Behavioral Neurology and Dementia*

Date/Time: Tuesday, September 12, 2023 - 11:00 AM – 12:30 PM
Track: Special Interest Group (SIG) Session
Room: Franklin Hall 2 (4th Floor)
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Chair: Thomas Wingo, MD

Co-Chair: Lenora Higginbotham, MD

The session covers important facets of dementia and behavioral neurology.
About 90% of early-onset Alzheimer's disease is not caused by well-known AD-causing mutations; however, compared to autosomal dominant causes of AD, comparatively much less is known about the clinical course, biomarkers, and imaging of these individuals with AD. The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) aims to address these knowledge gaps. The session will include interim results of LEADS clinical observational study, discuss their implications for the practice of clinical neurology.
Dementia with Lewy Bodies is a prevalent cause of dementia. Yet, there are no current treatments specifically addressing the unique constellation of clinical symptoms affecting individuals with this condition. The session will outline the challenges and progress for creating therapeutics for dementia with Lewy Bodies and share insights from phase 2 clinical trials for the condition.
One of the most devastating sequala of stroke is the loss of language abilities. While most people with aphasia recover some language function there is substantial variability in the degree of recovery that presents a challenge for deciding timing and type of language therapy, the specific behavior and augmentation therapies that may aide recovery, and the ability to provide realistic prognostication for patients and families.

Learning Objectives:

  • To recognize the most recent therapeutic trials for Dementia with Lewy bodies and gain an understanding of advancements that may impact clinical care.

Early-onset AD advances and findings from LEADS

Speaker: Liana G. Apostolova, MD, MSc, FAAN

Approximately 5% of the 5.8 million victims of Alzheimer’s disease in the US develop symptoms at age 65 or younger and are classified as having early-onset AD (EOAD). Although EOAD and late-onset AD (LOAD) share the same pathologic substrate, there are notable differences in their clinical and biological phenotypes. Compared to LOAD, sporadic EOAD patients show faster cognitive decline, lower prevalence of amnestic versus non-amnestic presentations, greater baseline cortical atrophy/hypometabolism, less medial temporal lobe involvement and more severe AD pathology. Studies suggest higher heritability in EOAD compared to LOAD in the absence of known mutations or APOE4, suggesting that this population is enriched for novel genetic risk factors.

Despite being highly motivated and having fewer age-related comorbidities compared to LOAD, EOAD are commonly excluded from clinical research and therapeutic trials. The Longitudinal Early-onset AD study (LEADS) is a multi-site, observational clinical and biomarker study of EOAD. We are comprehensively characterizing the cognitive, imaging and biofluid changes over time in EOAD and applying next generation sequencing to assess for novel AD genetic risk factors. This presentation will describe the recent research advances in LEADS.

Language recovery after stroke

Speaker: Argye E. Hillis, MD, MA, FANA

I will discuss distinct mechanisms of recovery of language at different stages in post-stroke aphasia, and interventions that can be helpful at each stage.

Dementia with Lewy Bodies advances - including phase 2 trials

Speaker: James E. Galvin, MD, MPH

Dementia with Lewy Bodies (DLB) is the second most common cause of dementia after Alzheimer's disease but to date there are few treatments to offer patients other than symptomatic medications originally from Alzheimer's disease, Parkinson's disease, and psychiatric indications.  However, there are number of exciting advances in therapeutics in DLB with novel, potentially disease-modifying molecules in phase 1 and phase 2 trials that offer hope for patients and their families.  There is also interest in repurposing medications from other indications that may have secondary mechanisms relevant for Lewy body pathology. We will review current trials and study design and discuss results of failed trials as lessons learned to advance the field forward.

Improving Early Recognition of Potentially Treatment-Responsive Causes of Rapidly Progressive Dementia

