Geschwind, Michael D.

Behavioral neurology & neuropsychiatry (BNNP) is a field that seeks to understand brain–behavior relationships, including fundamental brain organization principles and the many ways that brain structures and connectivity can be disrupted, leading to abnormalities of behavior, cognition, emotion, perception, and social cognition. In North America, BNNP has existed as an integrated subspecialty through the United Council for Neurologic Subspecialties since 2006. Nonetheless, the number of behavioral neurologists across academic medical centers and community settings is not keeping pace with increasing clinical and research demand. In this commentary, we provide a brief history of BNNP followed by an outline of the current challenges and opportunities for BNNP from the behavioral neurologist’s perspective across clinical, research, and educational spheres. We provide a practical guide for promoting BNNP and addressing the shortage of behavioral neurologists to facilitate the continued growth and development of the subspecialty. We also urge a greater commitment to recruit trainees from diverse backgrounds so as to dismantle persistent obstacles that hinder inclusivity in BNNP—efforts that will further enhance the growth and impact of the subspecialty. With rapidly expanding diagnostic and therapeutic approaches across a range of conditions at the intersection of neurology and psychiatry, BNNP is well positioned to attract new trainees and expand its reach across clinical, research, and educational activities.

AbstractBackgroundThe causes of rapidly progressive dementia are heterogeneous, including neurodegenerative, vascular, and autoimmune/inflammatory diseases. Overlap in presenting symptoms and signs, results of cognitive testing, and findings on brain imaging and other common diagnostic tests confounds the etiologic diagnosis, contributing to diagnostic delays, missed opportunities for treatment, and poorer outcomes in patients with RPD. New tools and approaches are needed to improve diagnostic accuracy, with particular emphasis on improving early recognition of patients with potentially treatable causes of RPD.MethodsEstablished and emerging biomarkers of Alzheimer disease neuropathology (Aβ42/40, p‐tau181, p‐tau231), neuroaxonal and neuronal injury (neurofilament light [NfL], VILIP‐1, total tau), neuroinflammation (YKL‐40, sTREM2, GFAP, MCP‐1), and synaptic dysfunction (SNAP‐25, neurogranin) were measured in cerebrospinal fluid obtained at presentation from 78 prospectively accrued patients with RPD due to neurodegenerative (n = 35), vascular (n = 9), and autoimmune/inflammatory (n = 34) diseases, and 72 age‐ and sex‐similar cognitively normal individuals (controls). Causes of RPD were further classified as potentially treatment‐responsive or nonresponsive, referencing the extant literature. Biomarker levels were compared across etiologic diagnoses and by treatment responsiveness, referencing control values. Analyses were adjusted for the effects of age (ANCOVA).ResultsAlzheimer disease biomarkers (low Aβ42/40 and elevated p‐tau181 and p‐tau231) were associated with neurodegenerative causes of RPD (ANCOVA, p = 0.02 p = 0.30, p = 0.15), while high NfL (p = 0.61), low VILIP‐1 (p = 0.009), and elevated markers of inflammation (sTREM2, p = 0.009; YKL‐40, p<0.001) identified patients with autoimmune/inflammatory diseases (Figure). MCP‐1 levels were highest in patients with vascular causes of RPD (p = 0.08). 44 patients (56.4%) had potentially treatment‐responsive causes of RPD. Treatment responsiveness was associated with higher levels of CSF Aβ42/40 (p = 0.003), NfL (p<0.001), sTREM2 (p<0.001) and YKL‐40 (p<0.001); and lower levels of p‐tau‐181 and p‐tau231 (p<0.001, p<0.001) and VILIP‐1 (p<0.001).ConclusionSelected biomarkers measured in CSF at presentation associate with etiologic diagnosis and treatment responsiveness in patients with neurodegenerative, vascular, and autoimmune/inflammatory causes of RPD. Biomarker panels may be adapted to improve recognition of patients with treatment‐responsive causes of RPD early in the symptomatic course when treatments may be most effective.

