Association Between Disrupted Resting-State Functional Connectivity and Language Impairments in PPA
Poster No:
204
Submission Type:
Abstract Submission
Authors:
Michele Masson-Trottier1, Jessie Gallegos1, Alexandros Afthinos1, Sophia Norvillas1, Cecia Diaz1, Kyrana Tsapkini1
Institutions:
1Johns Hopkins School of Medecine, Baltimore, MD
First Author:
Co-Author(s):
Introduction:
Primary progressive aphasia (PPA) is a neurodegenerative disorder characterized by language deficits (Gorno-Tempini et al., 2011). There are three main variants of PPA: semantic (svPPA), logopenic (lvPPA), and nonfluent (nfvPPA). These variants display distinct clinical, atrophic, and pathological profiles.
Diagnosing lvPPA and nfvPPA is challenging due to overlapping symptoms, especially in the early stages. According to the consensus diagnosis criteria, sentence repetition impairment is a key differentiator between these two variants, which is more pronounced in lvPPA (Gorno-Tempini et al., 2011). However, in clinical assessments, this distinction is not as clear (Mesulam et al., 2022).
This study aims to explore the contribution of demographic (age, sex, years of education), clinical (global severity measured by FTLD-CDR sum of Boxes (Knopman et al., 2008), language severity measured by FTLD-CDR Language domain score, years post-onset) and neural factors (resting-state functional connectivity (rsFC)) in predicting language performance (sentence repetition) in nfvPPA and lvPPA.
Diagnosing lvPPA and nfvPPA is challenging due to overlapping symptoms, especially in the early stages. According to the consensus diagnosis criteria, sentence repetition impairment is a key differentiator between these two variants, which is more pronounced in lvPPA (Gorno-Tempini et al., 2011). However, in clinical assessments, this distinction is not as clear (Mesulam et al., 2022).
This study aims to explore the contribution of demographic (age, sex, years of education), clinical (global severity measured by FTLD-CDR sum of Boxes (Knopman et al., 2008), language severity measured by FTLD-CDR Language domain score, years post-onset) and neural factors (resting-state functional connectivity (rsFC)) in predicting language performance (sentence repetition) in nfvPPA and lvPPA.
Methods:
We examined 84 participants with PPA (49 lvPPA, 35 nfvPPA) and 33 age-matched controls. All participants underwent neurocognitive assessments and imaging, including a rsfMRI scan. rsFC was analyzed using the CONN toolbox (Nieto-Castanon & Whitfield-Gabrieli, 2022), following standard preprocessing steps. We examined ROI-to-ROI connectivity between 91 cortical regions and identified the rsFC disruptions in the lvPPA and nfvPPA groups independently, based on differences from the control group. Stepwise regression models with forward and backward selection were performed using demographic factors, clinical factors and rsFC disruptions to identify the most significant contributors. Models accounted for multicollinearity.
Results:
Both groups performed equally on the sentence repetition task (p=0.986).
In the lvPPA group, rsFC disruptions were characterized by distributed hypoconnectivity spanning fronto-tempo-parietal regions, including areas in the Default Mode Network (DMN) and involved in language and visual processing. However, when predicting their sentence repetition score, the model including only demographic and clinical predictors best fit the data, explaining 23.6%. The addition of the rsFC disruptions did not significantly improve the fit of the model.
Conversely, the nfvPPA group shows hyperconnectivity in ventral frontal and temporal areas, as well as between areas in the Dorsal-attentional Network (DAN) and visual areas. The addition of these rsFC disruptions improved significantly the prediction of the sentence repetition performance, above and beyond demographic and clinical predictors alone. The model including only demographic and clinical predictors explained only 11.2% of the variance, and adding the rsFC disruptions increased the R2 to 20.0%.
In the lvPPA group, rsFC disruptions were characterized by distributed hypoconnectivity spanning fronto-tempo-parietal regions, including areas in the Default Mode Network (DMN) and involved in language and visual processing. However, when predicting their sentence repetition score, the model including only demographic and clinical predictors best fit the data, explaining 23.6%. The addition of the rsFC disruptions did not significantly improve the fit of the model.
Conversely, the nfvPPA group shows hyperconnectivity in ventral frontal and temporal areas, as well as between areas in the Dorsal-attentional Network (DAN) and visual areas. The addition of these rsFC disruptions improved significantly the prediction of the sentence repetition performance, above and beyond demographic and clinical predictors alone. The model including only demographic and clinical predictors explained only 11.2% of the variance, and adding the rsFC disruptions increased the R2 to 20.0%.
