Clinical Correlates of Cerebral Amyloid Deposition in Parkinson's Disease Dementia: Evidence from a PET Study

Background: Dementia in Parkinson's disease (PDD) is common presumably due to combined neuropathological substrates. Amyloid-β (Aβ) plaques are well described in PDD but their contribution in synucleinopathies is still controversial. Objective: To investigate regional [18F]Florbetapir binding and its relative contribution to cognitive dysfunction in a cohort of PDD patients and to test whether PDD patients with comorbid amyloidopathy have different clinical and neuropsychological characteristics. Methods: 21 PDD patients, 20 with Alzheimer's disease (AD), and 9 control subjects underwent amyloid positron emission tomography (PET) imaging, neurological, and neuropsychological assessment. Radioligand binding was compared across the groups. PDD scans were interpreted qualitatively and semiquantitatively and categorized as positive or negative. Annual longitudinal Mini-Mental State Examination (MMSE) of PDD subjects was retrospectively collected in order to relate Aβ burden to the course of cognitive impairment. Results: [18F]Florbetapir PET imaging was positive in 11 PDD patients (52.38%) using the semi-quantitative method. There were no group differences between PDD subjects with increased cortical [18F]Florbetapir (+) and those without (-), according to demographic and clinical parameters. PDD+ performed worse on Digit Span Foward and on Rey Auditory Verbal Learning Test delayed recall than the PDD- with a significant negative correlation between global cortical retention and specific memory tests. Aβ load did not correlate with MMSE ratings although PDD+ demonstrated a faster clinical progression of dementia. Conclusions: Significant Aβ deposition is common in PDD patients contributing to memory impairment and driving a faster rate of cognitive decline

The precuneus-a witness for excessive aβ gathering in alzheimer's disease pathology

Evidence of cortical beta-amyloid (Aβ) load, assessed by Aβ positron emission tomography (Aβ-PET), is an established in vivo biomarker of Alzheimer's disease (AD)-related pathophysiology. Qualitative assessment of Aβ-PET provides binary information; meanwhile semiquantitative approaches require a parcellation of PET image either manually or by placement of atlas-based volumes of interest. We supposed that a whole-brain approach with voxel-by-voxel standardized uptake value ratio (SUVr) parametric images may better elucidate the spatial trajectories of Aβ burden along the continuum of AD. Methods: We recruited 32 subjects with a diagnosis of probable AD dementia (ADD, n = 20) and mild cognitive impairment due to AD (MCI-AD, n = 12) according to the NIA-AA 2011 criteria. We also enrolled a control group of 6 cognitively healthy individuals (HCs) with preserved cognitive functions and negative Aβ-PET scan. The PET images were spatially normalized using the AV45 PET template in the MNI brain space. Subsequently, parametric SUVr images were calculated using the whole cerebellum as a reference region. A voxel-wise analysis of covariance was used to compare (between groups) the Îβ distribution pattern considering age as a nuisance covariate. Results: Both ADD and MCI-AD subjects showed a widespread increase in radiotracer uptake when compared with HC participants (p < 0.001, uncorrected). After applying a multiple comparison correction (p < 0.05, corrected), a relative large cluster of increased [ 18 F]-flor-betapir uptake was observed in the precuneus in the ADD and MCI-AD groups compared to HCs. Voxel-wise regression analysis showed a significant positive linear association between the voxel-wise SUVr values and the disease duration. Conclusions: The voxel-wise semiquantitative analysis shows that the precuneus is a region with higher vulnerability to Aβ depositions when compared to other cortical regions in both MCI-AD and ADD subjects. We think that the precuneus is a promising PET-based outcome measure for clinical trials of drugs targeting brain Aβ. We found a positive association between the overall Aβ-PET SUVr and the disease duration suggesting that the region-specific slow saturation of Aβ deposition continuously takes place as the disease progresses

