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Article: Performance of the Lumipulse plasma Aβ42/40 and pTau181 immunoassays in the detection of amyloid pathology.

Figdore, Daniel J / Wiste, Heather J / Bornhorst, Joshua A / Bateman, Randall J / Li, Yan / Graff-Radford, Jonathan / Knopman, David S / Vemuri, Prashanthi / Lowe, Val J / Jr, Clifford R Jack / Petersen, Ronald C / Algeciras-Schimnich, Alicia

Alzheimer's & dementia (Amsterdam, Netherlands)

2024 Volume 16, Issue 1, Page(s) e12545

Abstract: Introduction: This study evaluated the performance of the Lumipulse plasma beta-amyloid (Aβ) 42/40 and pTau181 compared to other assays to detect an abnormal amyloid-positron emission tomography (PET).: Methods: Plasma samples from cognitively ... ...

Abstract	Introduction: This study evaluated the performance of the Lumipulse plasma beta-amyloid (Aβ) 42/40 and pTau181 compared to other assays to detect an abnormal amyloid-positron emission tomography (PET). Methods: Plasma samples from cognitively unimpaired ( Results: Lumipulse and IP-MS Aβ42/40 exhibited the highest diagnostic accuracy for detecting an abnormal amyloid-PET (areas under the curve [AUCs] of 0.81 and 0.84, respectively). The Lumipulse and Simoa pTau181 assays exhibited lower performance (AUCs of 0.74 and 0.72, respectively). The Simoa Aβ42/40 assay demonstrated the lowest diagnostic accuracy (AUC 0.57). Combining Aβ42/40 and pTau181 did not significantly improve performance over Aβ42/40 alone for Lumipulse (AUC 0.83) or over pTau181 alone for Simoa (AUC 0.71). Discussion: The Lumipulse Aβ42/40 assay showed similar performance to the IP-MS Aβ42/40 assay for detection of an abnormal amyloid-PET; and both assays performed better than the two p-tau181 immunoassays. The Simoa Aβ42/Aβ40 assay was the least accurate at predicting an abnormal amyloid-PET status. Highlights: Lumipulse plasma Aβ42/Aβ40 AUC for abnormal amyloid-PET detection was 0.81.This performance was comparable to previously reported IP-MS and higher than Simoa.Performance of Alzheimer's disease blood biomarkers varies between assays.
Language	English
Publishing date	2024-01-31
Publishing country	United States
Document type	Journal Article
ZDB-ID	2832898-X
ISSN	2352-8729
ISSN	2352-8729
DOI	10.1002/dad2.12545
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Article ; Online: Longitudinal rates of atrophy and tau accumulation differ between the visual and language variants of atypical Alzheimer's disease.

Sintini, Irene / Graff-Radford, Jonathan / Schwarz, Christopher G / Machulda, Mary M / Singh, Neha Atulkumar / Carlos, Arenn F / Senjem, Matthew L / Jr, Clifford R Jack / Lowe, Val J / Josephs, Keith A / Whitwell, Jennifer L

Alzheimer's & dementia : the journal of the Alzheimer's Association

2023 Volume 19, Issue 10, Page(s) 4396–4406

Abstract: Introduction: Atypical variants of Alzheimer's disease (AD) include the visual variant, known as posterior cortical atrophy (PCA), and the language variant, known as logopenic progressive aphasia (LPA). Clinically, rates of disease progression differ ... ...