Conclusions:
Each PPA variant shows distinctive rsFC abnormalities, consistent with what is reported in literature. Individuals with lvPPA show more hypoconnectivity involving DMN and language areas whereas those with nfvPPA show more hyperconnectivity in the DAN and DMN networks, mainly in fronto-temporal areas.
Our results, along with those published by Mesulam et al. (2022), challenge the notion that repetition impairments alone can be used as marker for lvPPA. However, while the overt behaviors in both lvPPA and nfvPPA groups may converge, the pathways leading to those behaviors (demographic and rsFC factors contributing to the performance) seem to differ. Only participants with nfvPPA show rsFC disturbances as significant predictors to the sentence repetition impairment. This may be due to the method, as clusters were extracted independently by diagnosis group, potentially overlooking cross-group patterns. Alternatively, in the lvPPA group, significant atrophy in sentence repetition-related areas may disrupt rsFC to the extent that these abnormalities no longer correlate with behavioral performance.
Our results, along with those published by Mesulam et al. (2022), challenge the notion that repetition impairments alone can be used as marker for lvPPA. However, while the overt behaviors in both lvPPA and nfvPPA groups may converge, the pathways leading to those behaviors (demographic and rsFC factors contributing to the performance) seem to differ. Only participants with nfvPPA show rsFC disturbances as significant predictors to the sentence repetition impairment. This may be due to the method, as clusters were extracted independently by diagnosis group, potentially overlooking cross-group patterns. Alternatively, in the lvPPA group, significant atrophy in sentence repetition-related areas may disrupt rsFC to the extent that these abnormalities no longer correlate with behavioral performance.
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 1
Language:
Speech Production 2
Lifespan Development:
Aging
Keywords:
Aging
Aphasia
FUNCTIONAL MRI
Language
MRI
Other - Primary Progressive Aphasia
1|2Indicates the priority used for review
Abstract Information
By submitting your proposal, you grant permission for the Organization for Human Brain Mapping (OHBM) to distribute your work in any format, including video, audio print and electronic text through OHBM OnDemand, social media channels, the OHBM website, or other electronic publications and media.
The Open Science Special Interest Group (OSSIG) is introducing a reproducibility challenge for OHBM 2025. This new initiative aims to enhance the reproducibility of scientific results and foster collaborations between labs. Teams will consist of a “source” party and a “reproducing” party, and will be evaluated on the success of their replication, the openness of the source work, and additional deliverables. Click here for more information. Propose your OHBM abstract(s) as source work for future OHBM meetings by selecting one of the following options:
Please indicate below if your study was a "resting state" or "task-activation” study.
Healthy subjects only or patients (note that patient studies may also involve healthy subjects):
Was this research conducted in the United States?
Are you Internal Review Board (IRB) certified? Please note: Failure to have IRB, if applicable will lead to automatic rejection of abstract.
Were any human subjects research approved by the relevant Institutional Review Board or ethics panel? NOTE: Any human subjects studies without IRB approval will be automatically rejected.
Were any animal research approved by the relevant IACUC or other animal research panel? NOTE: Any animal studies without IACUC approval will be automatically rejected.
Please indicate which methods were used in your research:
For human MRI, what field strength scanner do you use?
Which processing packages did you use for your study?
Provide references using APA citation style.
Knopman, D. S., Kramer, J. H., Boeve, B. F., Caselli, R. J., Graff-Radford, N. R., Mendez, M. F., Miller, B. L., & Mercaldo, N. (2008). Development of methodology for conducting clinical trials in frontotemporal lobar degeneration. Brain, 131(Pt 11), 2957-2968. https://doi.org/10.1093/brain/awn234
Mesulam, M. M., Coventry, C. A., Bigio, E. H., Sridhar, J., Gill, N., Fought, A. J., Zhang, H., Thompson, C. K., Geula, C., Gefen, T., Flanagan, M., Mao, Q., Weintraub, S., & Rogalski, E. J. (2022). Neuropathological fingerprints of survival, atrophy and language in primary progressive aphasia. Brain, 145(6), 2133-2148. https://doi.org/10.1093/brain/awab410
Nieto-Castanon, A., & Whitfield-Gabrieli, S. (2022). CONN functional connectivity toolbox: RRID SCR_009550, release 22. https://doi.org/10.56441/hilbertpress.2246.5840