Fortschritte in Früh- und Verlaufsdiagnostik bei Morbus Huntington

Zusammenfassung

Bereits lange vor der Möglichkeit einer molekulargenetischen Untersuchung war es Ziel der Neurologie, Methoden zu entwickeln, die eine möglichst frühzeitige Diagnose und prognostische Vorhersage bei Morbus Huntington ermöglichen. Die Entwicklung von verlässlichen Indikatoren für frühe neuronale Funktionsbeeinträchtigungen und von möglichen Endpunkten in Studien zur Prüfung neuroprotektiv wirksamer Substanzen hat an Intensität und Dringlichkeit gewonnen. Neuere Daten, insbesondere aus der PREDICT-Studie, bestätigen das Auftreten objektivierbarer Veränderungen Jahre vor Auftritt motorischer Symptome. In dieser Übersichtsarbeit soll ein Überblick über den derzeitigen Stand der Forschung zur Gewinnung objektiver Verlaufsparameter gegeben werden. Behandelt werden klinisch-neurologische, psychiatrische, neuropsychologische und neurophysiologische Befunde, Motorikuntersuchungen, bildgebende Verfahren (MRT, fMRT, PET und SPECT), Magnetresonanzspektroskopie (MRS), statistische und mathematische Ansätze sowie laborchemische Ansätze. Zusammenfassend lassen sich mithilfe der verschiedenen Techniken erste Veränderungen bei den Mutationsträgern bereits 10–20 Jahre vor dem Auftreten von diagnosesichernden motorischen Symptomen nachweisen. Zusätzlich zeigen sich in aktuellen Untersuchungen überraschend hochregulierte Prozesse bei Probanden, welche weit entfernt sind vom vermuteten Erkrankungsbeginn (> 10 Jahre). Es ist noch nicht geklärt, ob es sich dabei um einen Teil der Pathologie oder um Kompensationsmechanismen handelt. Die Autoren schlagen vor, aufgrund dieser Befunde in zumindest 2 Phasen bei prämanifesten Mutationsträgern zu unterscheiden, eine erste frühe Phase, bei der (im Vergleich zu Kontrollen) hochregulierte Prozesse im Vordergrund stehen, und eine zweite, spätere Phase, bei der Defizite das Bild beherrschen, die mittels funktioneller Untersuchungstechniken detektierbar werden.

Abstract

For a long time – even before genetic testing became available – neurologists have been searching for reliable markers or tests to predict the diagnosis of Huntington's disease (HD) before the first clinical symptoms appear. Today the development of indicators which allow reliable detection of disease progression is becoming increasingly important in the context of clinical neuroprotective studies. New data which derive from studies like PREDICT-HD confirm the occurrence of objective changes many years before first motor symptoms are detectable. In this review we give an overview over the various methods that are currently under clinical testing to evaluate disease onset and progression. We focus on clinical tests as well as psychiatric, neuropsychiatric, neurophysiological tests, and tests using MRI, fMRI, PET or SPECT as well as blood tests. In summary, it is possible with various methods to detect subtle changes in HD gene carriers 10–20 years before occurrence of motor signs that establish the clinical diagnosis of manifest HD. Interestingly, in a number of studies functional up-regulation in specific brain areas was found in HD gene carriers who were more than 10 years beyond the expected disease onset. So far it is unclear whether this is part of the disease cascade or whether this reflects compensating mechanisms. However, on the basis of these findings the authors suggest to divide the preclinical phase of HD into at least two parts: a very early phase with predominantly up-regulated processes followed by a later phase with predominant deficits in functional investigations compared to controls.

Schlüsselwörter

Huntington - Biomarker - Diagnostik

Keywords

Huntington's disease - Biomarkers - diagnostics

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