Bischof GN, Jaeger E, Giehl K, Jessen F, Onur OA, O'Bryant S, Kara E, Weiss PH, Drzezga A.
Cortical Tau Aggregation Patterns Associated With Apraxia in Patients With Alzheimer Disease.
Neurology. 2024 Dec 24;103(12):e210062. Epub 2024 Dec 3
PubMed.
This study reports associations between apraxia symptoms and tau PET signal in a sample of 34 individuals with a clinical diagnosis of Alzheimer’s disease and biomarker evidence of AD neuropathologic change. The study is a clear example of brain mapping with direct clinical applicability, linking apraxia to AD tau aggregation at the juncture of the parietal, occipital, and temporal lobes. Informative mappings of this type enhance the clinical value of imaging and can help inform interpretation of ambiguous exam results or neuropsychological testing (e.g., when it may be unclear whether a patient’s poor performance is due to apraxia, inattention, or a failure to understand instructions).
Pathologically, Bischof et al. provide further evidence for the role of tau pathology (in this case, AD-type tau) in apraxia. It is consistent with findings in the broader literature that apraxia is most commonly associated with tauopathies, and infrequently with α-synuclein (Zadikoff and Lang, 2005) or TDP-43, except in apraxia of speech (Langheinrich et al., 2024) or in some unusual clinical presentations of TDP-43 (Rusina et al., 2011).
These findings provide a valuable lens for interpreting atypical clinical and anatomical presentations of AD. Braak and Braak’s original study highlighted a strong correlation between the extent of NFT spread and NFT severity. While most Alzheimer’s brains are best described by a stepwise increase in both Braak stage and regional tau burdens, recent neuropathological and imaging studies have uncovered distinct tau patterns or types in a subset of patients that not only indicate a disconnect between canonical Braak stage and severity but also have clinical relevance (Murray et al., 2011; Phillips et al., 2018; Vogel et al., 2021).
Bischof et al.’s results lay the basis for potential future work examining the specificity of the mapping between apraxia and posterior parietal, occipital, and temporal cortex. For example, what proportion of individuals in a dataset such as ADNI have elevated tau in these areas, and is that tau burden associated with apraxia severity?
Interestingly, the authors found exclusively neocortical correlates of apraxia severity; in contrast, Palleis et al., 2021, also reported elevated basal ganglia tau in corticobasal syndrome participants with apraxia. On one hand, these differences may relate to differences in the PET acquisition window and analysis methods between the two studies—the longer, dynamic PI-2620 acquisition that Palleis and colleagues use is potentially more sensitive to basal ganglia tau, particularly in amyloid-negative CBS participants with likely 4R tau. At the same time, the neocortical associations reported by Bischof et al. make sense given their focus on clinical AD, a predominantly cortical disease (e.g., compared to corticobasal degeneration), and highlight the nature of praxis as a higher-order cognitive ability incorporating not only motor function but also semantic memory, social cognition, and cognitive control.
We hope that the authors will follow up with further work demonstrating the utility of tau PET for diagnosis of individuals of rare dementia syndromes associated with focal AD and frontotemporal lobar degeneration pathology.
References:
Zadikoff C, Lang AE.
Apraxia in movement disorders.
Brain. 2005 Jul;128(Pt 7):1480-97.
PubMed.
Langheinrich TC, Thompson JC, Jones M, Richardson AM, Mann DM, Snowden JS.
Apraxia phenotypes and frontotemporal lobar degeneration.
J Neurol. 2024 Dec;271(12):7471-7488. Epub 2024 Oct 10
PubMed.
Rusina R, Kovacs GG, Fiala J, Hort J, Ridzoň P, Holmerová I, Ströbel T, Matěj R.
FTLD-TDP with motor neuron disease, visuospatial impairment and a progressive supranuclear palsy-like syndrome: broadening the clinical phenotype of TDP-43 proteinopathies. A report of three cases.
BMC Neurol. 2011;11:50.
PubMed.
Murray ME, Graff-Radford NR, Ross OA, Petersen RC, Duara R, Dickson DW.
Neuropathologically defined subtypes of Alzheimer's disease with distinct clinical characteristics: a retrospective study.
Lancet Neurol. 2011 Sep;10(9):785-96.
PubMed.
Phillips JS, Da Re F, Dratch L, Xie SX, Irwin DJ, McMillan CT, Vaishnavi SN, Ferrarese C, Lee EB, Shaw LM, Trojanowski JQ, Wolk DA, Grossman M.
Neocortical origin and progression of gray matter atrophy in nonamnestic Alzheimer's disease.
Neurobiol Aging. 2018 Mar;63:75-87. Epub 2017 Nov 21
PubMed.
Vogel JW, Young AL, Oxtoby NP, Smith R, Ossenkoppele R, Strandberg OT, La Joie R, Aksman LM, Grothe MJ, Iturria-Medina Y, Alzheimer’s Disease Neuroimaging Initiative, Pontecorvo MJ, Devous MD, Rabinovici GD, Alexander DC, Lyoo CH, Evans AC, Hansson O.
Four distinct trajectories of tau deposition identified in Alzheimer's disease.
Nat Med. 2021 May;27(5):871-881. Epub 2021 Apr 29
PubMed.
Palleis C, Brendel M, Finze A, Weidinger E, Bötzel K, Danek A, Beyer L, Nitschmann A, Kern M, Biechele G, Rauchmann BS, Häckert J, Höllerhage M, Stephens AW, Drzezga A, van Eimeren T, Villemagne VL, Schildan A, Barthel H, Patt M, Sabri O, German Imaging Initiative for Tauopathies (GII4T), Bartenstein P, Perneczky R, Haass C, Levin J, Höglinger GU.
Cortical [18 F]PI-2620 Binding Differentiates Corticobasal Syndrome Subtypes.
