Afasias primarias progresivas. Caracterización clínica y marcadores biológicos

Autor: Gil Navarro, Silvia
Přispěvatelé: Sánchez del Valle Díaz, Raquel, Lladó Plarrumaní, Albert, Universitat de Barcelona. Departament de Medicina
Jazyk: Spanish; Castilian
Rok vydání: 2013
Předmět:
Zdroj: TDX (Tesis Doctorals en Xarxa)
TDR. Tesis Doctorales en Red
instname
Dipòsit Digital de la UB
Universidad de Barcelona
Popis: INTRODUCCIÓN: La actual clasificación de afasia primaria progresiva (APP) reconoce tres variantes clínicas principales: no-fluente/agramatical (APP-vnf), semántica (APP-vs) y logopénica (APP-vl). Cada una presenta un patrón de neuroimagen estructural y/o funcional característico, que sirve como biomarcador de apoyo al diagnóstico clínico; sin embargo, la asociación entre ambos criterios diagnósticos no ha sido evaluada a nivel individual en la práctica clínica. Además, el papel de diversos marcadores genéticos y bioquímicos (como los niveles séricos de progranulina y los biomarcadores de enfermedad de Alzheimer (EA) en líquido cefalorraquídeo (LCR)), todavía no ha sido establecido en el estudio de la APP y éstos no figuran en la actual clasificación. Por otra parte, evolutivamente algunos pacientes con APP-vnf desarrollan un parkinsonismo atípico con sustrato neuropatológico de una degeneración lobular fronto-temporal (DLFT)-tau. Sin embargo, no hay estudios que valoren in vivo la integridad de la vía nigroestriatal mediante 123I-FP-CIT SPECT en sujetos con APP sin parkinsonismo clínico. MÉTODOS: En el trabajo 1, centrado en una cohorte prospectiva de sujetos con APP, se realizó: exploración clínica y neuropsicológica, neuroimagen estructural (RM) y funcional (PET/SPECT), genotipado APOE, estudio de biomarcadores de EA en LCR (Aβ42, tau-total y tau fosforilada), niveles séricos de progranulina y cribado de mutaciones en MAPT, GRN y C9ORF72. En el trabajo 2 se compararon los niveles séricos de progranulina en una cohorte retrospectiva de pacientes con diagnóstico clínico de DFT, APP y EA. Se realizó secuenciación directa de GRN en aquellos sujetos con niveles séricos de progranulina
INTRODUCTION: Clinical diagnosis of the three variants of primary progressive aphasia (PPA) -non-fluent/agrammatical variant (nfvPPA), semantic (svPPA) and logopenic (lvPPA)- may be further supported by neuroimaging. However the association between PPA clinical variants and consensus neuroimaging-supported diagnostic criteria and available biochemical and genetic markers has not been. Moreover, some nfvPPA patients develop atypical parkinsonism related to FTLD-tau but the nigrostriatal pathway using 123I-FP-CIT SPECT in PPA patients without clinical parkinsonism has not been evaluated. METHODS: Article 1. We performed clinical, neuropsychological evaluation, MRI and/or PET/SPECT in a cohort of PPA participants. To rule out GRN mutations and underlying AD, serum progranulin levels and CSF-AD biochemical markers (Aβ42, total- tau and phosphorylated- tau) were determined. Cases with a first-degree family history of early-onset dementia were genetically tested. Article 2. Serum progranulin levels were analyzed in patients diagnosed of FTD, PPA and AD. DNA was screened for GRN mutations when progranulin levels were < 120 ng/ml. Article 3. Visual and semi-quantitative assessment of the striatal 123I-FP-CIT uptake ratios were analyzed in nfvPPA and lvPPA patients without clinical parkinsonism and controls. CSF-AD biochemical markers and serum progranulin levels were also studied. RESULTS 1. The majority of patients fulfilled clinical criteria for the three variants of PPA but 15.6% were unclassifiable (uPPA) according to establish criteria. All svPPA and lvPPA patients presented at least one positive neuroimaging-supported diagnostic criteria but that was the case of 66% of nfvPPA. AD-CSF biomarkers were associated to lvPPA and 60% of uPPA. Two nfvPPA patients carried a GRN mutation and two nfvPPA the C9orf72 mutation. 2. We detected no differences in progranulin serum levels between DFT, PPA and AD patients. Serum progranulin levels of the three null mutations carriers found were reduced 1/3 respect to controls. 3. NfvPPA patients, especially those with normal progranulin and CSF-AD biomarkers, presented a reduced striatal 123I-FP-CIT uptake compared to controls and lvPPA. 70% of nfvPPA patients with normal biochemical markers develop clinical parkinsonism on follow-up, 85% of them with an abnormal 123I-FP-CIT SPECT at inclusion. CONCLUSIONS: 1. We found an excellent association between clinical and neuroimaging-supported diagnostic criteria in svPPA and lvPPA. Neuroimaging, genetic and biochemical markers suggested a heterogeneous substrate in nfvPPA. Incorporating genetic and biochemical markers into the assessment of PPA could improve neuropathological predictions, especially of nfvPPA and uPPA. 2. There are no differences in the serum progranulin levels in patients with PPA, DFT and AD, after excluding the cases of null GRN mutations. The determination of serum progranulin levels is a useful biomarker to detect GRN mutations independently of the clinical phenotype. 3. 123I-FP-CIT SPECT detects reduced striatal uptake in nfvPPA without clinical parkinsonism indicating the existence of subclinical nigrostriatal. This technique could be a potential biomarker to identify PPA patients at risk of developing atypical parkinsonism, probably related to FTLD-tau.
Databáze: OpenAIRE
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