Association of Early ß-Amyloid Accumulation and Neuroinflammation Measured With [11C]PBR28 in Elderly Individuals Without Dementia.

OBJECTIVE: To examine whether early ß-amyloid (Aß) accumulation and metabolic risk factors are associated with neuroinflammation in elderly individuals without dementia. METHODS: We examined 54 volunteers (mean age 70.0 years, 56% women, 51% APOE ɛ4 carriers) with the translocator protein (TSPO) tracer [11C]PBR28 to assess neuroinflammation and with [11C] Pittsburgh compound B (PiB) to assess cerebral Aß accumulation. [11C]PBR28 and [11C]PiB standardized uptake value ratios (SUVRs) were quantified in 6 regions of interests by using the cerebellar cortex as a pseudo-reference and reference region, respectively. Fasting venous glucose, insulin, and high-sensitivity C-reactive protein (hs-CRP) values were determined. Homeostatic model assessment of insulin resistance (HOMA-IR) was calculated. A subset of individuals (n = 11) underwent CSF sampling, and Aß40, Aß42, total tau, phospho-tau, soluble TREM2, and YKL-40 levels were measured. RESULTS: Among the whole study group, no significant association was found between [11C]PiB and [11C]PBR28 SUVR composite scores (slope 0.02, p = 0.30). However, higher [11C]PiB binding was associated with higher [11C]PBR28 binding among amyloid-negative ([11C]PiB composite score ≤1.5) (TSPO genotype-, age- and sex-adjusted slope 0.26, p = 0.008) but not among amyloid-positive (slope -0.004, p = 0.88) participants. Higher CSF soluble TREM2 (r s = 0.72, p = 0.01) and YKL-40 (r s = 0.63, p = 0.04) concentrations were associated with a higher [11C]PBR28 composite score. Higher body mass index, HOMA-IR, and hs-CRP were associated with higher [11C]PBR28 binding in brain regions where Aß accumulation is first detected in Alzheimer disease. CONCLUSIONS: While there was no association between amyloid and neuroinflammation in the overall study group, neuroinflammation was associated with amyloid among the subgroup at early stages of amyloid pathology.

Long-term test-retest reliability of striatal and extrastriatal dopamine D2/3 receptor binding: study with [(11)C]raclopride and high-resolution PET.

We measured the long-term test-retest reliability of [(11)C]raclopride binding in striatal subregions, the thalamus and the cortex using the bolus-plus-infusion method and a high-resolution positron emission scanner. Seven healthy male volunteers underwent two positron emission tomography (PET) [(11)C]raclopride assessments, with a 5-week retest interval. D2/3 receptor availability was quantified as binding potential using the simplified reference tissue model. Absolute variability (VAR) and intraclass correlation coefficient (ICC) values indicated very good reproducibility for the striatum and were 4.5%/0.82, 3.9%/0.83, and 3.9%/0.82, for the caudate nucleus, putamen, and ventral striatum, respectively. Thalamic reliability was also very good, with VAR of 3.7% and ICC of 0.92. Test-retest data for cortical areas showed good to moderate reproducibility (6.1% to 13.1%). Our results are in line with previous test-retest studies of [(11)C]raclopride binding in the striatum. A novel finding is the relatively low variability of [(11)C]raclopride binding, providing suggestive evidence that extrastriatal D2/3 binding can be studied in vivo with [(11)C]raclopride PET to be verified in future studies.

Rostrocaudal gradients of dopamine D2/3 receptor binding in striatal subregions measured with [(11)C]raclopride and high-resolution positron emission tomography.

The human striatum has structural and functional subdivisions, both dorsoventrally and rostrocaudally. To date, the gradients of dopamine D2/3 receptor binding in the human striatum have not been measured with positron emission tomography (PET). Seven healthy male subjects aged 24.5 ± 3.5 years were scanned with brain-dedicated high-resolution research tomography (HRRT, Siemens Medical Solutions, Knoxville, TN, USA) and [(11)C]raclopride. Coronally defined regions of interest (ROIs) of the caudate nucleus, putamen and ventral striatum (VST) were sampled plane-by-plane, 1.5mm apart, on spatially normalized binding potential (BPND) images. Regional [(11)C]raclopride BPND values were calculated using the simplified reference tissue model (SRTM) from a total of 25 coronal planes. An increasing rostrocaudal gradient of the D2/3 receptor binding was detected in the putamen, which is consistent with the known distribution of D2/3 dopamine receptors. In the caudate nucleus, there was an initial increase in the BPND values in the most anterior planes, suggesting that the highest D2/3 receptor binding occurred in the head; however, there was an overall descending gradient. A declining trend was also observed in the VST. The novelty of this study lies in the presentation, for the first time, of the D2/3 receptor binding gradients in each striatal subregion in the brains of living healthy humans. The high spatial resolution provided by HRRT enables frequent sampling of BPND along the longitudinal extent of striatum; this method is superior to the sectioning used in previous post mortem studies. Regarding the functional organization of the striatum, our findings can inform future investigations of normal neurophysiology as well as efforts to differentiate neuropsychiatric disorders affecting the brain dopamine (DA) system. Furthermore, the average distribution of D2/3 receptor binding revealed in this study could serve as a basis for a database that includes distributions of various DA markers as a function of healthy aging.

Reproducibility of striatal and thalamic dopamine D2 receptor binding using [11C]raclopride with high-resolution positron emission tomography.

Positron emission tomography (PET) imaging of small striatal brain structures such as the ventral striatum (VST) has been hampered by low spatial resolution causing partial-volume effects. The high-resolution research tomograph (HRRT) is a brain-dedicated PET scanner that has considerably better spatial resolution than its predecessors. However, its superior spatial resolution is associated with a lower signal-to-noise ratio. We evaluated the test-retest reliability of the striatal and thalamic dopamine D(2) receptor binding using the HRRT scanner. Seven healthy male volunteers underwent two [(11)C]raclopride PET scans with a 2.5-hour interval. Dopamine D(2) receptor availability was quantified as binding potential (BP(ND)) using the simplified reference tissue model. To evaluate the reproducibility of repeated BP(ND) estimations, absolute variability (VAR) and intraclass correlation coefficients (ICCs) were calculated. VAR values indicated fairly good reproducibility and were 3.6% to 4.5% for the caudate nucleus and putamen and 4.5% to 6.4% for the lateral and medial part of the thalamus. In the VST, the VAR value was 5.8% when the definition was made in the coronal plane. However, the ICC values were only moderate, in the range of 0.34 to 0.66, for all regions except the putamen (0.87). Experimental signal processing methods improved neither ICC nor VAR values significantly.