Demenzdiagnostik mit der Amyloid-PET

Zusammenfassung

Moderne Erkrankungsmodelle der Neurodegeneration gehen davon aus, dass die vermehrte Produktion spezifischer Proteine und deren pathologische Ablagerung im Gehirn früh im Erkrankungsprozess vieler neurodegenerativer Erkrankungen steht. Im Fall der Alzheimer-Erkrankung, welche die häufigste Ursache neurodegenerativer Demenzen darstellt, handelt sich dabei um die extrazellulären Ablagerungen des β-Amyloid-Peptids (sog. Amyloid-Plaques) und intrazelluläre Aggregationen des Tau-Proteins (sog. neurofibrilläre Tangles). Speziell der Amyloid-Pathologie wird aktuell eine mögliche kausale Rolle in der Entwicklung der Alzheimer-Demenz zugesprochen, und verschiedene moderne Therapieansätze wie die Immunisierungs-Strategien oder bestimmte Enzyminhibitoren sind gegen diese Pathologie ausgerichtet.

Es ergibt sich allerdings ein diagnostisches Dilemma durch den Umstand, dass sich die Amyloid-Pathologie, wie auch andere neuropathologische Veränderungen bei der Alzheimer-Erkrankung, Jahre bis Jahrzehnte vor Einsetzen der klinischen Demenzsymptomatik zu entwickeln scheinen. Dies limitiert die Frühdiagnose der Erkrankung erheblich und verhindert damit auch den Einsatz neuer Therapieformen in einem frühen Stadium, d. h. vor der Entwicklung ausgedehnter irreversibler neuronaler Schäden. Auch die Differenzialdiagnose verschiedener Demenzerkrankungen ist auf der Basis der klinisch/neuropsychologischen Beurteilung nicht immer zuverlässig möglich, da sich Überlappungen der Symptomatik ergeben. Nicht zuletzt behindert die symptomatische Fluktuation und die langsame Entwicklung der Erkrankung auch die Verlaufsbeobachtung bzw. das Therapiemonitoring.

Die schlechte Zugänglichkeit des Gehirngewebes hat bisher bedingt, dass eine sichere Diagnose der Alzheimer-Pathologie nur durch den histopathologischen Nachweis der Amyloidplaques und der neurofibrillären Tangles in Post-mortem-Analysen des Gehirngewebes gestellt werden konnte. Mit modernen Tracern für die Positronen-Emissions-Tomografie (PET) stehen nun erstmals Methoden der molekularen Bildgebung zur Verfügung, die es ermöglichen, Amyloid-Plaque Ablagerungen im Gehirn in vivo nachzuweisen. Diese Methoden eröffnen die Möglichkeit, neurodegenerative Demenzerkrankungen auf der Basis der zugrunde liegenden Pathologie zu charakterisieren, anstelle der rein klinisch-symptomatischen Diagnostik. Diese Art der „In-vivo-Histopathologie“ bietet eine außergewöhnliche Möglichkeit zur Frühdiagnostik und zur Differenzialdiagnostik verschiedener neurodegenerativer Syndrome. Besonders bietet sich dies für die Patientenselektion für Therapiestudien an, die sich spezifisch gegen die Amyloid-Plaque-Pathologie richten, sowie auch zur objektiven Verlaufskontrolle unter Therapie.

Abstract

Modern disease models of neurodegeneration suggest that increased production and aggregation of specific proteins in the brain is an early event of neurodegeneration. In the case of Alzheimer’s disease extracellular aggregates of the β-amyloid peptide (amyloid-plaques) and intracellular aggregates of Tau-protein (neurofibrillary tangles) are key pathologies. Amyloid aggregation is considered to play a potentially causal role in the development of Alzheimer’s disease and modern therapy approaches such as immunization and secretase-inhibitors are directed towards this pathology.

A diagnostic dilemma can be found in the circumstance that amyloid-aggregation pathology seems to develop years to decades ahead of the onset of clinical symptoms. This limits early diagnosis and the initiation of therapy in stages ahead of irreversible neuronal damage. Also, differential diagnosis is limited due to the overlap of clinical symptoms. Symptomatic fluctuation and slow progression of the disorder inhibits follow-up and therapy monitoring. Due to the limited access to brain tissue a definite diagnosis of Alzheimer’s disease was usually only possible by post mortem histopathological evaluation of brain tissue.

Modern tracers for Positron Emission Tomography (PET) finally allow the detection of cerebral amyloid-pathology in vivo. These methods open new opportunities to classify neurodegenerative disorders on the basis of underlying pathology rather than by the symptomatic appearance. This new type of “in vivo histopathology” may improve early and differential diagnosis of various neurodegenerative syndromes. Particularly the method may be indispensable for patient selection and follow-up in specific therapy trials.

Schlüsselwörter

Alzheimer-Demenz - Amyloid-Bildgebung - PET - β-Amyloid - Plaques - MCI - [¹¹C]PiB

Key words

Alzheimer‘s disease - amyloid-imaging - PET - β-amyloid - amyloid-plaques - MCI - [¹¹C]PiB

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