Alexander Drzezga

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. 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.

The recently introduced first integrated whole-body PET/MR scanner allows simultaneous acquisition of PET and MRI data in humans and, thus, may offer new opportunities, particularly regarding diagnostics in oncology. This scanner features major technologic differences from conventional PET/CT devices, including the replacement of photomultipliers with avalanche photodiodes and the need for MRI-based attenuation correction. The aim of this study was to evaluate the comparability of clinical performance between conventional PET/CT and PET/MR in patients with oncologic diseases. Methods: Thirty-two patients with different oncologic diagnoses underwent a single-injection, dual-imaging protocol consisting of a PET/CT and subsequent PET/MR scan. PET/CT scans were performed according to standard clinical protocols (86 ± 8 min after injection of 401 ± 42 MBq of ¹⁸F-FDG, 2 min/bed position). Subsequently (140 ± 24 min after injection), PET/MR was performed (4 min/bed position). PET images of both modalities were reconstructed iteratively. Attenuation and scatter correction as well as regional allocation of PET findings were performed using low-dose CT data for PET/CT and Dixon MRI sequences for PET/MR. PET/MR and PET/CT were compared visually by 2 teams of observers by rating the number and location of lesions suspicious for malignancy, as well as image quality and alignment. For quantitative comparison, standardized uptake values (SUVs) of the detected lesions and of different tissue types were assessed. Results: Simultaneous PET/MR acquisition was feasible with high quality in short acquisition time (≤20 min). No significant difference was found between the numbers of suspicious lesions (n = 80) or lesion-positive patients (n = 20) detected with PET/MR or PET/CT. Anatomic allocation of PET/MR findings by means of the Dixon MRI sequence was comparable to allocation of PET/CT findings by means of low-dose CT. Quantitative evaluation revealed a high correlation between mean SUVs measured with PET/MR and PET/CT in lesions (ρ = 0.93) and background tissue (ρ = 0.92). Conclusion: This study demonstrates, for what is to our knowledge the first time, that integrated whole-body PET/MR is feasible in a clinical setting with high quality and in a short examination time. The reliability of PET/MR was comparable to that of PET/CT in allowing the detection of hypermetabolic lesions suspicious for malignancy in patients with oncologic diagnoses. Despite different attenuation correction approaches, tracer uptake in lesions and background correlated well between PET/MR and PET/CT. The Dixon MRI sequences acquired for attenuation correction were found useful for anatomic allocation of PET findings obtained by PET/MR in the entire body. These encouraging results may form the foundation for future studies aiming to define the added value of PET/MR over PET/CT.

Disruption of functional connectivity between brain regions may represent an early functional consequence of β-amyloid pathology prior to clinical Alzheimer's disease. We aimed to investigate if non-demented older individuals with increased amyloid burden demonstrate disruptions of functional whole-brain connectivity in cortical hubs (brain regions typically highly connected to multiple other brain areas) and if these disruptions are associated with neuronal dysfunction as measured with fluorodeoxyglucose-positron emission tomography. In healthy subjects without cognitive symptoms and patients with mild cognitive impairment, we used positron emission tomography to assess amyloid burden and cerebral glucose metabolism, structural magnetic resonance imaging to quantify atrophy and novel resting state functional magnetic resonance imaging processing methods to calculate whole-brain connectivity. Significant disruptions of whole-brain connectivity were found in amyloid-positive patients with mild cognitive impairment in typical cortical hubs (posterior cingulate cortex/precuneus), strongly overlapping with regional hypometabolism. Subtle connectivity disruptions and hypometabolism were already present in amyloid-positive asymptomatic subjects. Voxel-based morphometry measures indicate that these findings were not solely a consequence of regional atrophy. Whole-brain connectivity values and metabolism showed a positive correlation with each other and a negative correlation with amyloid burden. These results indicate that disruption of functional connectivity and hypometabolism may represent early functional consequences of emerging molecular Alzheimer's disease pathology, evolving prior to clinical onset of dementia. The spatial overlap between hypometabolism and disruption of connectivity in cortical hubs points to a particular susceptibility of these regions to early Alzheimer's-type neurodegeneration and may reflect a link between synaptic dysfunction and functional disconnection.

