Jochen Hammes

Impact of tau and amyloid burden on glucose metabolism in Alzheimer's disease.

In a multimodal PET imaging approach, we determined the differential contribution of neurofibrillary tangles (measured with [18F]AV‐1451) and beta‐amyloid burden (measured with [11C]PiB) on degree of neurodegeneration (i.e., glucose metabolism measured with [18F]FDG‐PET) in patients with Alzheimers disease. Across brain regions, we observed an interactive effect of beta‐amyloid burden and tau deposition on glucose metabolism which was most pronounced in the parietal lobe. Elevated beta‐amyloid burden was associated with a stronger influence of tau accumulation on glucose metabolism. Our data provide the first in vivo insights into the differential contribution of Aβ and tau to neurodegeneration in Alzheimers disease.

In vivo Patterns of Tau Pathology, Amyloid-β Burden, and Neuronal Dysfunction in Clinical Variants of Alzheimer’s Disease

The clinical heterogeneity of Alzheimers disease is not reflected in the rather diffuse cortical deposition of amyloid-β. We assessed the relationship between clinical symptoms, in vivo tau pathology, amyloid distribution, and hypometabolism in variants of Alzheimers disease using novel multimodal PET imaging techniques. Tau pathology was primarily observed in brain regions related to clinical symptoms and overlapped with areas of hypometabolism. In contrast, amyloid-β deposition was diffusely distributed over the entire cortex. Tau PET imaging may thus serve as a valuable biomarker for the localization of neuronal injury in vivo and may help to validate atypical subtypes of Alzheimers disease.

Networks of tau distribution in Alzheimer’s disease

See Whitwell (doi:10.1093/brain/awy001) for a scientific commentary on this article.A stereotypical anatomical propagation of tau pathology has been described in Alzheimers disease. According to recent concepts (network degeneration hypothesis), this propagation is thought to be indicative of misfolded tau proteins possibly spreading along functional networks. If true, tau pathology accumulation should correlate in functionally connected brain regions. Therefore, we examined whether independent components could be identified in the distribution pattern of in vivo tau pathology and whether these components correspond with specific functional connectivity networks. Twenty-two 18F-AV-1451 PET scans of patients with amnestic Alzheimers disease (mean age = 66.00 ± 7.22 years, 14 males/eight females) were spatially normalized, intensity standardized to the cerebellum, and z-transformed using the mean and deviation image of a healthy control sample to assess Alzheimers disease-related tau pathology. First, to detect distinct tau pathology networks, the deviation maps were subjected to an independent component analysis. Second, to investigate if regions of high tau burden are associated with functional connectivity networks, we extracted the region with the maximum z-value in each of the generated tau pathology networks and used them as seeds in a subsequent resting-state functional MRI analysis, conducted in a group of healthy adults (n = 26) who were part of the 1000 Functional Connectomes Project. Third, to examine if tau pathology co-localizes with functional connectivity networks, we quantified the spatial overlap between the seed-based networks and the corresponding tau pathology network by calculating the Dice similarity coefficient. Additionally, we assessed if the tau-dependent seed-based networks correspond with known functional resting-state networks. Finally, we examined the relevance of the identified components in regard to the neuropathological Braak stages. We identified 10 independently coherent tau pathology networks with the majority showing a symmetrical bi-hemispheric expansion and coinciding with highly functionally connected brain regions such as the precuneus and cingulate cortex. A fair-to-moderate overlap was observed between the tau pathology networks and corresponding seed-based networks (Dice range: 0.13-0.57), which in turn resembled known resting-state networks, particularly the default mode network (Dice range: 0.42-0.56). Moreover, greater tau burden in the tau pathology networks was associated with more advanced Braak stages. Using the data-driven approach of an independent component analysis, we observed a set of independently coherent tau pathology networks in Alzheimers disease, which were associated with disease progression and coincided with functional networks previously reported to be impaired in Alzheimers disease. Together, our results provide novel information regarding the impact of tau pathology networks on the mechanistic pathway of Alzheimers disease.

Pearls & Oy-sters: Ocular motor apraxia as essential differential diagnosis to supranuclear gaze palsy: Eyes up

Ocular motor apraxia (OA) is an inability to initiate voluntary saccades in a head-fixed position, while saccades can be initiated by the vestibulo-ocular reflex (indicating dysfunction in the frontal eye fields).

Molecular imaging in early diagnosis, differential diagnosis and follow-up of patients with neurodegenerative diseases

PurposeCurrent disease models suggest that many neurodegenerative disorders are associated with pathological protein aggregations that start to develop in the brain long before the onset of clinical symptoms. Therefore, biomarkers allowing early and reliable characterization of neurodegenerative disease are required. Here we illustrate the potential value of neuroimaging procedures by means of selected examples.MethodsMultimodal imaging data of exemplary patients who underwent FDG, Amyloid and AV-1451-PET, FP-CIT-SPECT and MRI imaging in the routine clinical workup in our department is presented and the currently available literature on the topic of imaging in neurodegenerative diseases was reviewed.ResultsThe complementary value of the applied imaging methods is demonstrated in pairs of representative cases. Depending on the clinical question, individual methods or a meaningful multimodal combination is required to achieve optimal diagnostic benefit.ConclusionImaging biomarkers have high potential for early diagnosis, differential diagnosis and follow-up of patients with neurodegenerative diseases already and will gain an even higher importance in the future, when specific pathology-targeted therapies will be evaluated in clinical trials.

