Anton Forsberg

PET imaging of amyloid deposition in patients with mild cognitive impairment

It is of great clinical value to identify subjects at a high risk of developing AD. We previously found that the amyloid positron emission tomography (PET) tracer PIB showed a robust difference in retention in the brain between AD patients and healthy controls (HC). Twenty-one patients diagnosed with MCI (mean age 63.3+/-7.8 (S.D.) years) underwent PET studies with (11)C-PIB, and (18)F-fluoro-deoxy-glucose (FDG) to measure cerebral glucose metabolism, as well as assessment of cognitive function and CSF sampling. Reference group data from 27 AD patients and 6 healthy controls, respectively, were used for comparison. The mean cortical PIB retention for the MCI patients was intermediate compared to HC and AD. Seven MCI patients that later at clinical follow-up converted to AD (8.1+/-6.0 (S.D.) months) showed significant higher PIB retention compared to non-converting MCI patients and HC, respectively (ps<0.01). The PIB retention in MCI converters was comparable to AD patients (p>0.01). Correlations were observed in the MCI patients between PIB retention and CSF Abeta(1-42), total Tau and episodic memory, respectively.

Dynamic changes in PET amyloid and FDG imaging at different stages of Alzheimer's disease

In this study 5 patients with mild cognitive impairment (MCI) and 9 Alzheimers disease (AD) patients underwent respectively 3- and 5-year follow-up positron emission tomography (PET) studies with N-methyl [(11)C] 2-(4-methylaminophenyl)-6-hydroxy-benzothiazole ((11)C-PIB) and (18)F-fluorodeoxyglucose ((18)F-FDG) to understand the time courses in AD disease processes. Significant increase in PIB retention as well as decrease in regional cerebral metabolic rate of glucose (rCMRglc) was observed at group level in the MCI patients while no significant change was observed in cognitive function. At group level the AD patients showed unchanged high PIB retention at 5-year follow-up compared with baseline. At the individual level, increased, stable, and decreased PIB retention were observed while disease progression was reflected in significant decrease in rCMRglc and cognition. In conclusion, after a long-term follow-up with PET, we observed an increase in fibrillar amyloid load in MCI patients followed by more stable level in clinical AD patients. The rCMRglc starts to decline in MCI patients and became more pronounced in clinical stage which related to continuous decline in cognition.

Effect of phenserine treatment on brain functional activity and amyloid in Alzheimer's disease

The effects of (−)‐phenserine (phenserine) and placebo/donepezil treatment on regional cerebral metabolic rate for glucose (rCMRglc) and brain amyloid load were investigated by positron emission tomography in 20 patients with mild Alzheimers disease in relation to cerebrospinal fluid (CSF) and plasma biomarkers, and cognitive function.

High PIB Retention in Alzheimer's Disease is an Early Event with Complex Relationship with CSF Biomarkers and Functional Parameters

BACKGROUND New in vivo amyloid PET imaging tracers, such as (11)C-PIB, provide possibilities to deeper understand the underlying pathological processes in Alzheimers disease (AD). In this study we investigated how (11)C-PIB retention is related to cerebral glucose metabolism, episodic memory and CSF biomarkers. METHOD Thirty-seven patients with mild AD and 21 patients with mild cognitive impairment (MCI) underwent PET examinations with the amyloid tracer (11)C-PIB, (18)F-FDG for measurement of regional cerebral metabolic rate of glucose (rCMRglc), assessment of episodic memory and assay of cerebral spinal fluid (CSF) levels of amyloid-beta (Abeta(1-42)), total tau and phosphorylated tau respectively. Analyses were performed using Statistical Parametric Mapping (SPM) and regions of interest (ROIs). RESULTS Pooled data from AD and MCI patients showed strong correlations between (11)C-PIB retention, levels of CSF biomarkers (especially Abeta(1-42)), rCMRglc and episodic memory. Analysis of the MCI group alone revealed significant correlations between (11)C-PIB retention and CSF biomarkers and between CSF biomarkers and episodic memory respectively. A strong correlation was observed in the AD group between rCMRglc and episodic memory as well as a significant correlation between (11)C-PIB retention and rCMRglc in some cortical regions. Regional differences were observed as sign for changes in temporal patterns across brain regions. CONCLUSIONS A complex pattern was observed between pathological and functional markers with respect to disease stage (MCI versus AD) and brain regions. Regional differences over time were evident during disease progression. (11)C-PIB PET and CSF Abeta(42) allowed detection of prodromal stages of AD. Amyloid imaging is useful for early diagnosis and evaluation of new therapeutic interventions in AD.