Oral Abstract Presenter: Nihal Satyadev, MD, MPH, Mayo Clinic Florida

Objectives: To improve the timely recognition of patients with treatment-responsive causes of rapidly progressive dementia (RPD). Background: The term RPD encompasses patients who progress from first symptom to dementia in less than one year or to complete incapacitation within two years. Although RPD is often associated with fatal neurodegenerative diseases, including Alzheimer disease or Creutzfeldt-Jakob disease, treatable forms of RPD are increasingly recognized. Early recognition of patients with potentially treatment-responsive causes of RPD is critical to minimize morbidity and optimize outcomes. Methods: Patients with suspected RPD were enrolled between February 2016 and August 2022 in a prospective observational study of RPD and followed for two years or until death. Etiologic diagnoses were independently assigned by two neurologists and causes of RPD classified as treatment-responsive or nonresponsive, referencing the clinical literature. Disease progression was objectively measured using the Clinical Dementia Rating® Sum-of-Box scores. Clinical and paraclinical features associated with treatment responsiveness were assessed using multivariable logistic regression. Results of multivariable analyses informed development of a practical and accessible clinical criteria to improve recognition of patients with potentially treatable causes of RPD. Results: 87/155 patients (56.1%) had a potentially treatment-responsive cause of RPD, including autoimmune/inflammatory disease (n=52, 59.8%), vasculitis (n=13, 14.9%), primary psychiatric disease (n=4, 4.6%), or nutritional deficiency (n=4, 4.6%). Seizures (OR: 10.49, 95%CI: 3.07-35.79), Tumor (disease-associated; OR: 12.86, 95%CI: 2.11-78.3), Age <50-years (OR: 6.41, 95%CI: 1.49-27.61), MRI suggestive of autoimmune encephalitis (OR: 23.47, 95%CI: 2.33-236.67), Mania (OR: 21.57, 95%CI: 2.04-227.92), Movement abnormalities (OR: 5.27, 95%CI: 1.89, 14.97), and Pleocytosis (≥10 cells/μL of CSF; OR: 30.30, 95%CI: 5.54, 165.65) at presentation were independently associated with treatment-responsive causes of RPD (c-statistic = 0.91, 95%CI: 0.86-0.95; p<0.001). Detection of any “STAM3P” feature at presentation captured 83/87 cases of treatment-responsive RPD (sensitivity = 95%, specificity = 63%, positive predictive value = 77%, negative predictive value = 92%). The presence of ≥3 of these features had a positive predictive value of 100%. Interpretation: Treatment-responsive causes of RPD were common in our series. The detection of selected features reliably identified patients with potentially treatment-responsive causes of RPD early in the symptomatic course. Adaptation of the STAM3P screening score in clinical practice may minimize diagnostic delays and missed opportunities for treatment in patients with RPD.

Differential ATN Networks of Cerebrospinal Fluid and Neuroimaging Biomarkers and Their Prediction of Cognition between Self-Reported Black and Non-Hispanic White Individuals

Oral Abstract Presenter: Samuele Bonomi, MD, Washington University in St. Louis

Background: Biomarkers of Alzheimer's disease (AD), including cerebrospinal fluid (CSF), amyloid PET, and MRI imaging measures, have been reported to vary between self-reported Black/African American and Non-Hispanic White individuals. It is unknown whether different racialized groups have differences in the network of connections between AD biomarkers, or in the prediction of cognition by these biomarkers. Method: The Study of Race to Understand Alzheimer Biomarkers (SORTOUT-AB) centrally re-processed CSF samples and imaging scans collected at four AD Research Centers/studies: Washington University, University of Pennsylvania, Emory University, and the Harvard Aging Brain Study. Data included CSF measures for 286 Black and 2,080 White participants, amyloid PET for 157 Black and 936 White participants, tau PET for 67 Black and 492 White participants, and structural MRI for 322 Black and 1,530 White participants. Spearman correlations between biomarkers and cognitive measures were estimated within each racial group, then compared between groups, adjusting for age, sex, APOE ε4 carrier status, cognitive status, years of education, and medical comorbidities. Results: CSF Aβ42 was positively correlated with both total tau and p-tau181 in Black but not White participants. CSF Aβ42/40 was negatively correlated with total tau and p-tau181 in both racial groups, but at a smaller magnitude in Black individuals. CSF Aβ40 was positively associated with p-tau181 in both racial groups, but at a larger magnitude in Black individuals. CSF neurofilament light (NfL) was correlated with all other CSF biomarkers in both racial groups and did not vary by race. CSF Aβ42, Aβ42/40, and p-tau181 had stronger correlations with global cognition and memory in White than Black participants. No racial differences were found in correlations between different imaging biomarkers, or in correlations between imaging biomarkers and cognition. Amyloid PET Centiloid was negatively correlated with CSF Aβ42 and Aβ42/40 in White but not Black individuals. Conclusion: Relationships between CSF and imaging biomarkers, and between AD biomarkers and cognitive measures, differed between Black and White groups. This suggests that AD biomarkers may not have consistent meanings across racialized groups. Use of biomarkers in designing/analyzing AD prevention and treatment trials must appropriately address racial differences.