Capgras delusion in posterior cortical atrophy: A quantitative multimodal imaging single case study

Although Alzheimer's disease presents homogeneous histopathology, it causes several clinical phenotypes depending on brain regions involved. Beside the most abundant memory variant, several atypical variants exist. Among them posterior cortical atrophy (PCA) is associated with severe visuospatial/visuoperceptual deficits in the absence of significant primary ocular disease. Here, we report for the first time a case of Capgras delusion-a delusional misidentification syndrome, where patients think that familiar persons are replaced by identical "doubles" or an impostor-in a patient with PCA. The 57-year-old female patient was diagnosed with PCA and developed Capgras delusion 8 years after first symptoms. The patient did not recognize her husband, misidentified him as a stranger, and perceived him as a threat. Such misidentifications did not happen for other persons. Events could be interrupted by reassuring the husband's identity by the patient's female friend or children. We applied in-depth multimodal neuroimaging phenotyping and used single-subject voxel-based morphometry to identify atrophy changes specifically related to the development of the Capgras delusion. The latter, based on structural T1 magnetic resonance imaging, revealed progressive gray matter volume decline in occipital and temporoparietal areas, involving more the right than the left hemisphere, especially at the beginning. Correspondingly, the right fusiform gyrus was already affected by atrophy at baseline, whereas the left fusiform gyrus became involved in the further disease course. At baseline, glucose hypometabolism as measured by positron emission tomography (PET) with F18-fluorodesoxyglucose (FDG-PET) was evident in the parietooccipital cortex, more pronounced right-sided, and in the right frontotemporal cortex. Amyloid accumulation as assessed by PET with F18-florbetaben was found in the gray matter of the neocortex indicating underlying Alzheimer's disease. Appearance of the Capgras delusion was related to atrophy in the right posterior cingulate gyrus/precuneus, as well as right middle frontal gyrus/frontal eye field, supporting right frontal areas as particularly relevant for Capgras delusion. Atrophy in these regions respectively might affect the default mode and dorsal attention networks as shown by meta-analytical co-activation and resting state functional connectivity analyses. This case elucidates the brain-behavior relationship in PCA and Capgras delusion

Current radiotracers to image neurodegenerative diseases

The term of neurodegenerative diseases covers a heterogeneous group of disorders that are distinguished by progressive degeneration of the structure and function of the nervous system such as dementias, movement disorders, motor neuron disorders, as well as some prion disorders. In recent years, a paradigm shift started for the diagnosis of neurodegenerative diseases, for which successively clinical testing is supplemented by biomarker information. In research scenarios, it was even proposed recently to substitute the current syndromic by a biological definition of Alzheimer’s diseases. PET examinations with various radiotracers play an important role in providing non-invasive biomarkers and co-morbidity information in neurodegeneration. Information on co-morbidity, e.g. Aβ plaques and Lewy-bodies or Aβ plaques in patients with aphasia or the absence of Aβ plaques in clinical AD patients are of interest to expand our knowledge about the pathogenesis of different phenotypically defined neurodegenerative diseases. Moreover, this information is also important in therapeutic trials targeting histopathological abnormalities. The aim of this review is to present an overview of the currently available radiotracers for imaging neurodegenerative diseases in research and in routine clinical settings. In this context, we also provide a short summary of the most frequent neurodegenerative diseases from a nuclear medicine point of view, their clinical and pathophysiological as well as nuclear imaging characteristics, and the resulting need for new radiotracers

Alzheimer’s disease FDG PET imaging pattern in an amyloid-negative mild cognitive impairment subject

The revised NIA-AA diagnostic criteria for Alzheimer’s disease (AD) and mild cognitive impairment (MCI) due to AD make use of amyloid pathology and neurodegeneration biomarkers which increase the diagnostic confidence in the majority of patients. However, in daily praxis, cases with conflicting biomarker constellations occur. A MCI subject underwent neuropsychological testing supplemented by FDG and amyloid PET/MRI as well as CSF sampling. In this subject, the biomarkers of Aβ deposition were negative. [18F]FDG PET, however, showed an AD-typical hypometabolism. Further studies are required to determine frequency and relevance of cases with neurodegeneration-first biomarker constellations to improve our understanding on pathogenesis and diagnosis of AD

Impact of attenuation correction on clinical [18F]FDG brain PET in combined PET/MRI

Background: In PET/MRI, linear photon attenuation coefficients for attenuation correction (AC) cannot be directly derived, and cortical bone is, so far, usually not considered. This results in an underestimation of the average PET signal in PET/MRI. Recently introduced MR-AC methods predicting bone information from anatomic MRI or proton density weighted zero-time imaging may solve this problem in the future. However, there is an ongoing debate if the current error is acceptable for clinical use and/or research. Methods: We examined this feature for [18F] fluorodeoxyglucose (FDG) brain PET in 13 patients with clinical signs of dementia or movement disorders who subsequently underwent PET/CT and PET/MRI on the same day. Multiple MR-AC approaches including a CT-derived AC were applied. Results: The resulting PET data was compared to the CT-derived standard regarding the quantification error and its clinical impact. On a quantitative level, −11.9 to +2 % deviations from the CT-AC standard were found. These deviations, however, did not translate into a systematic diagnostic error. This, as overall patterns of hypometabolism (which are decisive for clinical diagnostics), remained largely unchanged. Conclusions: Despite a quantitative error by the omission of bone in MR-AC, clinical quality of brain [18F]FDG is not relevantly affected. Thus, brain [18F]FDG PET can already, even now with suboptimal MR-AC, be utilized for clinical routine purposes, even though the MR-AC warrants improvement

Quantitative susceptibility mapping in β-Amyloid PET-stratified patients with dementia and healthy controls: A hybrid PET/MRI study