The Role of Tau Imaging in Parkinsonian Disorders

Purpose of ReviewDifferential diagnosis of atypical Parkinson syndromes (APS) is difficult as clinical presentations may vary and as there is a strong overlap between disease entities. Aggregations of misfolded and hyperphosphorylated tau proteins are the common denominator of many of these diseases.Recent FindingsSeveral tau targeting positron emission tomography (PET) tracers have been evaluated as possible biomarkers in APS in the recent years. For Parkinson’s disease, dementia with Lewy bodies, progressive supranuclear palsy, and corticobasal degeneration, promising results have been reported with regard to the ability to detect the presence of disease and to discriminate patients from controls. However, the discussion about the specificity of the first-generation radiotracers and their value in the clinical context is ongoing.SummaryA combined interpretation of signal strength and distribution pattern in PET scans with first- and second-generation tracers may be helpful in clinical diagnosis and follow-up of patients with APS.

EBONI: A tool for automated quantification of bone metastasis load in PSMA PET/CT

Prostate-specific membrane antigen (PSMA) PET/CT has a high diagnostic accuracy for lesion detection in metastatic prostate cancer, including bone metastases. Novel therapeutic approaches require valid biomarkers for standardized disease staging and for evaluation of progression and therapy response. Here, we introduce EBONI (Evaluation of Bone Involvement), a software tool to automatically quantify the bone metastasis load in PSMA PET/CT. Lesion quantity, mean and maximum lesional SUV, z score, and percentage of affected bone volume are determined. EBONI is open source and freely available. Methods: To validate EBONI, the results of automated quantification of 38 PSMA PET/CT scans with different levels of bone involvement were compared with visual expert reading. The influence of SUV threshold and Hounsfield unit thresholds was analyzed. Results: A high correlation between bone lesion quantity as determined visually and automatically was found (SUVmax, r2 = 0.97; SUVmean, r2 = 0.88; lesion count, r2 = 0.97). The Hounsfield unit threshold had no significant influence, whereas an SUV threshold of 2.5 proved optimal for automated lesion quantification. The systematic error of false-positive tissue misclassification was low, occurred mainly around the salivary and lacrimal glands, and could easily be corrected. There were no false-negative ratings. Conclusion: EBONI analysis is robust, quick (<3 min per scan), and 100% reproducible. It allows rater-independent quantification of bone metastasis in metastatic prostate cancer. It provides lesion quantification equivalent to that of visual assessment, as well as providing complementary information. It can be easily implemented as an add-on to visual analysis of PSMA PET/CT scans and has the potential to reduce turnaround time.

Orbital Hemangiopericytoma in 68Ga–Prostate-Specific Membrane Antigen–HBED–CC PET/CT

A 76-year-old man with biochemical relapse of prostate cancer underwent Ga-prostate-specific membrane antigen PET/CT. Besides a local lymph node metastasis, a nodular structure inside the left orbit caudal to the optic nerve showed increased uptake. A metastasis in this location is unlikely. The subsequently performed MRI showed the structure being T1 hypointense, T2 indifferent, and strongly gadolinium contrast agent enhancing. Histopathologic examination after surgical removal identified the tumor as hemangiopericytoma, which rarely occurs in the orbit. Regarding the intense uptake observed, prostate-specific membrane antigen-targeting PET tracers could bear potential for staging purposes of this tumor entity.

Tau pathology burden associated with level of cognitive reserve in Alzheimer’s disease.

longitudinal study helps in identifying aging windows in APOE-ε4 carriers, which are predictive of metabolic and neurological changes. Female APOE-ε4 rats demonstrate a state of bioenergetic deficit after the perimenopausal transition. Coincident increase in ketone body levels may reflect a metabolic state, which is shifting to a ketogenic system from a glucogenic system, andmay be related to an increase in white matter catabolism. Grant support: National Institute on Aging (NIA) grants R01AG032236 and P01AG026572 to RDB, Paul Slavic Trust and Alzheimer’s Association.

D26 Pathological tau signal in huntington’s disease – an in vivo [18F]-AV-1451 pet imaging report

Background Tau aggregation has been implicated in the pathological process and clinical expression in Huntington’s disease (HD). Detection of cerebral pathological Tau protein deposits may therefore be useful to track and predict disease progression. Methods We report on three manifest HD patients, who underwent [18F]AV-1451 PET and were compared to age-matched controls. PET images were acquired using a PET-Siemens Biograph mCT Flow-Edge 128 scanner (Siemens, Knoxville, TN). All patients were scanned for 15 minutes, 97 ± 10 minutes after intravenous injection of 218 ± 95 MBq of [18F]-AV-1451. PET scans were co-registered to the corresponding high-resolution anatomical MR images (3 T Prisma Siemens, Erlangen) and spatially normalised to stereotactic MNI space using the normalisation parameters acquired during MR segmentation. Results We found pathological in vivo Tau signal in HD mainly in the striatum, but also in the cortex and cerebellum. Patient 3, who was cognitively least impaired, displayed the weakest subcortical and cortical signal, while highest tau tracer uptake was observed in patient 2, presenting longest disease duration and highest total motor score as well as disease burden score. Conclusions We conclude that Tau PET imaging in HD may enable the assessment of propagation of tau deposition, its relation to neurodegeneration and effects of potential disease-modifying interventions.