Objective: To examine the influence of the APOE genotype on levels of β-amyloid (Aβ) plaque load and atrophy in patients with Alzheimer disease (AD) in vivo. Methods: Thirty-two patients with moderate AD were divided into carriers and noncarriers of the ε4 allele. These groups were matched for age, disease duration, education, and cognitive impairment. In all subjects, [¹¹C]PIB-PET was performed for measurement of cerebral Aβ plaque deposition and cranial MRI for the assessment of gray matter volume by voxel-based morphometry (VBM) and for correction of partial volume effects (PVE) in the PET data. Voxel-based comparisons (SPM5) were performed between patient groups and healthy control populations and completed with multiple regression analyses between imaging data and ε4 allele frequency. Results: Compared to controls, AD-typical patterns of [¹¹C]PIB retention and atrophy were detected in both ε4-positive and ε4-negative patient groups. In direct comparison, significantly stronger and more extended [¹¹C]PIB uptake was found in ε4-positive patients in bilateral temporoparietal and frontal cortex, surviving PVE correction. VBM analysis demonstrated comparable levels of atrophy in both patient groups. Regression analyses revealed a linear association between higher ε4 allele frequency and stronger temporoparietal Aβ plaque deposition, independently of other confounds. No major correlation between ε4 allele frequency and gray matter decrease was observed. Conclusion: These results indicate that the ε4-positive APOE genotype not only represents a risk factor for Alzheimer disease (AD), but also results in higher levels of Aβ plaque deposition in ε4-positive patients with AD compared to age-matched ε4-negative patients with similar levels of cognitive impairment and brain atrophy. The potential role of Aβ plaque imaging for patient inclusion and follow-up in anti-amyloid therapy trials is strengthened by these findings.

Der Nutzen vieler konventioneller szintigraphischer Untersuchungen für die Diagnostik in der Inneren Medizin ist ungebrochen: Zahlreiche Fragestellungen sind nur mit szintigraphischen Verfahren zu beantworten. Die Verwendung spezifischer Tracer bietet oft die einzigartige Möglichkeit funktionelle (patho-) physiologische Prozesse zu visualisieren, die mit Erkrankungen aus dem internistischen Formenkreis assoziiert sind. Das Potential modernerer Methoden wie der PET ist auch für den Einsatz in der Inneren Medizin derzeit nicht ausgeschöpft und wird durch die Verfügbarkeit der neuen Hybrid-Systeme (PET/CT, SPECT/CT) weiteren Zuwachs erfahren. Scintigraphy continues to play an important diagnostic role in internal medicine. Many diagnostic questions can only be answered with scintigraphic methods. The application of specific radiopharmaceutical tracers offers the unique possibility to visualize ongoing functional changes, associated with diseases concerning internal medicine. The diagnostic potential of modern scintigraphic procedures such as PET for internal medicine is not yet sufficiently used and will continue to grow with hybrid systems, such as PET-CT and SPECT-CT.

Successful cognitive performance depends not only on the activation of specific neuronal networks but also on selective suppression of task-irrelevant modalities, i.e., deactivation of non-required cerebral regions. This ability to suppress the activation of specific brain regions has, to our knowledge, never been systematically evaluated in patients with Alzheimer disease (AD). The aim of the current study was to evaluate both cerebral activation and deactivation in (1) healthy volunteers, (2) patients with mild cognitive impairment (MCI) who are at risk for AD, and (3) patients with moderate AD during active navigation, representing a cognitive task typically affected in AD. Changes in regional cerebral blood flow (rCBF) were assessed with PET imaging during an active navigation task in a 3D virtual-reality environment. The task was based on visual cues exclusively; no auditory cues were provided. Age-matched groups of healthy individuals, patients with MCI, and patients with AD were examined. Specific differences in the activation patterns were observed in the three groups, with stronger activation of cerebellar portions and visual association cortex in controls and stronger activation of primary visual and frontal cortical areas in patients with MCI and AD. Highly significant bilateral decrease of rCBF in task-irrelevant auditory cortical regions was detected in healthy individuals during performance of the task. This rCBF decrease was interpreted as a cross-modal inhibitory effect. It was diminished in patients with MCI and completely absent in patients with AD. A regression analysis across all individuals revealed a clear positive relation between cognitive status (mini mental state examination score) and the extent of auditory cortical deactivation. During active navigation, a high level of movement automation and an involvement of higher-order cerebral association functions were observed in healthy controls. Conversely, in patients with MCI and AD, increased cognitive effort and attention towards movement planning, as well as stronger involvement of lower-order cerebral systems, was found. Successful cognitive performance in healthy individuals is associated with deactivation of task-irrelevant cerebral regions, whereas the development of AD appears to be characterized by a progressive impairment of cross-modal cerebral deactivation functions. These changes may cause the generally decreased ability of patients with AD to direct attention primarily to the relevant cognitive modality.