Purpose Post-mortem and in-vivo MRI data suggest an accumulation of iron in the brain of Alzheimer’s disease (AD) patients. The majority of studies in clinically diagnosed AD patients found an increase of iron-sensitive MRI signals in the putamen. As the clinical diagnosis shows only a moderate sensitivity, Aβ-PET was used to further stratify patients with the clinical diagnosis of AD. Aim of this exploratory study was to examine whether Aβ-positive (AD) and Aβ-negative (non-AD) patients differ in their regional magnetic susceptibility compared to healthy controls (HCs) and whether regional susceptibility values correlate with mini mental state examination (MMSE) scores or global Aβ-load. Methods We retrospectively analyzed [11C]PiB PET/MRI data of 11 HCs, 16 AD and 10 non-AD patients. We used quantitative susceptibility mapping (QSM) as iron-sensitive MRI signal measured at the 3 T PET/MR scanner. Global cerebral Aβ-load was determined by composite [11C]PiB SUV ratios. Results Compared to HCs, AD patients showed higher QSM values in putamen (0.049 ± 0.033 vs. 0.002 ± 0.031; p = 0.006), while non-AD patients showed lower QSM values in caudate nucleus (0.003 ± 0.027 vs. 0.051 ± 0.039; p = 0.006). There was a trend towards a significant correlation between putaminal QSM and MMSE values (ρ=-0.340, p = 0.053). In AD patients, global Aβ-load and putaminal QSM values were significantly correlated (ρ=-0.574, p = 0.020). Conclusions These data indicate that AD and non-AD patients may show different cerebral iron pathologies which might be detectable by QSM MRI, and might be linked to neurodegeneration. Overall, the data encourage further investigations in well-defined patient cohorts to clarify the value of QSM/magnetic susceptibility in the course of neurodegenerative diseases and its potential as diagnostic biomarker

Early [¹⁸F]florbetaben and [¹¹C]PiB PET images are a surrogate biomarker of neuronal injury in Alzheimer’s disease

Purpose [18F]FDG is a commonly used neuronal injury biomarker for early and differential diagnosis of dementia. Typically, the blood supply to the brain is closely coupled to glucose consumption. Early uptake of the Aβ tracer [11C]PiB on PET images is mainly determined by cerebral blood flow and shows a high correlation with [18F]FDG uptake. Uptake data for 18F-labelled Aβ PET tracers are, however, scarce. We investigated the value of early PET images using the novel Aβ tracer [18F]FBB in the diagnosis of Alzhimers disease (AD). Methods This retrospective analysis included 22 patients with MCI or dementia who underwent dual time-point PET imaging with either [11C]PiB (11 patients) or [18F]FBB (11 patients) in routine clinical practice. Images were acquired 1 – 9 min after administration of both tracers and 40 – 70 min and 90 – 110 min after administration of [11C]PiB and [18F]FBB, respectively. The patients also underwent [18F]FDG brain PET imaging. PET data were analysed visually and semiquantitatively. Associations between early Aβ tracer uptake and dementia as well as brain atrophy were investigated. Results Regional visual scores of early Aβ tracer and [18F]FDG PET images were significantly correlated (Spearman’s ρ = 0.780, P < 0.001). Global brain visual analysis revealed identical results between early Aβ tracer and [18F]FDG PET images. In a VOI-based analysis, the early Aβ tracer data correlated significantly with the [18F]FDG data (r = 0.779, P < 0.001), but there were no differences between [18F]FBB and [11C]PiB. Cortical SUVRs in regions typically affected in AD on early Aβ tracer and [18F]FDG PET images were correlated with MMSE scores (ρ = 0.458, P = 0.032, and ρ = 0.456, P = 0.033, respectively). A voxel-wise group-based search for areas with relatively higher tracer uptake on early Aβ tracer PET images compared with [18F]FDG PET images revealed a small cluster in the midbrain/pons; no significant clusters were found for the opposite comparison. Conclusion Early [18F]FBB and [11C]PiB PET brain images are similar to [18F]FDG PET images in AD patients, and these tracers could potentially be used as biomarkers in place of [18F]FDG. Thus, Aβ tracer PET imaging has the potential to provide biomarker information on AD pathology and neuronal injury. The potential of this approach for supporting the diagnosis of AD needs to be confirmed in prospective studies in larger cohorts

Dissociation of amyloid biomarkers in PET and CSF in Alzheimer’s disease: A case report

Background Recently, biomarkers have been suggested to be incorporated into diagnostic criteria for Alzheimer’s disease (AD). Regarding disease-specific brain amyloid-beta deposition these comprise low amyloid-beta 1–42 in cerebrospinal fluid (CSF) and positive positron emission tomography (PET) amyloid imaging, while neuronal degeneration is evidenced by high total and phosphorylated tau levels in CSF (t-/p-tau), regional hypometabolism ([18F]fluorodeoxyglucose PET, FDG-PET) and characteristic atrophy-patterns (magnetic resonance imaging, MRI). Case presentation Here we present a case of clinically and biomarker supported AD (CSF t-/p-tau, MRI, FDG-PET) in a 59-year-old Caucasian man in whom indicators of amyloid-beta deposition dissociated between CSF parameters and the respective PET imaging. Conclusions Such cases highlight the necessity to better understand potential dissociations between PET and CSF data for amyloid-beta biomarkers, because they are currently considered interchangeably valid with regard to in-vivo evidence for AD pathology. This is more important since amyloid deposition markers can be considered a very first prognostic indicator of imminent AD, prior to neurodegenerative biomarkers and cognitive symptoms. The case illustrates the need for further longitudinal data on potential dissociations of AD biomarkers to devise recommendations for their better prognostic and diagnostic interpretation in the future