,240 practice/clinics, and 22 hospitals, providing care to >50% of Floridians. The repository is representative of routine healthcare encounters (diagnosis, treatment, and test results) in Florida. Because the OneFlorida Data Trust includes information for a large segment of the Florida population and captures clinical outcome measures, it is more likely that the findings from BI-eH supported studies will generalize to the real-world population. We will develop, replicate, implement, and disseminate an ADRD prediction model and CDS tools that support practice-based primary prevention initiatives. We will also develop and share study design tools that identify patients representing targeted populations and likely to enroll and be retained, making clinical trials more efficient and more likely to generalize to diverse populations. The BI-eH Core will provide the opportunity to study a large sample of patients with AD and less common dementia types, including in minority populations. The BI-eH will also employ several informatics methods beyond diagnostic codes to compute a phenotype of “successful brain aging” in persons ages 90+, and identify factors associated with brain health. The linkages between the BI-eH, other 1Florida ADRC cores, other ADRCs, other PCOREnets, and other stakeholder organizations support studies nationally and internationally of a broader scope than the examples provided here.

Nikolaus McFarland, MD, PhD

University of Florida

Nikolaus McFarland, MD, PhD, is an Associate Professor of Neurology and current Division Chief of Movement Disorders at the University of Florida, College of Medicine. He holds The Wright/Falls/Simmons Professorship in PSP/Atypical Parkinson’s.

He joined the UF Department of Neurology and the Center for Movement Disorders & Neurorestoration in 2010 (recently renamed, the Norman Fixel Institute for Neurological Diseases). He is also a member of the Center for Translational Research in Neurodegenerative Disease (CTRND) that aims to bring the bench closer to the bedside.

He completed his medical and graduate training at the University of Rochester School of Medicine & Dentistry and neurology residency at the University of Virginia. At the Massachusetts General Hospital, he pursued fellowship training in Movement Disorders and research in Parkinson disease and related disorders. He has received support from the NIH-NINDS, the American Parkinson Disease Association and Michael J. Fox Foundation. Dr. McFarland directs a comprehensive multidisciplinary clinical-research program (a Cure PSP Center of Care) for Atypical Parkinson disorders including dementia with Lewy bodies (DLB), multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal syndrome. He is also Director of the UF Huntington Disease Society of America (HDSA) Center of Excellence and the Fixel Institute Biomarker laboratory.

The Unraveling Story of Tyrosine Kinase Inhibition In Parkinson’s Disease and Dementia with Lewy Bodies

Charbel Moussa
Georgetown University, Washington, DC, USA

We evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of a potential disease modifying drug in Parkinson’s disease.
The primary objective was to assess nilotinib effects on safety and pharmacokinetics. Secondary objective was to measure the change in exploratory biomarkers; and exploratory objectives were clinical outcomes in moderately severe Parkinson’s patients with mild cognitive impairment (MCI).

This was a single center, phase II randomized, double-blind, placebo-controlled study with approximately 300 patients approached in clinic, about 200 declined to participate, 100 were screened, 25 were excluded and 75 were randomized 1:1:1 into placebo, 150 mg or 300 mg nilotinib groups taken orally, once daily for 12 months. Recruitment started in May 2017 and ended April 2018. Follow-up ended August 2019. Parkinson’s disease was confirmed according to the UK Brain Bank diagnostic criteria and symptoms were stabilized on optimal levodopa and/or dopamine agonists and other Parkinson’s medications.

We hypothesized that nilotinib is safe and is detected in the brain. We predicted that nilotinib alters exploratory biomarkers via inhibition of Abl in the cerebrospinal fluid and may improve clinical outcomes. We found that Nilotinib is reasonably safe. The 150 mg nilotinib group shows an increase in dopamine metabolites homovanillic acid and 3.4-Dihydroxyphenylacetic acid and the 300 mg nilotinib group shows an increase in 3-4-Dihydroxyphenylacetic acid. The 150 mg nilotinib but not the 300 mg group shows reduction of alpha-synuclein oligomers. A significant reduction of hyper-phosphorylated tau is seen in the 150 mg nilotinib and the 300 mg nilotinib groups. This study met its primary objectives that nilotinib is reasonably safe and detected in the cerebrospinal fluid. Exploratory biomarkers were also altered in response to nilotinib. A twelve-month treatment with nilotinib alters exploratory CSF biomarkers, including brain dopamine turnover, oligomeric alpha-synuclein and hyper-phosphorylated tau.

Taken together, our data will guide the development of a phase III study to investigate the effects of nilotinib in Parkinson’s disease and Dementia with Lewy Bodies.