Brain effect of bariatric surgery in people with obesity

Background/Objectives The link between obesity and brain function is a fascinating but still an enigmatic topic. We evaluated the effect of Roux-en-Y gastric bypass (RYGB) on peripheral glucose metabolism, insulin sensitivity, brain glucose utilization and cognitive abilities in people with obesity. Subjects/Methods Thirteen subjects with obesity (F/M 11/2; age 44.4 +/- 9.8 years; BMI 46.1 +/- 4.9 kg/m(2)) underwent 75-g OGTT during a [18F]FDG dynamic brain PET/CT study at baseline and 6 months after RYGB. At the same timepoints, cognitive performance was tested with Mini Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Trail making test (TMT) and Token test (TT). Glucose, insulin, C-peptide, GLP-1, GIP, and VIP levels were measured during OGTT. Leptin and BDNF levels were measured before glucose ingestion. Results RYGB resulted in significant weight loss (from 46.1 +/- 4.9 to 35.3 +/- 5.0 kg/m(2); p < 0.01 vs baseline). Insulin sensitivity improved (disposition index: from 1.1 +/- 0.2 to 2.9 +/- 1.1; p = 0.02) and cerebral glucose metabolic rate (CMRg) declined in various brain areas (all p <= 0.01). MMSE and MoCA score significantly improved (p = 0.001 and p = 0.002, respectively). TMT and TT scores showed a slight improvement. A positive correlation was found between CMRg change and HOMA-IR change in the caudate nucleus (rho = 0.65, p = 0.01). Fasting leptin decreased (from 80.4 +/- 13.0 to 16.1 +/- 2.4 ng/dl; p = 0.001) and correlated with CMRg change in the hippocampus (rho = 0.50; p = 0.008). CMRg change was correlated with cognitive scores changes on the TMT and TT (all p = 0.04 or less). Conclusions Bariatric surgery improves CMRg directly related to a better cognitive testing result. This study highlights the potential pleiotropic effects of bariatric surgery. Trial registry number NCT03414333

Plasticity of the human visual brain after an early cortical lesion

In adults, partial damage to V1 or optic radiations abolishes perception in the corresponding part of the visual field, causing a scotoma. However, it is widely accepted that the developing cortex has superior capacities to reorganize following an early lesion to endorse adaptive plasticity. Here we report a single patient case (G.S.) with near normal central field vision despite a massive unilateral lesion to the optic radiations acquired early in life. The patient underwent surgical removal of a right hemisphere parieto-temporal-occipital atypical choroid plexus papilloma of the right lateral ventricle at four months of age, which presumably altered the visual pathways during in utero development. Both the tumor and surgery severely compromised the optic radiations. Residual vision of G.S. was tested psychophysically when the patient was 7 years old. We found a close-to-normal visual acuity and contrast sensitivity within the central 25° and a great impairment in form and contrast vision in the far periphery (40-50°) of the left visual hemifield. BOLD response to full field luminance flicker was recorded from the primary visual cortex (V1) and in a region in the residual temporal-occipital region, presumably corresponding to the middle temporal complex (MT+), of the lesioned (right) hemisphere. A population receptive field analysis of the BOLD responses to contrast modulated stimuli revealed a retinotopic organization just for the MT+ region but not for the calcarine regions. Interestingly, consistent islands of ipsilateral activity were found in MT+ and in the parieto-occipital sulcus (POS) of the intact hemisphere. Probabilistic tractography revealed that optic radiations between LGN and V1 were very sparse in the lesioned hemisphere consistently with the post-surgery cerebral resection, while normal in the intact hemisphere. On the other hand, strong structural connections between MT+ and LGN were found in the lesioned hemisphere, while the equivalent tract in the spared hemisphere showed minimal structural connectivity. These results suggest that during development of the pathological brain, abnormal thalamic projections can lead to functional cortical changes, which may mediate functional recovery of vision

Effects of bariatric surgery on brain glucose metabolism and cognitive function: insight from dynamic FDG PET/CT study

