RESUMEN
BACKGROUND: Primary progressive aphasia (PPA) defines a group of neurodegenerative disorders characterised by language decline. Three PPA variants correlate with distinct underlying pathologies: semantic variant PPA (svPPA) with transactive response DNA-binding protein of 43 kD (TDP-43) proteinopathy, agrammatic variant PPA (agPPA) with tau deposition and logopenic variant PPA (lvPPA) with Alzheimer's disease (AD). Our objectives were to differentiate PPA variants using clinical and neuroimaging features, assess progression and evaluate structural MRI and a novel 18-F fluorodeoxyglucose positron emission tomography (FDG-PET) image decomposition machine learning algorithm for neuropathology prediction. METHODS: We analysed 82 autopsied patients diagnosed with PPA from 1998 to 2022. Clinical histories, language characteristics, neuropsychological results and brain imaging were reviewed. A machine learning framework using a k-nearest neighbours classifier assessed FDG-PET scans from 45 patients compared with a large reference database. RESULTS: PPA variant distribution: 35 lvPPA (80% AD), 28 agPPA (89% tauopathy) and 18 svPPA (72% frontotemporal lobar degeneration-TAR DNA-binding protein (FTLD-TDP)). Apraxia of speech was associated with 4R-tauopathy in agPPA, while pure agrammatic PPA without apraxia was linked to 3R-tauopathy. Longitudinal data revealed language dysfunction remained the predominant deficit for patients with lvPPA, agPPA evolved to corticobasal or progressive supranuclear palsy syndrome (64%) and svPPA progressed to behavioural variant frontotemporal dementia (44%). agPPA-4R-tauopathy exhibited limited pre-supplementary motor area atrophy, lvPPA-AD displayed temporal atrophy extending to the superior temporal sulcus and svPPA-FTLD-TDP had severe temporal pole atrophy. The FDG-PET-based machine learning algorithm accurately predicted clinical diagnoses and underlying pathologies. CONCLUSIONS: Distinguishing 3R-taupathy and 4R-tauopathy in agPPA may rely on apraxia of speech presence. Additional linguistic and clinical features can aid neuropathology prediction. Our data-driven brain metabolism decomposition approach effectively predicts underlying neuropathology.
RESUMEN
The dentate nucleus (DN) is a gray matter structure deep in the cerebellum involved in motor coordination, sensory input integration, executive planning, language, and visuospatial function. The DN is an emerging biomarker of disease, informing studies that advance pathophysiologic understanding of neurodegenerative and related disorders. The main challenge in defining the DN radiologically is that, like many deep gray matter structures, it has poor contrast in T1-weighted magnetic resonance (MR) images and therefore requires specialized MR acquisitions for visualization. Manual tracing of the DN across multiple acquisitions is resource-intensive and does not scale well to large datasets. We describe a technique that automatically segments the DN using deep learning (DL) on common imaging sequences, such as T1-weighted, T2-weighted, and diffusion MR imaging. We trained a DL algorithm that can automatically delineate the DN and provide an estimate of its volume. The automatic segmentation achieved higher agreement to the manual labels compared to template registration, which is the current common practice in DN segmentation or multiatlas segmentation of manual labels. Across all sequences, the FA maps achieved the highest mean Dice similarity coefficient (DSC) of 0.83 compared to T1 imaging ( DSC = 0.76 ), T2 imaging ( DSC = 0.79 ), or a multisequence approach ( DSC = 0.80 ). A single atlas registration approach using the spatially unbiased atlas template of the cerebellum and brainstem template achieved a DSC of 0.23, and multi-atlas segmentation achieved a DSC of 0.33. Overall, we propose a method of delineating the DN on clinical imaging that can reproduce manual labels with higher accuracy than current atlas-based tools.