Cognitive determinants of decisional capacity in neurodegenerative disorders.

OBJECTIVE: Cognitive contributions to decisional capacity are complex and not well understood. Capacity to consent for research has been linked to executive function, but executive function assessment tools are imperfect. In this study, we examine the relationship between decisional capacity and a newly developed executive function composite score and determine whether cognitive performance can predict impaired decisional capacity. METHODS: This is a cross sectional study of participants at the National Institutes of Health with frontotemporal dementia-amyotrophic lateral sclerosis spectrum disorders enrolled between 2017 and 2022. A structured interview tool was used to ascertain research decisional capacity. Study participant Uniform Data Set (v3.0) executive function (UDS3-EF) composite score, Clinical Dementia Rating Scale©, and Neuropsychiatric Inventory was determined. RESULTS: A decrease in UDS3-EF composite score significantly increased the odds of impaired decisional capacity (OR = 2.92, 95% CI [1.66-5.13], p = 0.0002). Executive function was most impaired in frontotemporal dementia (-2.86, SD = 1.26) and least impaired in amyotrophic lateral sclerosis (-0.52, SD = 1.25) participants. The UDS3-EF composite score was also strongly correlated to the Clinical Dementia Rating Scale©. INTERPRETATION: Decisional capacity is intrinsically related to executive function in neurodegenerative disorders, and executive dysfunction may predict a lack of decisional capacity alerting investigators of the need for additional scrutiny during the informed consent process.

Disease progression in C9orf72 mutation carriers.

OBJECTIVE: To assess changes in 3 clinical measures, the Revised ALS Functional Rating Scale (ALSFRS-R), letter fluency, and Frontal Behavioral Inventory (FBI), over time in C9orf72 mutation carriers (C9+) with varied clinical phenotypes. METHODS: Thirty-four unrelated participants with mutations in C9orf72 were enrolled in a prospective natural history study. Participants were classified as asymptomatic, amyotrophic lateral sclerosis (ALS), ALS-familial frontotemporal dementia (FTD), or behavioral-variant FTD by clinical diagnostic criteria. Diagnostic cognitive and motor tests were repeated at 6 and 18 months. The ALSFRS-R, letter fluency, and FBI were administered at baseline and follow-up visits at 6, 12, and 18 months. RESULTS: The clinical diagnosis of most patients did not change over the follow-up. ALSFRS-R scores correlated with measures of motor function. Letter fluency correlated with FBI and cognitive tests. ALSFRS-R, letter fluency, and FBI differed among the C9+ diagnostic subgroups at enrollment and worsened over follow-up in symptomatic patients, with different slopes among the subgroups. Most patients survived to the 6-month time point after enrollment. Survival of C9+ patients with ALS and C9+ patients with ALS-FTD declined over the 12- and 18-month follow-up. CONCLUSIONS: The pattern of scores of the ALSFRS-R, letter fluency, and FBI distinguished between ALS, ALS-FTD, and FTD presentations of C9orf72 mutation carriers and asymptomatic carriers. Longitudinal changes in these measures occurred with disease progression in a manner consistent with presenting phenotype.

Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis.

There is no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating motor neuron disease. However, discovery of a G4C2 repeat expansion in the C9ORF72 gene as the most common genetic cause of ALS has opened up new avenues for therapeutic intervention for this form of ALS. G4C2 repeat expansion RNAs and proteins of repeating dipeptides synthesized from these transcripts are believed to play a key role in C9ORF72-associated ALS (c9ALS). Therapeutics that target G4C2 RNA, such as antisense oligonucleotides (ASOs) and small molecules, are thus being actively investigated. A limitation in moving such treatments from bench to bedside is a lack of pharmacodynamic markers for use in clinical trials. We explored whether poly(GP) proteins translated from G4C2 RNA could serve such a purpose. Poly(GP) proteins were detected in cerebrospinal fluid (CSF) and in peripheral blood mononuclear cells from c9ALS patients and, notably, from asymptomatic C9ORF72 mutation carriers. Moreover, CSF poly(GP) proteins remained relatively constant over time, boding well for their use in gauging biochemical responses to potential treatments. Treating c9ALS patient cells or a mouse model of c9ALS with ASOs that target G4C2 RNA resulted in decreased intracellular and extracellular poly(GP) proteins. This decrease paralleled reductions in G4C2 RNA and downstream G4C2 RNA-mediated events. These findings indicate that tracking poly(GP) proteins in CSF could provide a means to assess target engagement of G4C2 RNA-based therapies in symptomatic C9ORF72 repeat expansion carriers and presymptomatic individuals who are expected to benefit from early therapeutic intervention.