Abstract	Introduction: Atypical variants of Alzheimer's disease (AD) include the visual variant, known as posterior cortical atrophy (PCA), and the language variant, known as logopenic progressive aphasia (LPA). Clinically, rates of disease progression differ between them. Methods: We evaluated 34 PCA and 29 LPA participants. Structural magnetic resonance imaging and Results: PCA had faster rates of occipital atrophy. LPA had faster rates of left temporal atrophy and faster rates of tau accumulation in the parietal, right temporal, and occipital lobes. Age was negatively associated with rates of atrophy and tau accumulation. Discussion: Longitudinal patterns of neuroimaging abnormalities differed between PCA and LPA, although with divergent results for tau accumulation and atrophy. Highlights: The language variant of Alzheimer's disease accumulates tau faster than the visual variant. Each variant shows faster rates of atrophy than the other in its signature regions. Age negatively influences rates of atrophy and tau accumulation in both variants.
MeSH term(s)	Humans ; Alzheimer Disease/diagnostic imaging ; Alzheimer Disease/pathology ; tau Proteins/metabolism ; Brain/pathology ; Neuroimaging ; Positron-Emission Tomography ; Magnetic Resonance Imaging ; Atrophy/pathology
Chemical Substances	tau Proteins
Language	English
Publishing date	2023-07-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2211627-8
ISSN	1552-5279 ; 1552-5260
ISSN (online)	1552-5279
ISSN	1552-5260
DOI	10.1002/alz.13396
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Article ; Online: Spatial patterns of elevated magnetic susceptibility in progressive apraxia of speech

Ryota Satoh / Arvin Arani / Matthew L. Senjem / Joseph R. Duffy / Heather M. Clark / Rene L. Utianski / Hugo Botha / Mary M. Machulda / Clifford R. Jack, Jr / Jennifer L. Whitwell / Keith A. Josephs

NeuroImage: Clinical, Vol 38, Iss , Pp 103394- (2023)

2023

Abstract: Purpose: Progressive apraxia of speech (PAOS) is a neurodegenerative disorder affecting the planning or programming of speech. Little is known about its magnetic susceptibility profiles indicative of biological processes such as iron deposition and ... ...

Abstract	Purpose: Progressive apraxia of speech (PAOS) is a neurodegenerative disorder affecting the planning or programming of speech. Little is known about its magnetic susceptibility profiles indicative of biological processes such as iron deposition and demyelination. This study aims to clarify (1) the pattern of susceptibility in PAOS patients, (2) the susceptibility differences between the phonetic (characterized by predominance of distorted sound substitutions and additions) and prosodic (characterized by predominance of slow speech rate and segmentation) subtypes of PAOS, and (3) the relationships between susceptibility and symptom severity. Methods: Twenty patients with PAOS (nine phonetic and eleven prosodic subtypes) were prospectively recruited and underwent a 3 Tesla MRI scan. They also underwent detailed speech, language, and neurological evaluations. Quantitative susceptibility maps (QSM) were reconstructed from multi-echo gradient echo MRI images. Region of interest analysis was conducted to estimate susceptibility coefficients in several subcortical and frontal regions. We compared susceptibility values between PAOS and an age-matched control group and performed a correlation analysis between susceptibilities and an apraxia of speech rating scale (ASRS) phonetic and prosodic feature ratings. Results: The magnetic susceptibility of PAOS was statistically greater than that of controls in subcortical regions (left putamen, left red nucleus, and right dentate nucleus) (p < 0.01, also survived FDR correction) and in the left white-matter precentral gyrus (p < 0.05, but not survived FDR correction). The prosodic patients showed greater susceptibilities than controls in these subcortical and precentral regions. The susceptibility in the left red nucleus and in the left precentral gyrus correlated with the prosodic sub-score of the ASRS. Conclusion: Magnetic susceptibility in PAOS patients was greater than controls mainly in the subcortical regions. While larger samples are needed before QSM is considered ...
Keywords	Apraxia of speech ; Progressive apraxia of speech ; Magnetic resonance imaging ; Quantitative susceptibility mapping ; Iron ; Computer applications to medicine. Medical informatics ; R858-859.7 ; Neurology. Diseases of the nervous system ; RC346-429
Subject code	410
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Differential effect of dementia etiology on cortical stiffness as assessed by MR elastography

KowsalyaDevi Pavuluri / Jonathan M. Scott / John Huston III / Richard L. Ehman / Armando Manduca / Clifford R. Jack Jr / Rodolfo Savica / Bradley F. Boeve / Kejal Kantarci / Ronald C. Petersen / David S. Knopman / Matthew C. Murphy

NeuroImage: Clinical, Vol 37, Iss , Pp 103328- (2023)

2023

Abstract: Background: Aging and dementia involve the disruption of brain molecular pathways leading to the alterations in tissue composition and gross morphology of the brain. Phenotypic and biomarker overlap between various etiologies of dementia supports a need ... ...