Longitudinal PET evaluation of cerebral glucose metabolism in rivastigmine treated patients with mild Alzheimer's disease.

Summary.In this study 11 patients with mild Alzheimer’s disease (AD) were treated with the cholinesterase inhibitor rivastigmine (mean dose 8.6 ± 1.3’mg) for 12 months and underwent positron emission tomography (PET) studies of cerebral glucose metabolism (CMRglc) and neuropsychological testing at baseline and after 12 months. An untreated group of 10 AD patients served as control group. While the untreated AD patients showed a significant decline of CMRglc in the temporo-parietal and frontal cortical regions after 12 months follow-up the rivastigmine-treated patients showed no decline in CMRglc in corresponding cortical brain regions. Furthermore, a significant dose-related increase in CMRglc was recorded in the right frontal association region after 12 months rivastigmine treatment. A positive correlation was observed between changes in CMRglc and several cognitive tests in patients receiving higher doses (10.5–12’mg) of rivastigmine. These results suggest a stabilization effect of rivastigmine on CMRglc in mild AD patients receiving long-term rivastigmine treatment.

Long-term effects of galantamine treatment on brain functional activities as measured by PET in Alzheimer's disease patients.

The effects of galantamine (16 to 24 mg/day) treatment on brain functional activities (blood flow and glucose metabolism) were examined in 18 patients with mild Alzheimers disease (AD) in relation to brain acetylcholinesterase (AChE) activity and nicotinic receptors and cognitive function. The study consisted of an initial double-blind phase of three months (short-term) followed by an open-label phase until twelve months after the beginning of the study (long-term). The AD patients underwent positron emission tomography (PET) studies with the tracers [15O]-H2O for measurement of regional cerebral blood flow (rCBF) at baseline, 3 weeks, 3 and 12 months treatment, and [18F]-fluoro-deoxyglucose (FDG) for measurement of regional cerebral metabolic rate for glucose (rCMRglc) at baseline and 12 months. A battery of neuropsychological assessments was performed on each patient in order to follow changes in cognition during the treatment period. Throughout the study, different cortical areas showed significant increases in rCBF after galantamine treatment. rCBF positively correlated with AChE activity, nicotinic receptors and cognition. In addition to these positive changes, an increase in rCMRglc in the frontal brain region and stabilization in other cortical areas was observed after 12 months galantamine treatment. This stabilization in rCMRglc was also correlated with a stabilization of cognition. Our results ultimately suggest that treatment with galantamine has a long-term positive effect on brain perfusion and rCMRglc and stabilizes cognition.

Unidirectional Influx and Net Accumulation of PIB.

The compound {N-methyl-[11C]}2-(4’-methylaminophenyl)-6-hydroxybenzothiazole, “PIB”, measured by positron emission tomography, has been demonstrated to image brain β-amyloid deposition in Alzheimer’s disease (AD). In the present study the benefit of measuring the PIB accumulation rate together with the unidirectional influx of PIB into the brain was investigated in healthy control subjects and patients with AD. In a monkey changes in the influx rate constant K1 of PIB closely followed changes in CBF, caused by alteration of PaCO2. In addition, K1 was high both in the monkey and in humans, suggesting that this parameter reflects CBF. Most AD patients studied showed clearly higher accumulation rate for PIB than the controls in cortical brain areas, while a few patients showed as low accumulation as the controls. K1 did not correlate with the accumulation rate, indicating that K1 for PIB provides extra information besides the accumulation rate.