ObjectiveThis study was undertaken to apply established and emerging cerebrospinal fluid (CSF) biomarkers to improve diagnostic accuracy in patients with rapidly progressive dementia (RPD). Overlap in clinical presentation and results of diagnostic tests confounds etiologic diagnosis in patients with RPD. Objective measures are needed to improve diagnostic accuracy and to recognize patients with potentially treatment‐responsive causes of RPD.MethodsBiomarkers of Alzheimer disease neuropathology (amyloid‐β 42/40 ratio, phosphorylated tau [p‐tau181, p‐tau231]), neuroaxonal/neuronal injury (neurofilament light chain [NfL], visinin‐like protein‐1 [VILIP‐1], total tau), neuroinflammation (chitinase‐3‐like protein [YKL‐40], soluble triggering receptor expressed on myeloid cells 2 [sTREM2], glial fibrillary acidic protein [GFAP], monocyte chemoattractant protein‐1 [MCP‐1]), and synaptic dysfunction (synaptosomal‐associated protein 25kDa, neurogranin) were measured in CSF obtained at presentation from 78 prospectively accrued patients with RPD due to neurodegenerative, vascular, and autoimmune/inflammatory diseases; 35 age‐ and sex‐matched patients with typically progressive neurodegenerative disease; and 72 cognitively normal controls. Biomarker levels were compared across etiologic diagnoses, by potential treatment responsiveness, and between patients with typical and rapidly progressive presentations of neurodegenerative disease.ResultsAlzheimer disease biomarkers were associated with neurodegenerative causes of RPD. High NfL, sTREM2, and YKL‐40 and low VILIP‐1 identified patients with autoimmune/inflammatory diseases. MCP‐1 levels were highest in patients with vascular causes of RPD. A multivariate model including GFAP, MCP‐1, p‐tau181, and sTREM2 identified the 44 patients with treatment‐responsive causes of RPD with 89% accuracy. Minimal differences were observed between typical and rapidly progressive presentations of neurodegenerative disease.InterpretationSelected CSF biomarkers at presentation were associated with etiologic diagnoses and treatment responsiveness in patients with heterogeneous causes of RPD. The ability of cross‐sectional biomarkers to inform upon mechanisms that drive rapidly progressive neurodegenerative disease is less clear. ANN NEUROL 2024;95:299–313

AbstractBackgroundOverlap in the presenting clinical features and test results in patients with rapidly progressive dementia (RPD) confounds the etiologic diagnoses of RPD, contributing to diagnostic delays, missed treatment opportunities, and poorer outcomes. There is a need to improve diagnostic accuracy in patients with RPD, with particular emphasis on identifying patients with potentially treatment‐responsive causes of RPD early in the symptomatic course.MethodPatients with RPD were prospectively enrolled and evaluated in inpatient settings and outpatient subspecialty (memory) clinics at Washington University (Saint Louis, MO; 2016–2019) and Mayo Clinic (Jacksonville, FL; 2020–2021). Etiologic diagnoses were independently assigned by two dementia specialists integrating clinical features and the results of widely accessible diagnostic testing and referencing established diagnostic criteria. Diagnostic disagreements were resolved via blinded review by a third specialist. Clinicopathologic correlation was evaluated using neuropathological and genetic data when available.Result160 patients with RPD were assessed, with average age‐at‐symptom onset 60.0±15.9 years; 50% were female. Diagnostic inter‐rater reliability (91% agreement; Cohen’s κ = 0.88, p<0.001) and clinicopathologic correlation were excellent (100% agreement in 24 patients with neuropathologic or genetic data). Autoimmune encephalitis was the leading cause of RPD (39%), followed by Alzheimer disease and related dementias (29%—i.e., frontotemporal dementia, Lewy body dementia, vascular cognitive impairment), Creutzfeldt‐Jakob disease (15%), and other causes (15%—e.g., neurosarcoid, metabolic disruptions, neoplastic disease). The average age of patients with potentially treatable causes (AE and selected “other” causes; 54.4±18.2) was younger than those with neurodegenerative dementing illnesses (67.3±9.5) or CJD (67.4±7.9; p<0.001). Patients with potentially treatable causes were more likely to present with altered level of consciousness and seizures (p<0.05). CSF pleocytosis (>5 WBC/hpf) was more common in AE patients (p<0.05).ConclusionEtiologic diagnoses can be reliably established in RPD patients using available clinical data. Treatment‐responsive causes of RPD are common warranting consideration, particularly in younger patients with altered consciousness, seizures, and CSF pleocytosis.