Abstract	Background: Aging and dementia involve the disruption of brain molecular pathways leading to the alterations in tissue composition and gross morphology of the brain. Phenotypic and biomarker overlap between various etiologies of dementia supports a need for new modes of information to more accurately distinguish these disorders. Brain mechanical properties, which can be measured noninvasively by MR elastography, represent one understudied feature that are sensitive to neurodegenerative processes. In this study, we used two stiffness estimation schemes to test the hypothesis that different etiologies of dementia are associated with unique patterns of mechanical alterations across the cerebral cortex. Methods: MR elastography data were acquired for six clinical groups including amyloid-negative cognitively unimpaired (CU), amyloid-positive cognitively unimpaired (A + CU), amyloid-positive participants with mild cognitive impairment (A + MCI), amyloid-positive participants with Alzheimer’s clinical syndrome (A + ACS), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). Stiffness maps were computed using two neural network inversions with the objective to at least partially separate the parenchyma-specific and morphological effects of neurodegeneration on mechanical property estimates. A tissue-confined inversion algorithm was designed to obtain the best estimate of stiffness in the brain parenchyma itself, while a regionally-aware inversion algorithm was used to measure the tissue stiffness along with the surroundings. Mean stiffness of 15 bilateral gray matter cortical regions were considered for statistical analysis. First, we tested the hypothesis that cortical stiffness changes in the aging brain. Next, we tested the overall study hypothesis by first comparing stiffness in each clinical group to the CU group, and then comparing the clinical groups against one another. Finally, we assessed the spatial and statistical overlap between atrophy and stiffness changes for both inversions. Results: ...
Keywords	Magnetic resonance elastography (MRE) ; Dementia ; Brain stiffness ; Neurodegeneration ; Alzheimer’s ; Dementia with Lewy bodies ; Computer applications to medicine. Medical informatics ; R858-859.7 ; Neurology. Diseases of the nervous system ; RC346-429
Subject code	616
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Causal structure discovery identifies risk factors and early brain markers related to evolution of white matter hyperintensities

Xinpeng Shen / Sheelakumari Raghavan / Scott A. Przybelski / Timothy G. Lesnick / Sisi Ma / Robert I. Reid / Jonathan Graff-Radford / Michelle M. Mielke / David S. Knopman / Ronald C. Petersen / Clifford R. Jack Jr. / György J. Simon / Prashanthi Vemuri

NeuroImage: Clinical, Vol 35, Iss , Pp 103077- (2022)

2022

Abstract: Our goal was to understand the complex relationship between age, sex, midlife risk factors, and early white matter changes measured by diffusion tensor imaging (DTI) and their role in the evolution of longitudinal white matter hyperintensities (WMH). We ... ...

