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[¹⁸F]-AV-1451 binding in the substantia nigra as a marker of neuromelanin in Lewy body diseases.

ABSTRACT: While [¹⁸F]-AV-1451 was developed as a PET radiotracer with high affinity for hyperphosphorylated tau, it has been proposed that loss of 'off-target' [¹⁸F]-AV-1451 binding to neuromelanin in the substantia nigra could be a surrogate marker of Lewy body diseases. [¹⁸F]-AV-1451 binding was measured in the substantia nigra of patients with Parkinson's disease (n = 35), dementia with Lewy bodies (n = 10) and separate control groups (n = 37; n = 14). Associations with motor symptoms, cognition and disease duration were evaluated using linear regression models. The dementia with Lewy bodies group had significantly reduced substantia nigra [¹⁸F]-AV-1451 binding compared to controls after adjusting for age (P < 0.05). However, there were no significant differences in substantia nigra [¹⁸F]-AV-1451 binding between Parkinson's disease and controls. Substantia nigra [¹⁸F]-AV-1451 binding was not associated with age, disease duration, Movement Disorders Society-Unified Parkinson's Disease Rating Scale and cognitive scores in dementia with Lewy bodies and Parkinson's disease groups. Despite the reduction of substantia nigra [¹⁸F]-AV-1451 binding in dementia with Lewy bodies, these findings suggest that substantia nigra [¹⁸F]-AV-1451 binding has no value as a diagnostic marker in early Parkinson's disease. Further investigations in longitudinal cohorts are warranted.

SUBMITTER: Mak E

PROVIDER: S-EPMC8410984 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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[18F]-AV-1451 binding in the substantia nigra as a marker of neuromelanin in Lewy body diseases.

Mak Elijah E Kouli Antonina A Holland Negin N Nicastro Nicolas N Savulich George G Surendranathan Ajenthan A Malpetti Maura M Manavaki Roido R Hong Young T YT Fryer Tim D TD Aigbirhio Franklin F Rowe James B JB O'Brien John T JT Williams-Gray Caroline H CH

Brain communications 20210828 3

While [18F]-AV-1451 was developed as a PET radiotracer with high affinity for hyperphosphorylated tau, it has been proposed that loss of 'off-target' [18F]-AV-1451 binding to neuromelanin in the substantia nigra could be a surrogate marker of Lewy body diseases. [18F]-AV-1451 binding was measured in the substantia nigra of patients with Parkinson's disease (n = 35), dementia with Lewy bodies (n = 10) and separate control groups (n = 37; n< ...[more]

PMID: 34485906

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Project description:BackgroundThe tau positron emission tomography (PET) ligand 18F-flortaucipir binds to paired helical filaments of tau in aging and Alzheimer's disease (AD), but its utility in detecting tau aggregates in frontotemporal dementia (FTD) is uncertain.MethodsWe performed 18F-flortaucipir imaging in patients with the FTD syndromes (n = 45): nonfluent variant primary progressive aphasia (nfvPPA) (n = 11), corticobasal syndrome (CBS) (n = 10), behavioral variant frontotemporal dementia (bvFTD) (n = 10), semantic variant primary progressive aphasia (svPPA) (n = 2) and FTD associated pathogenic genetic mutations microtubule-associated protein tau (MAPT) (n = 6), chromosome 9 open reading frame 72 (C9ORF72) (n = 5), and progranulin (GRN) (n = 1). All patients underwent MRI and β-amyloid biomarker testing via 11C-PiB or cerebrospinal fluid. 18F-flortaucipir uptake in patients was compared to 53 β-amyloid negative normal controls using voxelwise and pre-specified region of interest approaches.ResultsOn qualitative assessment, patients with nfvPPA showed elevated 18F-flortacupir binding in the left greater than right inferior frontal gyrus. Patients with CBS showed elevated binding in frontal white matter, with higher cortical gray matter uptake in a subset of β-amyloid-positive patients. Five of ten patients with sporadic bvFTD demonstrated increased frontotemporal binding. MAPT mutation carriers had elevated 18F-flortaucipir retention primarily, but not exclusively, in mutations with Alzheimer's-like neurofibrillary tangles. However, tracer retention was also seen in patients with svPPA, and the mutations C9ORF72, GRN predicted to have TDP-43 pathology. Quantitative region-of-interest differences between patients and controls were seen only in inferior frontal gyrus in nfvPPA and left insula and bilateral temporal poles in MAPT carriers. No significant regional differences were found in CBS or sporadic bvFTD. Two patients underwent postmortem neuropathological examination. A patient with C9ORF72, TDP-43-type B pathology, and incidental co-pathology of scattered neurofibrillary tangles in the middle frontal, inferior temporal gyrus showed corresponding mild 18F-flortaucipir retention without additional uptake matching the widespread TDP-43 type B pathology. A patient with sporadic bvFTD demonstrated punctate inferior temporal and hippocampus tracer retention, corresponding to the area of severe argyrophilic grain disease pathology.Conclusions18F-flortaucipir in patients with FTD and predicted tauopathy or TDP-43 pathology demonstrated limited sensitivity and specificity. Further postmortem pathological confirmation and development of FTD tau-specific ligands are needed.

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[¹⁸F]-AV-1451 binding in the substantia nigra as a marker of neuromelanin in Lewy body diseases.

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[<sup>18</sup>F]-AV-1451 binding in the substantia nigra as a marker of neuromelanin in Lewy body diseases.

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[18F]-AV-1451 binding in the substantia nigra as a marker of neuromelanin in Lewy body diseases.

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[¹⁸F]-AV-1451 binding in the substantia nigra as a marker of neuromelanin in Lewy body diseases.

[<sup>18</sup>F]-AV-1451 binding in the substantia nigra as a marker of neuromelanin in Lewy body diseases.