Structural and metabolic correlates of neuropsychological profiles in multiple system atrophy and Parkinson's disease.

BACKGROUND: Despite increased recognition of cognitive impairment in Multiple System Atrophy (MSA), its neuroanatomical correlates are not well defined. We aimed to explore cognitive profiles in MSA with predominant parkinsonism (MSA-P) and Parkinson's disease (PD) and their relationship to frontostriatal structural and metabolic changes. METHODS: Detailed clinical and neuropsychological evaluation was performed together with diffusion tensor imaging (DTI) and [18F]-fluoro-deoxyglucose positron emission tomography ([18F]-FDG-PET) in patients with MSA-P (n = 11) and PD (n = 11). We compared clinical and neuropsychological data to healthy controls (n = 9) and correlated neuropsychological data with imaging findings in MSA-P and PD. RESULTS: Patients with MSA-P showed deficits in executive function (Trail Making Test B-A) and scored higher in measures of depression and anxiety compared to those with PD and healthy controls. Widespread frontostriatal white matter tract reduction in fractional anisotropy was seen in MSA-P and PD compared to an imaging control group. Stroop Test interference performance correlated with [18F]-FDG uptake in the bilateral dorsolateral prefrontal cortex (DLPFC) and with white matter integrity between the striatum and left inferior frontal gyrus (IFG) in PD. Trail Making Test performance correlated with corticostriatal white matter integrity along tracts from the bilateral IFG in MSA-P and from the right DLPFC in both groups. CONCLUSION: Executive dysfunction was more prominent in patients with MSA-P compared to PD. DLPFC metabolism and frontostriatal white matter integrity seem to be a driver of executive function in PD, whereas alterations in corticostriatal white matter integrity may contribute more to executive dysfunction in MSA-P.

Evaluation of in vivo staging of amyloid deposition in cognitively unimpaired elderly aged 78-94.

Amyloid-beta (Aß) deposition is common in cognitively unimpaired (CU) elderly >85 years. This study investigated amyloid distribution and evaluated three published in vivo amyloid-PET staging schemes from a cognitively unimpaired (CU) cohort aged 84.9 ± 4.3 years (n = 75). SUV-based principal component analysis (PCA) was applied to 18F-flutemetamol PET data to determine an unbiased regional covariance pattern of tracer uptake across grey matter regions. PET staging schemes were applied to the data and compared to the PCA output. Concentration of p-tau181 was measured in blood plasma. The PCA revealed three distinct components accounting for 91.2% of total SUV variance. PC1 driven by the large common variance of uptake in neocortical and striatal regions was significantly positively correlated with global SUVRs, APOE4 status and p-tau181 concentration. PC2 represented mainly non-specific uptake in typical amyloid-PET reference regions, and PC3 the occipital lobe. Application of the staging schemes demonstrated that the majority of the CU cohort (up to 93%) were classified as having pathological amount and distribution of Aß. Good correspondence existed between binary (+/-) classification and later amyloid stages, however, substantial differences existed between schemes for low stages with 8-17% of individuals being unstageable, i.e., not following the sequential progression of Aß deposition. In spite of the difference in staging outcomes there was broad spatial overlap between earlier stages and PC1, most prominently in default mode network regions. This study critically evaluated the utility of in vivo amyloid staging from a single PET scan in CU elderly and found that early amyloid stages could not be consistently classified. The majority of the cohort had pathological Aß, thus, it remains an open topic what constitutes abnormal brain Aß in the oldest-old and what is the best method to determine that.

[18F]fluorothymidine and [18F]fluorodeoxyglucose PET Imaging Demonstrates Uptake and Differentiates Growth in Neurofibromatosis 2 Related Vestibular Schwannoma.

OBJECTIVE: To investigate whether [F]fluorothymidine (FLT) and/or [F]fluorodeoxyglucose (FDG) positron emission tomography (PET) can differentiate growth in neurofibromatosis 2 (NF2) related vestibular schwannomas (VS) and to evaluate the importance of PET scanner spatial resolution on measured tumor uptake. METHODS: Six NF2 patients with 11 VS (4 rapidly growing, 7 indolent), were scanned with FLT and FDG using a high-resolution research tomograph (HRRT, Siemens) and a Siemens Biograph TrueV PET-CT, with and without resolution modeling image reconstruction. Mean, maximum, and peak standardised uptake values (SUV) for each tumor were derived and the intertumor correlation between FDG and FLT uptake was compared. The ability of FDG and FLT SUV values to discriminate between rapidly growing and slow growing (indolent) tumors was assessed using receiver operator characteristic (ROC) analysis. RESULTS: Tumor uptake was seen with both tracers, using both scanners, with and without resolution modeling. FDG and FLT uptake was correlated (R = 0.67-0.86, p < 0.01) and rapidly growing tumors displayed significantly higher uptake (SUVmean and SUVpeak) of both tracers (p < 0.05, one tailed t test). All of the PET analyses performed demonstrated better discriminatory power (AUCROC range = 0.71-0.86) than tumor size alone (AUCROC = 0.61). The use of standard resolution scanner with standard reconstruction did not result in a notable deterioration of discrimination accuracy. CONCLUSION: NF2 related VS demonstrate uptake of both FLT and FDG, which is significantly increased in rapidly growing tumors. A short static FDG PET scan with standard clinical resolution and reconstruction can provide relevant information on tumor growth to aid clinical decision making.