Abstract	Our goal was to understand the complex relationship between age, sex, midlife risk factors, and early white matter changes measured by diffusion tensor imaging (DTI) and their role in the evolution of longitudinal white matter hyperintensities (WMH). We identified 1564 participants (1396 cognitively unimpaired, 151 mild cognitive impairment and 17 dementia participants) with age ranges of 30–90 years from the population-based sample of Mayo Clinic Study of Aging. We used computational causal structure discovery and regression analyses to evaluate the predictors of WMH and DTI, and to ascertain the mediating effect of DTI on WMH. We further derived causal graphs to understand the complex interrelationships between midlife protective factors, vascular risk factors, diffusion changes, and WMH. Older age, female sex, and hypertension were associated with higher baseline and progression of WMH as well as DTI measures (P ≤ 0.003). The effects of hypertension and sex on WMH were partially mediated by microstructural changes measured on DTI. Higher midlife physical activity was predictive of lower WMH through a direct impact on better white matter tract integrity as well as an indirect effect through reducing the risk of hypertension by lowering BMI. This study identified key risks factors, early brain changes, and pathways that may lead to the evolution of WMH.
Keywords	Diffusion MRI ; White matter health ; FLAIR ; White matter hyperintensities ; Causal discovery ; Computer applications to medicine. Medical informatics ; R858-859.7 ; Neurology. Diseases of the nervous system ; RC346-429
Subject code	610
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Neuroimaging correlates of gait abnormalities in progressive supranuclear palsy

Irene Sintini / Kenton Kaufman / Hugo Botha / Peter R. Martin / Stacy R. Loushin / Matthew L. Senjem / Robert I. Reid / Christopher G. Schwarz / Clifford R. Jack Jr / Val J. Lowe / Keith A. Josephs / Jennifer L. Whitwell / Farwa Ali

NeuroImage: Clinical, Vol 32, Iss , Pp 102850- (2021)

2021

Abstract: Progressive supranuclear palsy is a neurodegenerative disorder characterized primarily by tau inclusions and neurodegeneration in the midbrain, basal ganglia, thalamus, premotor and frontal cortex. Neurodegenerative change in progressive supranuclear ... ...

Abstract	Progressive supranuclear palsy is a neurodegenerative disorder characterized primarily by tau inclusions and neurodegeneration in the midbrain, basal ganglia, thalamus, premotor and frontal cortex. Neurodegenerative change in progressive supranuclear palsy has been assessed using MRI. Degeneration of white matter tracts is evident with diffusion tensor imaging and PET methods have been used to assess brain metabolism or presence of tau protein deposits. Patients with progressive supranuclear palsy present with a variety of clinical syndromes; however early onset of gait impairments and postural instability are common features. In this study we assessed the relationship between multimodal imaging biomarkers (i.e., MRI atrophy, white matter tracts degeneration, flortaucipir-PET uptake) and laboratory-based measures of gait and balance abnormalities in a cohort of nineteen patients with progressive supranuclear palsy, using univariate and multivariate statistical analyses. The PSP rating scale and its gait midline sub-score were strongly correlated to gait abnormalities but not to postural imbalance. Principal component analysis on gait variables identified velocity, stride length, gait stability ratio, length of gait phases and dynamic stability as the main contributors to the first component, which was associated with diffusion tensor imaging measures in the posterior thalamic radiation, external capsule, superior cerebellar peduncle, superior fronto-occipital fasciculus, body and splenium of the corpus callosum and sagittal stratum, with MRI volumes in frontal and precentral regions and with flortaucipir-PET uptake in the precentral gyrus. The main contributor to the second principal component was cadence, which was higher in patients presenting more abnormalities on mean diffusivity: this unexpected finding might be related to compensatory gait strategies adopted in progressive supranuclear palsy. Postural imbalance was the main contributor to the third principal component, which was related to flortaucipir-PET ...
Keywords	Progressive supranuclear palsy ; Diffusion tensor imaging ; Gait ; Balance ; MRI ; PET ; Computer applications to medicine. Medical informatics ; R858-859.7 ; Neurology. Diseases of the nervous system ; RC346-429
Subject code	616
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: TDP-43-associated atrophy in brains with and without frontotemporal lobar degeneration

Marina Buciuc / Peter R. Martin / Nirubol Tosakulwong / Melissa E. Murray / Leonard Petrucelli / Matthew L. Senjem / Anthony J. Spychalla / David S. Knopman / Bradley F. Boeve / Ronald C. Petersen / Joseph E. Parisi / R. Ross Reichard / Dennis W. Dickson / Clifford R. Jack, Jr. / Jennifer L. Whitwell / Keith A. Josephs

NeuroImage: Clinical, Vol 34, Iss , Pp 102954- (2022)

2022

Abstract: Transactive response DNA-binding protein of ∼43 kDa (TDP-43), a primary pathologic substrate in tau-negative frontotemporal lobar degeneration (FTLD), is also often found in the brains of elderly individuals without FTLD and is a key player in the ... ...