Safety and tolerability of intracerebroventricular PDGF-BB in Parkinson's disease patients.

BACKGROUND. Recombinant human PDGF-BB (rhPDGF-BB) reduces Parkinsonian symptoms and increases dopamine transporter (DAT) binding in several animal models of Parkinsons disease (PD). Effects of rhPDGF-BB are the result of proliferation of ventricular wall progenitor cells and reversed by blocking mitosis. Based on these restorative effects, we assessed the safety and tolerability of intracerebroventricular (i.c.v.) rhPDGF-BB administration in individuals with PD. METHODS. We conducted a double-blind, randomized, placebo-controlled phase I/IIa study at two clinical centers in Sweden. Twelve patients with moderate PD received rhPDGF-BB via an implanted drug infusion pump and an investigational i.c.v. catheter. Patients were assigned to a dose cohort (0.2, 1.5, or 5 μg rhPDGF-BB per day) and then randomized to active treatment or placebo (3:1) for a 12-day treatment period. The primary objective was to assess safety and tolerability of i.c.v.-delivered rhPDGF-BB. Secondary outcome assessments included several clinical rating scales and changes in DAT binding. The follow-up period was 85 days. RESULTS. All patients completed the study. There were no unresolved adverse events. Serious adverse events occurred in three patients; however, these were unrelated to rhPDGF-BB administration. Secondary outcome parameters did not show dose-dependent changes in clinical rating scales, but there was a positive effect on DAT binding in the right putamen. CONCLUSION. At all doses tested, i.c.v. administration of rhPDGF-BB was well tolerated. Results support further clinical development of rhPDGF-BB for patients with PD. TRIAL REGISTRATION. Clinical Trials.gov NCT00866502. FUNDING. Newron Sweden AB (former NeuroNova AB) and Swedish Governmental Agency for Innovation Systems (VINNOVA).

The use of PIB-PET as a dual pathological and functional biomarker in AD

Amyloid imaging with positron emission tomography (PET) is presently used in Alzheimers disease (AD) research. In this study we investigated the possibility to use early frames (ePIB) of the PIB scans as a rough index of CBF by comparing normalised early PIB values with cerebral glucose metabolism (rCMRglc). PIB-PET and FDG-PET were performed in 37 AD patients, 21 subjects with mild cognitive impairment (MCI) and 6 healthy controls (HC). The patients were divided based on their PIB retention (amyloid load) as either PIB positive (PIB+) or PIB negative (PIB-). Data of the unidirectional influx K(1) from a subset of the subjects including 7 AD patients and 3 HC was used for correlative analysis. Data was analysed using regions of interest (ROI) analysis. A strong, positive correlation was observed across brain regions between K(1) and ePIB (r=0.70; p≤0.001). The ePIB values were significantly lower in the posterior cingulate (p≤0.001) and the parietal cortices (p=0.002) in PIB+ subjects compared to PIB-, although the group difference were stronger for rCMRglc in cortical areas (p≤0.001). Strong positive correlations between ePIB and rCMRglc were observed in all cortical regions analysed, especially in the posterior cingulate and parietal cortices (p≤0.001). A single dynamic PIB-PET scan may provide information about pathological and functional changes (amyloidosis and impaired blood flow). This might be important for diagnosis of AD, enrichment of patients in clinical trials and evaluation of treatment effects. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.

The Immune Response of the Human Brain to Abdominal Surgery

Surgery launches a systemic inflammatory reaction that reaches the brain and associates with immune activation and cognitive decline. Although preclinical studies have in part described this systemic‐to‐brain signaling pathway, we lack information on how these changes appear in humans. This study examines the short‐ and long‐term impact of abdominal surgery on the human brain immune system by positron emission tomography (PET) in relation to blood immune reactivity, plasma inflammatory biomarkers, and cognitive function.