Aim/Introduction: We aimed to evaluate the impact of bariatric surgery (RYGB) on the brain glucose metabolism and the interplay between gut hormones/metabolomics, cerebral metabolic rate of glucose (CMRGlu) and cognitive function. Materials and Methods: Thirteen morbidly obese subjects with normal glucose tolerance (BMI 46±4.9 kg/m2; HbA1c 40.1±5.9 mmol/mol; age 42.4±9.8 years) planned for RYGB surgery were recruited. Theoral glucose tolerance test (OGTT) was performed, followed by 60 minutes FDG dynamic PET study.Continuous blood samples were drawn before and at 30, 60, 90, and 120 min for glucose, insulin, GLP, VIP, GIP and C-peptide measurements. The same venous blood samples were used for calculating radioactivity concentration in plasma. Fasting blood samples for metabolomics (leptin, brain derived neurotrophic factor, BDNF) were also collected and the homeostasis model assessment of insulin resistance (HOMA-IR) was calculated as an index of insulin resistance. The influx constant (Ki) and MRGlu were then quantified using the two tissue compartment Patlak approach with an imaged-derived input function (PMOD). Subsequently, the parametric CMRGlu images were created and spatially normalized in MNI space. The paired t-test and Spearman rank correlation were applied to assess changes and associations of voxel-wise CMRGlu and metabolomics. All patients underwent a battery of neuropsychiatric tests (MMSE, MoCA, Token test, TMT, etc) to assess cognitive function in several domains, before and 6 months after RYGB. Results: Six months after RYGB a significant BMI reduction (p<0.001) was achieved. Post-OGTT GLP1 was increased (p<0.01) as well as GIP (p<0.01). The HOMA- IR dropped significantly 6m after RYGB (p=0.02). Either whole brain and region-selective CMRGlu decreased 6m after surgery (15.9±4.6 to 10.5±5.1 μmol/min/100ml; p<0.01). Voxel-wise paired analysis displayed clusters of decreased CMRGlu 6m after RYGB in the widespread brain regions. In addition, we found a significant positive relationship between CMRGlu and HOMA-IR. All patients at baseline presented MMSE and MoCA scores in the normal range. However, 6 months after RYGB, the cognitive domains examined showed a trend of global improvement. MMSE score increased statistically significantly (p 0.002) as well as MoCA score (p <0.005). Conclusion: After bariatric surgery, there are several modifications of multiple factors that play a role in the so-called “intestinal-brain cross-talk”, in CMRGluand in cognitive function. CMRGluof morbidly obese subjects is abnormally enhanced in response to insulin. Bariatric surgery seems to reverse this insulin-mediated signal dysfunction and could produce significant CNS effects decreasing brain glucose over-consumption and promoting potential neuroprotective effect

What to trust, psa or [68ga]ga-psma-11: Learn from experience

Brain metastases from prostate cancer typically occur in the more advanced stages of the disease. Clinically, the early diagnosis of visceral disease is crucial, impacting on patient’s management and prognosis. Although magnetic resonance imaging (MRI) is the modality of choice for the detection of brain metastases, it is not routinely performed in the surveillance of prostate cancer patients unless neurological manifestations appear. Prostate-specific membrane antigen (PSMA) is a glycoprotein, a membrane-bound metallopeptidase, overexpressed in more than 90% of prostate cancer cells. This molecular target is a suitable tissue biomarker for prostate cancer functional imaging. We present a case of a 73-year gentleman diagnosed with prostate adenocarcinoma and surgically treated (pT3bN1Mx, Gleason Score of 9) in February 2016. Subsequently, he underwent androgen deprivation therapy because of the occurrence of a bone metastasis. Between 2016 and January 2019 PSA levels were maintained under control. Starting from September 2019, it progressively raised up to 0.85 ng/mL with a doubling time of 3.3 months. Therefore, he performed a [68Ga]Ga-PSMA-11 PET/CT which showed a focal radiopharmaceutical uptake in the right temporal lobe corresponding to the presence of a rounded cystic lesion on brain MRI. The subsequent excisional biopsy diagnosed a prostate adenocarcinoma metastasis. PSMA expression has been reported in brain parenchyma after ischemic strokes and in some brain tumors including gliomas, meningiomas, and neurofibromas. In our case, the lack of symptoms and the relatively low PSA level raised questions about the nature of the lesion, posing the differential diagnosis between brain metastases and primary brain tumor. Finally, our case shows the capability of [68Ga]Ga-PSMA-11 PET/CT to detect metachronous distant brain metastases in a low biochemical recurrent asymptomatic prostate cancer patient, indicating that proper acquisition – from the vertex to thigh – should be always considered, regardless of the PSA level