Biological effects of sodium phenylbutyrate and taurursodiol in Alzheimer's disease.

Introduction: Sodium phenylbutyrate and taurursodiol (PB and TURSO) is hypothesized to mitigate endoplasmic reticulum stress and mitochondrial dysfunction, two of many mechanisms implicated in Alzheimer's disease (AD) pathophysiology.

Methods: The first-in-indication phase 2a PEGASUS trial was designed to gain insight into PB and TURSO effects on mechanistic targets of engagement and disease biology in AD. The primary clinical efficacy outcome was a global statistical test combining three endpoints relevant to disease trajectory (cognition [Mild/Moderate Alzheimer's Disease Composite Score], function [Functional Activities Questionnaire], and total hippocampal volume on magnetic resonance imaging).

Promoting Growth in Behavioral Neurology: A Path Forward.

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.

Non-tremor motor dysfunction in Lewy body dementias is associated with AD biomarkers.

Motor features of Parkinson's disease (PD) are heterogeneous and well-studied; non-tremor features of postural instability and gait dysfunction (PIGD) have been linked to worse outcomes and Alzheimer's disease (AD) co-pathology. However, these features are understudied in Lewy body dementias (LBD). Here we perform retrospective analysis of a unique cohort of LBD (n = 30) with Unified Parkinson's Disease Rating Scale (UPDRS) data collected at baseline in proximity to cerebrospinal fluid collection to test the hypothesis that LBD patients with a positive AD biomarker profile (LBD + AD = 13) would have higher PIGD burden compared with LBD patients without AD biomarker positivity (LBD-AD = 17).

Tau immunotherapy is associated with glial responses in FTLD-tau.

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neuropathologic subtypes of frontotemporal lobar degeneration with tau inclusions (FTLD-tau), primary tauopathies in which intracellular tau aggregation contributes to neurodegeneration. Gosuranemab (BIIB092) is a humanized monoclonal antibody that binds to N-terminal tau. While Gosuranemab passive immunotherapy trials for PSP failed to demonstrate clinical benefit, Gosuranemab reduced N-terminal tau in the cerebrospinal fluid of transgenic mouse models and PSP patients.

Cognitive Profile and Markers of Alzheimer Disease-Type Pathology in Patients With Lewy Body Dementias.

Objective: To determine whether patients with Lewy body dementia (LBD) with likely Alzheimer disease (AD)-type copathology are more impaired on confrontation naming than those without likely AD-type copathology.

Methods: We selected 57 patients with LBD (dementia with Lewy bodies [DLB], n = 38; Parkinson disease dementia [PDD], n = 19) with available AD CSF biomarkers and neuropsychological data. CSF β-amyloid (Aβ), phosphorylated-tau (p-tau), and total-tau (t-tau) concentrations were measured.

Tau pathology associates with in vivo cortical thinning in Lewy body disorders.

Objectives: To investigate the impact of Alzheimer's disease (AD) co-pathology on an in vivo structural measure of neurodegeneration in Lewy body disorders (LBD).

Methods: We studied 72 LBD patients (Parkinson disease (PD) = 2, PD-MCI = 25, PD with dementia = 10, dementia with Lewy bodies = 35) with either CSF analysis or neuropathological examination and structural MRI during life. The cohort was divided into those harboring significant AD co-pathology, either at autopsy (intermediate/high AD neuropathologic change) or with CSF signature indicating AD co-pathology (t-tau/Aβ  > 0.

Multimodal in vivo and postmortem assessments of tau in Lewy body disorders.

We compared regional retention of F-flortaucipir between 20 patients with Lewy body disorders (LBD), 12 Alzheimer's disease patients with positive amyloid positron emission tomography (PET) scans (AD+Aβ) and 15 healthy controls with negative amyloid PET scans (HC-Aβ). In LBD subjects, we compared the relationship between F-flortaucipir retention and cerebrospinal fluid (CSF) tau, cognitive performance, and neuropathological tau at autopsy. The LBD cohort was stratified using an Aβ42 cut-off of 192 pg/mL to enrich for groups likely harboring tau pathology (LBD+Aβ = 11, LBD-Aβ = 9).

Longitudinal progression of grey matter atrophy in non-amnestic Alzheimer's disease.

Recent models of Alzheimer's disease progression propose that disease may be transmitted between brain areas either via local diffusion or long-distance transport via white matter fibre pathways. However, it is unclear whether such models are applicable in non-amnestic Alzheimer's disease, which is associated with domain-specific cognitive deficits and relatively spared episodic memory. To date, the anatomical progression of disease in non-amnestic patients remains understudied.

Neocortical origin and progression of gray matter atrophy in nonamnestic Alzheimer's disease.

Amnestic Alzheimer's disease (AD) is characterized by early atrophy of the hippocampus and medial temporal lobes before spreading to the neocortex. In contrast, nonamnestic Alzheimer's patients have relative sparing of the hippocampus, but the pattern in which the disease spreads is unclear. We examined spreading disease in nonamnestic AD using a novel magnetic resonance imaging-based analysis adapted from pathologic staging studies, applied here to cross-sectional imaging data.

Brain aerobic glycolysis and motor adaptation learning.

Ten percent to 15% of glucose used by the brain is metabolized nonoxidatively despite adequate tissue oxygenation, a process termed aerobic glycolysis (AG). Because of the known role of glycolysis in biosynthesis, we tested whether learning-induced synaptic plasticity would lead to regionally appropriate, learning-dependent changes in AG. Functional MRI (fMRI) before, during, and after performance of a visual-motor adaptation task demonstrated that left Brodmann area 44 (BA44) played a key role in adaptation, with learning-related changes to activity during the task and altered resting-state, functional connectivity after the task.

Suspected non-AD pathology in mild cognitive impairment.

We aim to better characterize mild cognitive impairment (MCI) patients with suspected non-Alzheimer's disease (AD) pathology (SNAP) based on their longitudinal outcome, cognition, biofluid, and neuroimaging profile. MCI participants (n = 361) from ADNI-GO/2 were designated "amyloid positive" with abnormal amyloid-beta 42 levels (AMY+) and "neurodegeneration positive" (NEU+) with abnormal hippocampal volume or hypometabolism using fluorodeoxyglucose-positron emission tomography. SNAP was compared with the other MCI groups and with AMY- controls.

Cultural competency in medical education: demographic differences associated with medical student communication styles and clinical clerkship feedback.

Purpose: We tested the significance of associations among students' demographics, communication styles, and feedback received during clerkships.

Methods: US medical students who completed at least one required clinical clerkship were invited between April and July 2006 to complete an anonymous, online survey inquiring about demographics, communication styles (assertiveness and reticence), feedback (positive and negative), and clerkship grades. The effects of self-identified race/ethnicity, gender, and generation (immigrant, first- or second-generation American) and their 2-way interactions on assertiveness, reticence, total positive and total negative feedback comments were tested using factorial analysis of covariance, controlling for age, clerkship grades, and mother's and father's education; pairwise comparisons used simple contrasts.

"Making the grade:" noncognitive predictors of medical students' clinical clerkship grades.

Objectives: Because clinical clerkship grades are associated with resident selection and performance and are largely based on residents'/attendings' subjective ratings, it is important to identify variables associated with clinical clerkship grades.

Methods: U.S.