Presymptomatic white matter integrity loss in familial frontotemporal dementia in the <scp>GENFI</scp> cohort: A cross‐sectional diffusion tensor imaging study
Bibliographic record
Abstract
Abstract Objective We aimed to investigate mutation‐specific white matter ( WM ) integrity changes in presymptomatic and symptomatic mutation carriers of the C9orf72 , MAPT , and GRN mutations by use of diffusion‐weighted imaging within the Genetic Frontotemporal dementia Initiative ( GENFI ) study. Methods One hundred and forty mutation carriers (54 C9orf72 , 30 MAPT , 56 GRN ), 104 presymptomatic and 36 symptomatic, and 115 noncarriers underwent 3T diffusion tensor imaging. Linear mixed effects models were used to examine the association between diffusion parameters and years from estimated symptom onset in C9orf72 , MAPT , and GRN mutation carriers versus noncarriers. Post hoc analyses were performed on presymptomatic mutation carriers only, as well as left–right asymmetry analyses on GRN mutation carriers versus noncarriers. Results Diffusion changes in C9orf72 mutation carriers are present significantly earlier than both MAPT and GRN mutation carriers – characteristically in the posterior thalamic radiation and more posteriorly located tracts (e.g., splenium of the corpus callosum, posterior corona radiata), as early as 30 years before estimated symptom onset. MAPT mutation carriers showed early involvement of the uncinate fasciculus and cingulum, sparing the internal capsule, whereas involvement of the anterior and posterior internal capsule was found in GRN . Restricting analyses to presymptomatic mutation carriers only, similar – albeit less extensive – patterns were found: posteriorly located WM tracts (e.g., posterior thalamic radiation, splenium of the corpus callosum, posterior corona radiata) in presymptomatic C9orf72 , the uncinate fasciculus in presymptomatic MAPT , and the internal capsule (anterior and posterior limbs) in presymptomatic GRN mutation carriers. In GRN , most tracts showed significant left–right differences in one or more diffusion parameter, with the most consistent results being found in the UF , EC , RPIC , and ALIC . Interpretation This study demonstrates the presence of early and widespread WM integrity loss in presymptomatic FTD , and suggests a clear genotypic “fingerprint.” Our findings corroborate the notion of FTD as a network‐based disease, where changes in connectivity are some of the earliest detectable features, and identify diffusion tensor imaging as a potential neuroimaging biomarker for disease‐tracking and ‐staging in presymptomatic to early‐stage familial FTD .
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".