Abstract	Transactive response DNA-binding protein of ∼43 kDa (TDP-43), a primary pathologic substrate in tau-negative frontotemporal lobar degeneration (FTLD), is also often found in the brains of elderly individuals without FTLD and is a key player in the process of neurodegeneration in brains with and without FTLD. It is unknown how rates and trajectories of TDP-43-associated brain atrophy compare between these two groups. Additionally, non-FTLD TDP-43 inclusions are not homogeneous and can be divided into two morphologic types: type-α and neurofibrillary tangle-associated type-β. Therefore, we explored whether neurodegeneration also varies due to the morphologic type. In this longitudinal retrospective study of 293 patients with 843 MRI scans spanning over ∼10 years, we used a Bayesian hierarchical linear model to quantify similarities and differences between the non-FTLD TDP-43 (type-α/type-β) and FTLD-TDP (n = 68) in both regional volume at various timepoints before death and annualized rate of atrophy. Since Alzheimer’s disease (AD) is a frequent co-pathology in non-FTLD TDP-43, we further divided types α/β based on presence/absence of intermediate-high likelihood AD: AD-TDP type-β (n = 90), AD-TDP type-α (n = 104), and Pure-TDP (n = 31, all type-α). FTLD-TDP was associated with faster atrophy rates in the inferior temporal lobe and temporal pole compared to all non-FTLD TDP-43 groups. The atrophy rate in the frontal lobe was modulated by age with younger FTLD-TDP having the fastest rates. Older FTLD-TDP showed a limbic predominant pattern of neurodegeneration. AD-TDP type-α showed faster rates of hippocampal atrophy and smaller volumes of amygdala, temporal pole, and inferior temporal lobe compared to AD-TDP type-β. Pure-TDP was associated with slowest rates and less atrophy in all brain regions. The results suggest that there are differences and similarities in longitudinal brain volume loss between FTLD-TDP and non-FTLD TDP-43. Within FTLD-TDP age plays a role in which brain regions are the most affected. ...
Keywords	Alzheimer’s disease ; TDP-43 ; MRI ; LATE ; Old age FTLD ; Computer applications to medicine. Medical informatics ; R858-859.7 ; Neurology. Diseases of the nervous system ; RC346-429
Subject code	616
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: CSF dynamics disorders

Petrice M. Cogswell / Jonathan Graff-Radford / Lincoln I. Wurtz / Neill R. Graff-Radford / Derek R. Johnson / Christopher H. Hunt / Jeffrey L. Gunter / Jeremy K. Cutsforth-Gregory / David T. Jones / Benjamin D. Elder / John Huston III / Clifford R. Jack Jr

NeuroImage: Clinical, Vol 28, Iss , Pp 102481- (2020)

Association of brain MRI and nuclear medicine cisternogram findings

2020

Abstract: Disproportionately enlarged subarachnoid space hydrocephalus (DESH), characterized by ventriculomegaly, high convexity/midline tight sulci, and enlarged sylvian fissures on brain MRI has been increasingly recognized as a distinct diagnostic imaging ... ...