Paradoxical Aging in Alzheimer’s Disease: A Clinicopathologic Perspective

Melissa Murray
Mayo Clinic, FL, USA

The strongest risk factor for Alzheimer’s disease (AD) dementia is increasing age, yet sporadic young onset AD sufferers are often observed to have a more severe disease course. Moreover, neuroimaging and neuropathologic studies demonstrate skewed cortical involvement that may underlay a higher frequency of observed focal cortical syndromes in those less than age 65 at presentation. To provide clinicopathologic evidence of paradoxical aging in AD, the FLorida Autopsied Multi-Ethnic (FLAME) cohort will be utilized. This autopsied series is derived from memory disorder clinic referral services throughout the state of Florida. The FLAME-AD cohort provides an invaluable opportunity to investigate the intersection of age (53-102 years at death) and sex (n=875/1625 [54%] females) in AD. Consideration of biomarker readouts evaluating therapeutic efficacy will be discussed, as it is still unclear the potential bearing of a more severe phenotype observed in young onset AD sufferers. While all young onset AD patients would become amyloid positive, utilization of hippocampal involvement or speed of decline as a biomarker readout may interfere with interpretation relative to late onset AD sufferers. Throughout the presentation, parallels to what has been reported in neuropathologic subtypes of AD will be discussed. Neurofibrillary tangle patterns that diverge from the well-established Braak staging method (hippocampus > cortex) have identified extreme phenotypes of hippocampal sparing AD (hippocampus <<< cortex) and limbic predominant AD (hippocampus >>> cortex). Hippocampal sparing AD is enriched in young onset AD patients, whereas limbic predominant AD is enriched in late onset AD patients. To examine the intersection between the concept of paradoxical aging and AD subtypes, neurofibrillary tangle accumulation in the cholinergic hub (i.e., nucleus basalis of Meynert) will be discussed.

The Brain Health Registry: Use of Web-based Technology for Detecting and Monitoring Changes in Cognition and Alzheimer’s Disease Risk

Rachel Nosheny
University of California, San Francisco, San Francisco, CA, USA

Background: A critical need in the field is development of efficient methods to identify older adults at risk for cognitive impairment, cognitive decline, and Alzheimer’s disease (AD). Web-based tools provide effective, scalable, low-cost methods for recruitment, screening, assessment, and longitudinal monitoring of older adults, and can be used to facilitate AD and aging clinical research.

Methods: Launched in 2014, the UCSF Brain Health Registry (BHR) is an internet-based registry that collects longitudinal health, genetic, and cognitive data using self- and study-partner report questionnaires, online cognitive tests, and remote DNA collection.

Results: Over 66,000 participants have enrolled in the BHR, and over 30,000 have provided longitudinal data. Over 2100 participants are co-enrolled in BHR and other, in clinic studies, and over 1000 have β-amyloid PET data linked to their online data. APOE ε4 genotyping has been performed on 1,330 participants. Ongoing analyses support the construct and predictive validity of BHR data, including online cognitive tests, and self- and study partner-reported measures of cognitive- and functional decline. New BHR projects include the development and validation of novel, electronic versions of the Clinical Dementia Rating Scale and the Financial Capacity Instrument; and collection of blood for analysis of plasma biomarkers. Shared BHR data has been used to evaluate the associations between online cognitive test performance and sleep, Parkinson’s disease, Traumatic Brain Injury, and Repetitive Head Injury in published manuscripts.

Conclusion: Web-based recruitment, assessment, and longitudinal monitoring is an effective, scalable, and low-cost approach to identify older adults at risk for cognitive decline, cognitive, impairment, and AD.

NIA-AA Framework for Alzheimer’s Disease Research: Implications for Mild Cognitive Impairment

Ronald Petersen
Mayo Clinic, Rochester, MN, USA

The newly formulated NIA-AA Alzheimer’s disease (AD) research framework that is based on the ATN scheme for describing the underlying pathophysiology of AD is being evaluated. The research framework defines AD based on the presence of amyloid and tau without reference to clinical symptoms. However, clinical phenotypes are used to stage the disease process. As such, two schemes were proposed: 1) The syndromic progression from cognitively unimpaired to MCI to dementia, and 2) a six-stage clinical scheme for individuals who are amyloid positive. Both of these clinical platforms have implications for the diagnosis and evaluation of individuals with MCI. Data from the Mayo Clinic Study of Aging will be used to discuss the proposed definitions of the clinical schemata, and preliminary data with regard to the utility will be discussed.

