The presymptomatic and early manifestations of semantic dementia
Bibliographic record
Abstract
People with semantic dementia (SD) or semantic variant primary progressive aphasia typically present with marked atrophy of the anterior temporal lobe, and thereafter progress more slowly than other forms of frontotemporal dementia. This suggests a prolonged prodromal phase with accumulation of neuropathology and minimal symptoms, about which little is known. To study early and presymptomatic SD, we first examine a well-characterized cohort of people with SD recruited from the Cambridge Centre for Frontotemporal Dementia. Five people with early SD had coincidental MRI prior to the onset of symptoms or were healthy volunteers in research with anterior temporal lobe atrophy as an incidental finding. We model longitudinal imaging changes in left- and right-lateralized SD to predict atrophy at symptom onset. We then assess 61 203 participants with structural brain MRI in the UK Biobank to find individuals with imaging changes in keeping with SD but with no neurodegenerative diagnosis. To identify these individuals in the UK Biobank, we design an ensemble-based classifier, differentiating baseline structural MRI in SD from healthy controls and patients with other neurodegenerative diseases, including other causes of frontotemporal lobar degeneration. We train the classifier on a Cambridge-based cohort (SD n = 47, other neurodegenerative diseases n = 498, healthy controls n = 88) and test it on a combined cohort from the Neuroimaging in Frontotemporal Dementia study and the Alzheimer's Disease Neuroimaging Initiative (SD n = 42, other neurodegenerative disease n = 449, healthy controls n = 127). From our case series, we find people with marked atrophy 3 to 5 years before recognition of symptom onset in left- or right-predominant SD. We present right-lateralized cases with subtle multimodal semantic impairment, found concurrently with only mild behavioural disturbance. We show that imaging measures can reliably and accurately differentiate clinical SD from other neurodegenerative diseases (recall: 0.88, precision: 0.95, F1 score: 0.91). We find individuals with no neurodegenerative diagnosis in the UK Biobank with striking left-lateralized (prevalence ages 45-85, 4.8/100 000) or right-lateralized (5.9/100 000) anterior temporal lobe atrophy, with deficits on cognitive testing suggestive of semantic impairment. These individuals show progressive involvement of other cognitive domains in longitudinal follow-up. Together, our findings suggest that (i) there is a burden of incipient early anterior temporal lobe atrophy in older populations, with comparable prevalence of left- and right-sided cases from this prospective unbiased approach to identification; (ii) substantial atrophy is required for manifest symptoms, particularly in right-lateralized cases; and (iii) semantic deficits across multiple domains can be detected in the early symptomatic phase.
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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 | 0.000 | 0.001 |
| 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 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| 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".