Mov Disord. 2021 Sep;36(9):2104-2115. Epub 2021 May 5
PubMed.
Comments
University of Pennsylvania
University of Pennsylvnia
This study reports associations between apraxia symptoms and tau PET signal in a sample of 34 individuals with a clinical diagnosis of Alzheimer’s disease and biomarker evidence of AD neuropathologic change. The study is a clear example of brain mapping with direct clinical applicability, linking apraxia to AD tau aggregation at the juncture of the parietal, occipital, and temporal lobes. Informative mappings of this type enhance the clinical value of imaging and can help inform interpretation of ambiguous exam results or neuropsychological testing (e.g., when it may be unclear whether a patient’s poor performance is due to apraxia, inattention, or a failure to understand instructions).
Pathologically, Bischof et al. provide further evidence for the role of tau pathology (in this case, AD-type tau) in apraxia. It is consistent with findings in the broader literature that apraxia is most commonly associated with tauopathies, and infrequently with α-synuclein (Zadikoff and Lang, 2005) or TDP-43, except in apraxia of speech (Langheinrich et al., 2024) or in some unusual clinical presentations of TDP-43 (Rusina et al., 2011).
These findings provide a valuable lens for interpreting atypical clinical and anatomical presentations of AD. Braak and Braak’s original study highlighted a strong correlation between the extent of NFT spread and NFT severity. While most Alzheimer’s brains are best described by a stepwise increase in both Braak stage and regional tau burdens, recent neuropathological and imaging studies have uncovered distinct tau patterns or types in a subset of patients that not only indicate a disconnect between canonical Braak stage and severity but also have clinical relevance (Murray et al., 2011; Phillips et al., 2018; Vogel et al., 2021).
Bischof et al.’s results lay the basis for potential future work examining the specificity of the mapping between apraxia and posterior parietal, occipital, and temporal cortex. For example, what proportion of individuals in a dataset such as ADNI have elevated tau in these areas, and is that tau burden associated with apraxia severity?
Interestingly, the authors found exclusively neocortical correlates of apraxia severity; in contrast, Palleis et al., 2021, also reported elevated basal ganglia tau in corticobasal syndrome participants with apraxia. On one hand, these differences may relate to differences in the PET acquisition window and analysis methods between the two studies—the longer, dynamic PI-2620 acquisition that Palleis and colleagues use is potentially more sensitive to basal ganglia tau, particularly in amyloid-negative CBS participants with likely 4R tau. At the same time, the neocortical associations reported by Bischof et al. make sense given their focus on clinical AD, a predominantly cortical disease (e.g., compared to corticobasal degeneration), and highlight the nature of praxis as a higher-order cognitive ability incorporating not only motor function but also semantic memory, social cognition, and cognitive control.
We hope that the authors will follow up with further work demonstrating the utility of tau PET for diagnosis of individuals of rare dementia syndromes associated with focal AD and frontotemporal lobar degeneration pathology.
References:
Zadikoff C, Lang AE. Apraxia in movement disorders. Brain. 2005 Jul;128(Pt 7):1480-97. PubMed.
Langheinrich TC, Thompson JC, Jones M, Richardson AM, Mann DM, Snowden JS. Apraxia phenotypes and frontotemporal lobar degeneration. J Neurol. 2024 Dec;271(12):7471-7488. Epub 2024 Oct 10 PubMed.
Rusina R, Kovacs GG, Fiala J, Hort J, Ridzoň P, Holmerová I, Ströbel T, Matěj R. FTLD-TDP with motor neuron disease, visuospatial impairment and a progressive supranuclear palsy-like syndrome: broadening the clinical phenotype of TDP-43 proteinopathies. A report of three cases. BMC Neurol. 2011;11:50. PubMed.
Murray ME, Graff-Radford NR, Ross OA, Petersen RC, Duara R, Dickson DW. Neuropathologically defined subtypes of Alzheimer's disease with distinct clinical characteristics: a retrospective study. Lancet Neurol. 2011 Sep;10(9):785-96. PubMed.
Phillips JS, Da Re F, Dratch L, Xie SX, Irwin DJ, McMillan CT, Vaishnavi SN, Ferrarese C, Lee EB, Shaw LM, Trojanowski JQ, Wolk DA, Grossman M. Neocortical origin and progression of gray matter atrophy in nonamnestic Alzheimer's disease. Neurobiol Aging. 2018 Mar;63:75-87. Epub 2017 Nov 21 PubMed.
Vogel JW, Young AL, Oxtoby NP, Smith R, Ossenkoppele R, Strandberg OT, La Joie R, Aksman LM, Grothe MJ, Iturria-Medina Y, Alzheimer’s Disease Neuroimaging Initiative, Pontecorvo MJ, Devous MD, Rabinovici GD, Alexander DC, Lyoo CH, Evans AC, Hansson O. Four distinct trajectories of tau deposition identified in Alzheimer's disease. Nat Med. 2021 May;27(5):871-881. Epub 2021 Apr 29 PubMed.
Palleis C, Brendel M, Finze A, Weidinger E, Bötzel K, Danek A, Beyer L, Nitschmann A, Kern M, Biechele G, Rauchmann BS, Häckert J, Höllerhage M, Stephens AW, Drzezga A, van Eimeren T, Villemagne VL, Schildan A, Barthel H, Patt M, Sabri O, German Imaging Initiative for Tauopathies (GII4T), Bartenstein P, Perneczky R, Haass C, Levin J, Höglinger GU. Cortical [18 F]PI-2620 Binding Differentiates Corticobasal Syndrome Subtypes. Mov Disord. 2021 Sep;36(9):2104-2115. Epub 2021 May 5 PubMed.
Make a Comment
To make a comment you must login or register.