The ATN Framework: The Importance of Lifestyle Factors in Predicting Progression

Jennifer Rabin
Sunnybrook Research Institute, Toronto, ON, Canada

It is well established that the pathophysiological process of Alzheimer’s disease (AD) begins decades before clinical symptoms emerge and is characterized by early accumulation of β-amyloid (Aβ). This “preclinical” stage provides an opportunity to intervene prior to substantial neuronal loss and clinical impairment. However, there are currently no available disease-modifying therapies for AD and several recent clinical trials targeting Aβ in the symptomatic phase of the disease have yielded disappointing results. As such, there is a pressing need to identify potentially modifiable risk factors that may delay the progression of AD. In this talk, I will present data from the Harvard Aging Brain Study, an ongoing longitudinal study designed to identify early markers of AD progression in asymptomatic adults. I will describe the results from several recent studies demonstrating that improved vascular health and greater engagement in physical activity may attenuate the negative impact of Aβ burden on cognitive decline, neurodegeneration, and tau deposition. The implication of these findings will be discussed in terms of informing interventional strategies for AD.

Julie Schneider, MD

Rush University

Julie Schneider, MD, is the Deborah R. And Edgar D. Jannotta Presidential Professor of Pathology (Neuropathology) and Neurological Sciences and Associate Director at the Rush Alzheimer’s Disease Center at Rush University Medical Center. She completed her Neurology residency at the University of Chicago and Neuropathology fellowship at Emory University in Atlanta and is board certified in both specialties.

Dr. Schneider is also certified in Geriatric Neurology and has master’s degree in Clinical Research with a focus in Epidemiology. She is the Neuropathology Core Leader of the Rush Alzheimer’s Disease Center and the senior neuropathologist for multiple studies including the Religious Orders Study, Rush Memory and Aging Project, and Rush Minority Aging Research Study, Rush Latino Core, and NCRAD (National Cell Repository for Alzheimer’s disease).

Dr. Schneider has provided peer review for over 25 journals; has been invited to multiple journal editorial boards; and has provided numerous grant peer reviews for the National Institutes of Health, Alzheimer’s Association, and other agencies. She has served on numerous scientific and external national and international advisory boards for academia and industry; and has presented findings from her research both nationally and internationally.

Dr. Schneider has extensive experience with clinical-pathologic epidemiologic studies of aging and dementia and has over 300 peer-reviewed publications and 4 book chapters. She also has extensive experience collaborating with researchers, participating in multicenter grants and initiatives, and partnerships with industry to advance science.  The foundation of Dr. Schneider’s research is the exploration of pathologic factors in the clinical expression of cognitive decline in aging, with a focus on vascular, TDP-43, hippocampal sclerosis and mixed pathologies in Alzheimer’s and related dementias.

Dr. Schneider has over 300 peer-reviewed publications and an H-factor of 104. Her current research leverages neuropathology to advance understanding of risk, methods for diagnosis, and biomarker development for vascular, TDP, and mixed pathologies.

The NIA-AA Research Framework: Implications for Clinical Care, Epidemiological and Genetic Studies

Sudha Seshadri
Glenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases, San Antonio, TX, USA

The desire to target preventive therapies based on logical biomarkers has led to the A/T/N research framework that equates cerebrospinal fluid or PET imaging evidence of cerebral amyloidosis with preclinical, prodromal or clinical Alzheimer disease. This reasonable approach however raises new challenges and concerns and conflicts with a growing recognition that underlying most dementias are multiple etiologies that vary between individuals. Affected and at-risk individuals can be defined by a range of endophenotypes and biomarkers and appear to cluster in groups that cross conventional clinical diagnostic categories.

The ATN Framework: Prediction of Progression from MCI to AD Dementia

Leslie Shaw
University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

A key characteristic of Alzheimer’s disease is its multifactorial nature. Important developments in this field include the standardization of imaging and biochemical biomarker measures that detect different aspects of the underlying pathologic processes of the disease. The recently described National Institute on Aging-Alzheimer’s Association research framework on Alzheimer’s disease provides a systematic approach to defining the state of Alzheimer’s pathologic change in patients using a combination of amyloid (A), tau(T) and neurodegeneration (N) biomarkers. Studies are underway evaluating the performance of the framework in various populations and across the pre-clinical and prodromal stages of AD. Biochemical and imaging biomarkers and clinical assessment data from the multicenter Alzheimer’s Disease Neuroimaging Initiative (ADNI) study will be used to illustrate the potential for the predictive performance of the ATN scheme for progression from a clinical diagnosis of MCI to dementia and for prediction of decline in memory, cognition and function.

