Longitudinal anatomic, functional, and molecular characterization of Pick disease phenotypes.

OBJECTIVE: To characterize longitudinal MRI and PET abnormalities in autopsy-confirmed Pick disease (PiD) and determine how patterns of neurodegeneration differ with respect to clinical syndrome. METHODS: Seventeen patients with PiD were identified who had antemortem MRI (8 with behavioral variant frontotemporal dementia [bvFTD-PiD], 6 with nonfluent/agrammatic primary progressive aphasia [naPPA-PiD], 1 with semantic primary progressive aphasia, 1 with unclassified primary progressive aphasia, and 1 with corticobasal syndrome). Thirteen patients had serial MRI for a total of 56 MRIs, 7 had [18F]fluorodeoxyglucose PET, 4 had Pittsburgh compound B (PiB) PET, and 1 patient had [18F]flortaucipir PET. Cross-sectional and longitudinal comparisons of gray matter volume and metabolism were performed between bvFTD-PiD, naPPA-PiD, and controls. Cortical PiB summaries were calculated to determine ß-amyloid positivity. RESULTS: The bvFTD-PiD and naPPA-PiD groups showed different foci of volume loss and hypometabolism early in the disease, with bvFTD-PiD involving bilateral prefrontal and anterior temporal cortices and naPPA-PiD involving left inferior frontal gyrus, insula, and orbitofrontal cortex. However, patterns merged over time, with progressive spread into prefrontal and anterior temporal lobe in naPPA-PiD, and eventual involvement of posterior temporal lobe, motor cortex, and parietal lobe in both groups. Rates of frontotemporal atrophy were faster in bvFTD-PiD than naPPA-PiD. One patient was ß-amyloid-positive on PET with low Alzheimer neuropathologic changes at autopsy. Flortaucipir PET showed elevated uptake in frontotemporal white matter. CONCLUSION: Patterns of atrophy and hypometabolism differ in PiD according to presenting syndrome, although patterns of neurodegeneration appear to converge over time.

Decreased striatal dopamine transporter uptake in the non-fluent/agrammatic variant of primary progressive aphasia.

BACKGROUND AND PURPOSE: Patients with the non-fluent/agrammatic variant of primary progressive aphasia (nfvPPA) may develop atypical parkinsonian syndromes. However, there is no current biomarker to assess which patients are at high risk of developing parkinsonism. 123I-2ß-carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane (123I-FP-CIT)-SPECT detects striatal dopamine dysfunction in vivo. The objective of the present study was to study whether non-fluent/agrammatic patients without parkinsonism at baseline present decreased striatal 123I-FP-CIT uptake. METHODS: Visual and semi-quantitative assessments of the striatal 123I-FP-CIT uptake ratio were carried out in 15 patients with nfvPPA, eight patients with the logopenic variant of PPA (lvPPA) and 18 controls. To rule out progranulin mutations or underlying Alzheimer's disease (AD), serum progranulin levels and cerebrospinal fluid (CSF) biomarkers of AD (Aß42 , total-tau, phosphorylated-tau181 ) were determined. A second 123I-FP-CIT-SPECT analysis in the biomarker-enriched groups was also carried out. RESULTS: Patients with nfvPPA presented reduced striatal 123I-FP-CIT binding, especially in the left hemisphere (P = 0.002), compared with controls. All lvPPA patients had normal striatal 123I-FP-CIT uptake. 123I-FP-CIT striatal binding in nfvPPA patients with normal progranulin and CSF biomarker levels (nfvPPA/bio-) was also significantly reduced (P < 0.05) compared with lvPPA patients with positive AD biomarkers. Sixty-four per cent (9/14) of nfvPPA patients and 80% of nfvPPA/bio- patients (8/10) showed a diminished individual left striatal 123I-FP-CIT uptake ratio. On follow-up, seven nfvPPA/bio- patients developed parkinsonism (median 1.9 years; range 1.2-2.9), six of them with baseline reduced 123I-FP-CIT uptake. CONCLUSIONS: Reduced striatal tracer uptake in nfvPPA patients prior to clinical parkinsonism can be detected by 123I-FP-CIT-SPECT, especially in those with nfvPPA/bio-, suggesting subclinical nigrostriatal degeneration. Decreased striatal 123I-FP-CIT binding might identify PPA patients at increased risk of developing atypical parkinsonian syndromes, probably related to tau-pathology.

Parálisis supranuclear progresiva / Progressive supranuclear palsy

Introducción. La parálisis supranuclear progresiva (PSP) es una enfermedad neurodegenerativa que se describió por primera vez en 1964 y en la que se produce una acumulación citoplasmática de proteína tau asociada a microtúbulos (MAPT) como consecuencia de su fosforilación anómala. Objetivo. El objetivo de este trabajo ha sido revisar los avances en el conocimiento de la PSP en los últimos años. Desarrollo. La PSP es la taupatía más frecuente, de aparición esporádica pero con algunos casos hereditarios por mutaciones en el gen MAPT. Las manifestaciones clínicas más características de esta enfermedad consisten en inestabilidad postural con caídas, deterioro cognitivo y parálisis supranuclear de la mirada. Se han descrito distintas variantes clínicas, entre las que destacan el Síndrome de Richardson, la PSP- Parkinsonismo, la acinesia pura con congelación de la marcha, la PSP-corticobasal y la afasia no fluente progresiva. Las diferentes características clínicas de estos subtipos vienen determinadas por la distinta densidad y localización de los agregados tau. El diagnóstico definitivo se realiza mediante confirmación anatomopatológica postmortem. Aunque se han producido algunos ensayos terapéuticos, en la actualidad no se dispone de tratamiento eficaz modificador de la enfermedad. Conclusiones. Los recientes avances han permitido un mejor conocimiento de la fisiopatología y genética de esta enfermedad. Existen distintas líneas de investigación abiertas en la actualidad siendo necesario que se profundice en estudios dirigidos a descubrir marcadores biológicos y agentes terapéuticos (AU)

Introduction. Progressive supranuclear palsy (PSP) is a neurodegenerative disease that was first reported in 1964 and which entails a cytoplasmic accumulation of microtubule-associated protein tau (MAPT) as a consequence of its abnormal phosphorylation. Aims. The objective of this research is to review the advances produced in the knowledge of PSP in recent years. Development. PSP is the most frequent tauopathy, which appears sporadically but with some hereditary cases due to mutations in the MAPT gene. The most characteristic clinical manifestations of this disease consist in postural instability with falls, cognitive impairment and supranuclear gaze palsy. Several different clinical variants have been described, including Richardson’s syndrome, Parkinsonism-PSP, pure akinesia with freezing of gait, corticobasal-PSP and progressive non-fluent aphasia. The different clinical features of these subtypes are determined by the different density and location of the tau aggregates. The definitive diagnosis is reached by confirmation from post-mortem pathological analyses. Although some therapeutic trials have been conducted, today there is still no effective disease-modifying treatment available. Conclusions. Recent advances have made it possible to gain a better understanding of the pathophysiology and genetics of this disease. Different lines of research are currently open, but there is a need for further in-depth studies aimed at discovering biological markers and therapeutic agents (AU)