Plasma inflammation for predicting phenotypic conversion and clinical progression of autosomal dominant frontotemporal lobar degeneration.

BACKGROUND: Measuring systemic inflammatory markers may improve clinical prognosis and help identify targetable pathways for treatment in patients with autosomal dominant forms of frontotemporal lobar degeneration (FTLD). METHODS: We measured plasma concentrations of IL-6, TNFα and YKL-40 in pathogenic variant carriers (MAPT, C9orf72, GRN) and non-carrier family members enrolled in the ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration consortium. We evaluated associations between baseline plasma inflammation and rate of clinical and neuroimaging changes (linear mixed effects models with standardised (z) outcomes). We compared inflammation between asymptomatic carriers who remained clinically normal ('asymptomatic non-converters') and those who became symptomatic ('asymptomatic converters') using area under the curve analyses. Discrimination accuracy was compared with that of plasma neurofilament light chain (NfL). RESULTS: We studied 394 participants (non-carriers=143, C9orf72=117, GRN=62, MAPT=72). In MAPT, higher TNFα was associated with faster functional decline (B=0.12 (0.02, 0.22), p=0.02) and temporal lobe atrophy. In C9orf72, higher TNFα was associated with faster functional decline (B=0.09 (0.03, 0.16), p=0.006) and cognitive decline (B=-0.16 (-0.22, -0.10), p<0.001), while higher IL-6 was associated with faster functional decline (B=0.12 (0.03, 0.21), p=0.01). TNFα was higher in asymptomatic converters than non-converters (ß=0.29 (0.09, 0.48), p=0.004) and improved discriminability compared with plasma NfL alone (ΔR2=0.16, p=0.007; NfL: OR=1.4 (1.03, 1.9), p=0.03; TNFα: OR=7.7 (1.7, 31.7), p=0.007). CONCLUSIONS: Systemic proinflammatory protein measurement, particularly TNFα, may improve clinical prognosis in autosomal dominant FTLD pathogenic variant carriers who are not yet exhibiting severe impairment. Integrating TNFα with markers of neuronal dysfunction like NfL could optimise detection of impending symptom conversion in asymptomatic pathogenic variant carriers and may help personalise therapeutic approaches.

MAPT R406W increases tau T217 phosphorylation in absence of amyloid pathology.

OBJECTIVE: Tau hyperphosphorylation at threonine 217 (pT217) in cerebrospinal fluid (CSF) has recently been linked to early amyloidosis and could serve as a highly sensitive biomarker for Alzheimer's disease (AD). However, it remains unclear whether other tauopathies induce pT217 modifications. To determine if pT217 modification is specific to AD, CSF pT217 was measured in AD and other tauopathies. METHODS: Using immunoprecipitation and mass spectrometry methods, we compared CSF T217 phosphorylation occupancy (pT217/T217) and amyloid-beta (Aß) 42/40 ratio in cognitively normal individuals and those with symptomatic AD, progressive supranuclear palsy, corticobasal syndrome, and sporadic and familial frontotemporal dementia. RESULTS: Individuals with AD had high CSF pT217/T217 and low Aß42/40. In contrast, cognitively normal individuals and the majority of those with 4R tauopathies had low CSF pT217/T217 and normal Aß 42/40. We identified a subgroup of individuals with increased CSF pT217/T217 and normal Aß 42/40 ratio, most of whom were MAPT R406W mutation carriers. Diagnostic accuracies of CSF Aß 42/40 and CSF pT217/T217, alone and in combination were compared. We show that CSF pT217/T217 × CSF Aß 42/40 is a sensitive composite biomarker that can separate MAPT R406W carriers from cognitively normal individuals and those with other tauopathies. INTERPRETATION: MAPT R406W is a tau mutation that leads to 3R+4R tauopathy similar to AD, but without amyloid neuropathology. These findings suggest that change in CSF pT217/T217 ratio is not specific to AD and might reflect common downstream tau pathophysiology common to 3R+4R tauopathies.

Development and interval testing of a naturalistic driving methodology to evaluate driving behavior in clinical research.

Background: The number of older adults in the United States will double by 2056. Additionally, the number of licensed drivers will increase along with extended driving-life expectancy. Motor vehicle crashes are a leading cause of injury and death in older adults. Alzheimer's disease (AD) also negatively impacts driving ability and increases crash risk. Conventional methods to evaluate driving ability are limited in predicting decline among older adults. Innovations in GPS hardware and software can monitor driving behavior in the actual environments people drive in. Commercial off-the-shelf (COTS) devices are affordable, easy to install and capture large volumes of data in real-time. However, adapting these methodologies for research can be challenging. This study sought to adapt a COTS device and determine an interval that produced accurate data on the actual route driven for use in future studies involving older adults with and without AD.  Methods: Three subjects drove a single course in different vehicles at different intervals (30, 60 and 120 seconds), at different times of day, morning (9:00-11:59AM), afternoon (2:00-5:00PM) and night (7:00-10pm). The nine datasets were examined to determine the optimal collection interval. Results: Compared to the 120-second and 60-second intervals, the 30-second interval was optimal in capturing the actual route driven along with the lowest number of incorrect paths and affordability weighing considerations for data storage and curation. Discussion: Use of COTS devices offers minimal installation efforts, unobtrusive monitoring and discreet data extraction.  However, these devices require strict protocols and controlled testing for adoption into research paradigms.  After reliability and validity testing, these devices may provide valuable insight into daily driving behaviors and intraindividual change over time for populations of older adults with and without AD.  Data can be aggregated over time to look at changes or adverse events and ascertain if decline in performance is occurring.