Experimental validation of estimated spatially variant radioisotope-specific point spread functions using published positron range simulations and fluorine-18 measurements.

In this work we compare spatially variant radioisotope-specific point spread functions (PSFs) derived from published positron range data with measured data using a high resolution research tomograph (HRRT). Spatially variant PSFs were measured on a HRRT for fluorine-18, carbon-11 and gallium-68 using an array of printed point sources. For gallium-68, this required modification of the original design to handle its longer positron range. Using the fluorine-18 measurements and previously published data from Monte-Carlo simulations of positron range, estimated PSFs for carbon-11 and gallium-68 were calculated and compared with experimental data. A double 3D Gaussian function was fitted to the estimated and measured data and used to model the spatially varying PSFs over the scanner field of view (FOV). Differences between the measured and estimated PSFs were quantified using the full-width-at-half-maximum (FWHM) and full-width-at-tenth-maximum (FWTM) in the tangential, radial and axial directions. While estimated PSFs were generally in agreement with the measured PSFs over the entire FOV better agreement was observed (FWHM and FWTM differences of less than 10%) when using one of the two sets of positron range simulations, especially for gallium-68 and for the FWTM. Spatially variant radioisotope specific PSFs can be accurately estimated from fluorine-18 measurements and published positron range data. We have experimentally validated this approach for carbon-11 and gallium-68, and such an approach may be applicable to other radioisotopes such as oxygen-15 for which measurements are not practical.

Elevated Translocator Protein in Anterior Cingulate in Major Depression and a Role for Inflammation in Suicidal Thinking: A Positron Emission Tomography Study.

BACKGROUND: Major depressive disorder is associated with raised peripheral inflammatory markers. Mounting evidence also suggests that inflammation is involved in suicidal behavior. However, the involvement of inflammation in the brains of individuals with depression, and its association with suicidal ideation, needs further clarification. Translocator protein (TSPO), which is upregulated in activated glia (predominantly microglia), can be measured as an indication of neuroinflammation in vivo using positron emission tomography and TSPO-specific radioligands. METHODS: We used [11C](R)-PK11195 positron emission tomography to compare TSPO availability in the anterior cingulate cortex (ACC), prefrontal cortex, and insula between 14 medication-free patients in a major depressive episode of at least moderate severity and 13 matched healthy control subjects. In a post hoc analysis, we also compared TSPO availability between patients with and without suicidal thoughts. RESULTS: Multivariate analysis of variance indicated significantly higher TSPO in patients compared with control subjects (p = .005). The elevation was of large effect size and significant in the ACC (p = .022, Cohen's d = 0.95), with smaller nonsignificant elevations in the prefrontal cortex (p = .342, Cohen's d = 0.38) and insula (p = .466, Cohen's d = 0.29). TSPO was not elevated in patients without suicidal thinking but was significantly increased in those with suicidal thoughts compared with those without, most robustly in the ACC (p = .008) and insula (p = .023). CONCLUSIONS: We confirm evidence for increased TSPO availability, suggestive of predominantly microglial activation, in the ACC during a moderate to severe major depressive episode. Our findings provide further incentive for evaluating anti-inflammatory therapies in major depressive disorder.

18F-florbetapir PET in patients with frontotemporal dementia and Alzheimer disease.

UNLABELLED: Pathologic deposition of amyloid ß (Aß) protein is a key component in the pathogenesis of Alzheimer disease (AD) but not a feature of frontotemporal dementia (FTD). PET ligands for Aß protein are increasingly used in diagnosis and research of dementia syndromes. Here, we report a PET study using (18)F-florbetapir in healthy controls and patients with AD and FTD. METHODS: Ten healthy controls (mean age ± SD, 62.5 ± 5.2 y), 10 AD patients (mean age ± SD, 62.6 ± 4.5), and 8 FTD patients (mean age ± SD, 62.5 ± 9.6) were recruited to the study. All patients underwent detailed clinical and neuropsychologic assessment and T1-weighted MR imaging and were genotyped for apolipoprotein E status. All participants underwent dynamic (18)F-florbetapir PET on a high-resolution research tomograph, and FTD patients also underwent (18)F-FDG PET scans. Standardized uptake value ratios (SUVRs) were extracted for predefined gray and white matter regions of interest using cerebellar gray matter as a reference region. Static PET images were evaluated by trained raters masked to clinical status and regional analysis. RESULTS: Total cortical gray matter (18)F-florbetapir uptake values were significantly higher in AD patients (median SUVR, 1.73) than FTD patients (SUVR, 1.13, P = 0.002) and controls (SUVR, 1.26, P = 0.04). (18)F-Florbetapir uptake was also higher in AD patients than FTD patients and controls in the frontal, parietal, occipital, and cingulate cortices and in the central subcortical regions. Only 1 FTD patient (homozygous for apolipoprotein E ε4) displayed high cortical (18)F-florbetapir retention, whereas (18)F-FDG PET demonstrated mesiofrontal hypometabolism consistent with the clinical diagnosis of FTD. Most visual raters classified 1 control (10%) and 8 AD (80%) and 2 FTD (25%) patients as amyloid-positive, whereas ratings were tied in another 2 FTD patients and 1 healthy control. CONCLUSION: Cortical (18)F-florbetapir uptake is low in most FTD patients, providing good discrimination from AD. However, visual rating of FTD scans was challenging, with a higher rate of discordance between interpreters than in AD and control subjects.