Abstract	Disproportionately enlarged subarachnoid space hydrocephalus (DESH), characterized by ventriculomegaly, high convexity/midline tight sulci, and enlarged sylvian fissures on brain MRI has been increasingly recognized as a distinct diagnostic imaging entity that falls within the larger category of idiopathic normal pressure hydrocephalus. Normal pressure hydrocephalus has been previously characterized as a CSF dynamics disorder based on abnormalities on nuclear medicine cisternography: radiotracer in the lateral ventricles and absent or delayed ascent of radiotracer over the cerebral convexity. The purpose of this work was to evaluate for differences in nuclear medicine cisternography between patients with vs without DESH and thereby provide support for the concept that DESH is a structural imaging marker of a CSF dynamics disorder. The study included 102 patients (mean age 71 years, range 46–86, 38 females), 58 patients with cisternogram performed to evaluate suspected normal pressure hydrocephalus (mean age 73 years, range 46–86 years, 24 female) and 44 patients evaluated for headache (mean age 68 years, range 60–82 years, 14 female). All patients had an MRI of the brain performed within 13 months of the cisternogram. Cisternogram imaging, typically acquired at 0.5, 1, 2, 4, and 24 h post injection, was evaluated for the time at which radiotracer reached the basal cisterns, presence of persistent radiotracer in the lateral ventricles, time radiotracer first entered the lateral ventricles, presence of radiotracer over the cerebral convexity, and time at which radiotracer was first visualized over the cerebral convexity. MRI features of ventriculomegaly (defined as Evans’ index ≥ 0.3) and high convexity tight sulci (HCTS) were recorded. Based on the MRI features, patients were grouped according to presence or absence of DESH (ventriculomegaly and HCTS). Those without DESH were separated into groups of ventriculomegaly alone, HCTS alone, and neither ventriculomegaly nor HCTS. Cisternogram metrics were compared ...
Keywords	Disproportionately enlarged subarachnoid space hydrocephalus (DESH) ; Normal pressure hydrocephalus (NPH) ; CSF dynamics disorders ; Nuclear medicine cisternography ; Computer applications to medicine. Medical informatics ; R858-859.7 ; Neurology. Diseases of the nervous system ; RC346-429
Subject code	610
Language	English
Publishing date	2020-01-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Automated detection of imaging features of disproportionately enlarged subarachnoid space hydrocephalus using machine learning methods

Nathaniel B. Gunter / Christopher G. Schwarz / Jonathan Graff-Radford / Jeffrey L. Gunter / David T. Jones / Neill R. Graff-Radford / Ronald C. Petersen / David S. Knopman / Clifford R. Jack, Jr.

NeuroImage: Clinical, Vol 21, Iss , Pp - (2019)

2019

Abstract: Objective: Create an automated classifier for imaging characteristics of disproportionately enlarged subarachnoid space hydrocephalus (DESH), a neuroimaging phenotype of idiopathic normal pressure hydrocephalus (iNPH). Methods: 1597 patients from the ... ...

Abstract	Objective: Create an automated classifier for imaging characteristics of disproportionately enlarged subarachnoid space hydrocephalus (DESH), a neuroimaging phenotype of idiopathic normal pressure hydrocephalus (iNPH). Methods: 1597 patients from the Mayo Clinic Study of Aging (MCSA) were reviewed for imaging characteristics of DESH. One core feature of DESH, the presence of tightened sulci in the high-convexities (THC), was used as a surrogate for the presence of DESH as the expert clinician-defined criterion on which the classifier was trained. Anatomical MRI scans were automatically segmented for cerebrospinal fluid (CSF) and overlaid with an atlas of 123 named sulcal regions. The volume of CSF in each sulcal region was summed and normalized to total intracranial volume. Area under the receiver operating characteristic curve (AUROC) values were computed for each region individually, and these values determined feature selection for the machine learning model. Due to class imbalance in the data (72 selected scans out of 1597 total scans) adaptive synthetic sampling (a technique which generates synthetic examples based on the original data points) was used to balance the data. A support vector machine model was then trained on the regions selected. Results: Using the automated classification model, we were able to classify scans for tightened sulci in the high convexities, as defined by the expert clinician, with an AUROC of about 0.99 (false negative ≈ 2%, false positive ≈ 5%). Ventricular volumes were among the classifier's most discriminative features but are not specific for DESH. The inclusion of regions outside the ventricles allowed specificity from atrophic neurodegenerative diseases that are also accompanied by ventricular enlargement. Conclusion: Automated detection of tight high convexity, a key imaging feature of DESH, is possible by using support vector machine models with selected sulcal CSF volumes as features. Keywords: Normal pressure ydrocephalus, Disproportionately enlarged subarachnoid ...
Keywords	Computer applications to medicine. Medical informatics ; R858-859.7 ; Neurology. Diseases of the nervous system ; RC346-429
Language	English
Publishing date	2019-01-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Longitudinal flortaucipir, metabolism and volume differ between phonetic and prosodic speech apraxia.

