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The neurobiology of two distinct subtypes of neurodegenerative apraxia of speech: phenotypes of Alzheimer disease related 4-repeat tauopathies

Award Number: R01DC014942
ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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The neurobiology of two distinct subtypes of neurodegenerative apraxia of speech: phenotypes of Alzheimer disease related 4-repeat tauopathies - PROJECT SUMMARY Progressive apraxia of speech (PAOS) is a devastating neurodegenerative syndrome that ultimately shortens lifespan and is most commonly due to an Alzheimer’s disease related disorders (ADRD) four-repeat tauopathy. Nine years ago, we described two distinct subtypes of PAOS: phonetic PAOS characterized predominantly by articulatory distortions and prosodic PAOS characterized predominantly by slow speech rate and abnormal prosody. In the 1st cycle we demonstrated that speech, language, and neurological features differ across PAOS subtypes which helped to validate these subtypes as being distinct. We performed cross-sectional analyses including voxel-based morphometry of structural MRI, diffusion tensor imaging and 18F- fluorodeoxyglucose PET (FDG-PET) and found evidence for greater cortical involvement in phonetic PAOS. Leveraging autopsy data, we also demonstrated that the PAOS subtypes are associated with specific 4-repeat tauopathies (phonetic with corticobasal degeneration and prosodic with PSP) and have neuronal loss in distinct cortico-striatal and pallido-nigro-luysial-cerebellar regions. However, there are still many gaps in knowledge. Little is known about progression, and whether longitudinal rates of clinical progression differ in PAOS subtypes, whether anatomic and metabolic rates differ and can be detected with advanced neuroimaging techniques, and whether genetic and histopathologic features of iron, Alzheimer disease neuropathologic changes or other co-pathologies play any role in PAOS subtypes. In the 2nd cycle we will proceed in new directions to address these knowledge gaps and limitations using data collected from 120 PAOS patients including 47 patients from the 1st cycle. In Aim 1, we will determine whether rates of decline in speech and other communication features, including acoustic characteristics derived from a novel rate modulation task, or time to the development of clinical outcomes, are associated with subtype. This aim will be critical to aid diagnosis and prognostication of disease progression. In Aim 2, we will determine whether advanced and novel neuroimaging techniques can detect regional longitudinal differences and whether imaging differences correlate with differences in clinical change over time, across PAOS subtypes. We will analyze structural MRI, FDG-PET and quantitative susceptibility mapping (QSM) to assess volume, metabolism, and iron deposition. This aim will improve understanding of how differential involvement of these regions relate to PAOS subtypes and provide specific neuroimaging biomarkers for diagnosis and disease tracking which is also important for clinical trials. In Aim 3, we will determine the relationship between tau- and Alzheimer disease related genetic risk alleles, regional iron burden, Alzheimer disease neuropathologic changes, and other co-pathologies, and PAOS subtype. Results from this aim will improve our understanding of the neurobiology of PAOS subtype. Achieving the aims of the 2nd cycle will have significant clinical relevance to every speech-language pathologist and neurologist who diagnose and care for patients with speech and language disorders.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $643,385 )
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Research Related to Deafness and Communication Disorders	001	8	4/21/2025	NON-COMPETING CONTINUATION	$64,338
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Research Related to Deafness and Communication Disorders	000	8	3/19/2025	NON-COMPETING CONTINUATION	$579,047
														Subtotal = $643,385

Issue Date FY: 2024 ( Subtotal = $650,000 )
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Research Related to Deafness and Communication Disorders	000	7	3/27/2024	NON-COMPETING CONTINUATION	$650,000
2024	2023	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Research Related to Deafness and Communication Disorders	002	6	6/25/2024	COMPETING CONTINUATION	$48,022
2024	2021	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Research Related to Deafness and Communication Disorders	001	5	6/25/2024	NON-COMPETING CONTINUATION	-$48,022
														Subtotal = $650,000

Issue Date FY: 2023 ( Subtotal = $651,834 )
2023	2023	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Research Related to Deafness and Communication Disorders	001	6	4/4/2023	COMPETING CONTINUATION	$643,168
2023	2023	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Research Related to Deafness and Communication Disorders	002	6	4/6/2023	COMPETING CONTINUATION	$8,666
2023	2021	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Research Related to Deafness and Communication Disorders	000	5	3/28/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $651,834

Issue Date FY: 2021 ( Subtotal = $470,979 )
2021	2021	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Research Related to Deafness and Communication Disorders	000	5	7/21/2021	NON-COMPETING CONTINUATION	$470,979
														Subtotal = $470,979

Issue Date FY: 2020 ( Subtotal = $475,360 )
2020	2020	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Research Related to Deafness and Communication Disorders	000	4	7/28/2020	NON-COMPETING CONTINUATION	$475,360
														Subtotal = $475,360

Issue Date FY: 2019 ( Subtotal = $475,360 )
2019	2019	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Research Related to Deafness and Communication Disorders	000	3	7/24/2019	NON-COMPETING CONTINUATION	$475,360
														Subtotal = $475,360

Issue Date FY: 2018 ( Subtotal = $465,513 )
2018	2018	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Research Related to Deafness and Communication Disorders	000	2	7/13/2018	NON-COMPETING CONTINUATION	$465,513
														Subtotal = $465,513

Issue Date FY: 2017 ( Subtotal = $459,162 )
2017	2017	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Research Related to Deafness and Communication Disorders	000	1	7/26/2017	NEW	$459,162
														Subtotal = $459,162

Grand Total All Awards = $4,291,593

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The neurobiology of two distinct subtypes of neurodegenerative apraxia of speech: phenotypes of Alzheimer disease related 4-repeat tauopathies

Award Number: R01DC014942

ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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