Memory Compensation Training and Computerized Cognitive Training in MCI

Glenn Smith
University of Florida, Gainesville, FL, USA

Not long after the concept of Mild Cognitive Impairment (MCI) gained wide acceptance our group began exploring models for intervening with people with MCI (pwMCI) and the partners of pwMCI. We explored both computerized brain training and memory compensation training as examples of restitution and compensation approaches, respectively. This presentation will summarize the decade worth of clinical experience, evaluation, and research data we have accumulated on these and other interventions.  It will discuss the comparative benefits of each of these approaches and who is most likely to adhere to them.  Ultimately, we developed a multicomponent behavioral intervention called HABIT® Healthy Action to Benefit Independence and Thinking.  This session will also include discussion of the results of a 5-year comparative effectiveness trial for pwPCI modeled on the HABIT® program. This presentation will explain the 40-hour group intervention, including memory compensation training, computerized cognitive training, yoga, patient and partner support groups, and/or wellness (e.g., sleep, diet) behavior change. It will review the outcomes measured and the make-up of the 272 MCI patients and partners that enrolled. Finally, the talk will describe how memory compensation and/or computerized training compared to other interventions on patient and caregiver quality of life, mood, and function.

The ATN Framework: Prediction of Progression from Normal Cognition to MCI

Reisa Sperling
Harvard Medical School, Boston, MA, USA

The National Institute on Aging-Alzheimer’s Association 2018 Research Framework sought to characterize the biological and clinical continuum of Alzheimer’s disease (AD). Beginning in 2011, the NIA-AA characterized a “preclinical stage” of AD that was defined by the presence of Alzheimer’s pathology, detectable through imaging and biomarkers. Since that time, evidence has continued to mount that markers of elevated amyloid (A) pathology (CSF or PET imaging) in cognitively unimpaired, clinically normal older individuals is associated with increased risk of cognitive decline, subjective report of change in cognitive function, subtle neuropsychiatric symptoms, and progression to mild cognitive impairment (MCI) and dementia. There is substantial heterogeneity in the rates of cognitive decline among normals with elevated amyloid, largely explained by the presence of markers of tau pathology (T). Cognitively unimpaired older individuals with markers of both A and T are at very high risk of imminent clinical decline. While markers of A and T define the neuropathologic hallmarks of AD, markers of neurodegeneration (N) are less specific to AD but may be useful in staging and prognosis of decline along the AD continuum. Research is ongoing to evaluate additional factors that may influence the rate of decline in those with elevated amyloid, including sex, genetics, and vascular risk. Perhaps most importantly, the question as to whether therapeutic intervention can slow cognitive decline at the stage of preclinical AD is being actively pursued in secondary prevention trials. These trials have multiple imbedded biomarkers, including tau PET, that may prove particularly valuable in tracking therapeutic response at this early stage of disease.

The role of Alpha-synuclein aggregates in the pathogenesis of Lewy Body and Parkinson’s disease

Maria Grazia Spillantini
University of Cambridge, Cambridge, UK

Parkinson’s disease (PD) is the most common movement disorder clinically characterized by rigidity, resting tremor and bradikenisia which are associated with degeneration of neurones in the substantia nigra and other brain regions. The movement features can be preceded by nonmotor symptoms such as depression, disturbed sleep and intestinal problems and can also be accompanied by cognitive alterations. Neuropathologically PD is characterized by the presence of the intracellular protein aggregates Lewy bodies and Lewy neurites that contain filaments made of the protein alpha-synuclein. Lewy bodies can be present very early on in the gut of PD patients leading to the suggestion that pathology can progress from the gut to the brain and when reaching cortical regions can be associated with to dementia.

Besides its presence in Lewy bodies, an involvement of alpha-synuclein in PD pathogenesis is also supported by the identification of missense mutations and multiplications of the alpha-synuclein gene as the cause of familial forms of PD where in some cases the motor dysfunction is associated with cognitive decline. However, how the protein contributes to PD development, the mechanism leading to Lewy bodies formation and their role in the neurodegenerative process remain unclear.

The pathogenesis of PD and other alpha-synucleinopathies is associated with aggregation of alpha-synuclein into oligomers and filaments with the former considered the toxic species. To investigate the mechanisms of alpha-synuclein toxicity and identify possible therapeutic targets we have produced a new transgenic mouse (MI2) expressing the aggregation prone truncated 1-120 alpha-synuclein transgene under the TH promoter specifically in dopaminergic neurons. These mice show progressive accumulation of alpha-synuclein in the substantia nigra and striatum associated with reduction in dopamine release in the striatum and dopaminergic cell death in the substantia nigra. Progressive motor alterations are also present. These features are rescued by treatment with the oligomer modifier Anle 138b. Using super resolution microscopy, we have observed that anle138b acts by reducing the density of the large alpha-synuclein aggregates and increasing the amount of monomeric synuclein in the environment. These mice provide an important model to understand the mechanisms linked to alpha-synuclein dysfunction and to test compounds for the treatment of Parkinson’s disease and other alpha-synucleinopathies.