Tetzloff, Katerina A / Martin, Peter R / Duffy, Joseph R / Utianski, Rene L / Clark, Heather M / Botha, Hugo / Machulda, Mary M / Thu Pham, Nha Trang / Schwarz, Christopher G / Senjem, Matthew L / Jack, Clifford R / Lowe, Val J / Josephs, Keith A / Whitwell, Jennifer L

Brain : a journal of neurology

2024

Abstract: Progressive apraxia of speech is a neurodegenerative motor-speech disorder that most commonly arises from a 4-repeat tauopathy. Recent studies have established that progressive apraxia of speech is not a homogenous disease, but rather there are distinct ... ...

Abstract	Progressive apraxia of speech is a neurodegenerative motor-speech disorder that most commonly arises from a 4-repeat tauopathy. Recent studies have established that progressive apraxia of speech is not a homogenous disease, but rather there are distinct subtypes: the phonetic subtype is characterized by distorted sound substitutions, the prosodic subtype by slow and segmented speech, and the mixed subtype by a combination of both but lack of predominance of either. There is some evidence that cross-sectional patterns of neurodegeneration differ across subtypes, although it is unknown whether longitudinal patterns of neurodegeneration differ. We examined longitudinal patterns of atrophy on MRI, hypometabolism on 18F-fluorodeoxyglucose-PET, and tau uptake on flortaucipir-PET in a large cohort of subjects with progressive apraxia of speech that had been followed for many years. Ninety-one subjects with progressive apraxia of speech (51 phonetic, 40 prosodic) were recruited by the Neurodegenerative Research Group. Of these, 54 (27 phonetic, 27 prosodic) returned for annual follow-up, with up to seven longitudinal visits (total visits analyzed = 217). Volumes, metabolism, and flortaucipir uptake was measured for subcortical and cortical regions, for all scans. Bayesian hierarchical models were used to model longitudinal change across imaging modalities with progressive apraxia of speech subtypes being compared at baseline, four years from baseline, and in terms of rates of change. The phonetic group showed smaller volumes and worse metabolism in Broca's area and the striatum at baseline and after four years, and faster rates of change in these regions, compared to the prosodic group. There was also evidence of faster spread of hypometabolism and flortaucipir uptake into the temporal and parietal lobes in the phonetic group. In contrast, the prosodic group showed smaller cerebellar dentate, midbrain, substantia nigra, and thalamus volumes at baseline and after four years, and faster rates of atrophy, than the phonetic group. Greater hypometabolism and flortaucipir uptake were also observed in the cerebellar dentate and substantia nigra in the prosodic group. Mixed findings were observed in the SMA and precentral cortex, with no clear differences observed across phonetic and prosodic groups. These findings support different patterns of disease spread in progressive apraxia of speech subtypes, with corticostriatal patterns in the phonetic subtype and brainstem and thalamic patterns in the prosodic subtype, providing insight into the pathophysiology and heterogeneity of progressive apraxia of speech.
Language	English
Publishing date	2024-01-13
Publishing country	England
Document type	Journal Article
ZDB-ID	80072-7
ISSN	1460-2156 ; 0006-8950
ISSN (online)	1460-2156
ISSN	0006-8950
DOI	10.1093/brain/awae016
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