PET Agents in Dementia:An Overview

This article presents an overview of imaging agents for PET that have been applied for research and diagnostic purposes in patients affected by dementia. Classified by the target which the agents visualize, seven groups of tracers can be distinguished, namely radiopharmaceuticals for: (1) Misfolded proteins (beta-amyloid, tau, alpha-synuclein), (2) Neuroinflammation (overexpression of translocator protein), (3) Elements of the cholinergic system, (4) Elements of monoamine neurotransmitter systems, (5) Synaptic density, (6) Cerebral energy metabolism (glucose transport/ hexokinase), and (7) Various other proteins. This last category contains proteins involved in mechanisms underlying neuroinflammation or cognitive impairment, which may also be potential therapeutic targets. Many receptors belong to this category: AMPA, cannabinoid, colony stimulating factor 1, metabotropic glutamate receptor 1 and 5 (mGluR1, mGluR5), opioid (kappa, mu), purinergic (P2X7, P2Y12), sigma-1, sigma-2, receptor for advanced glycation endproducts, and triggering receptor expressed on myeloid cells-1, besides several enzymes: cyclooxygenase-1 and 2 (COX-1, COX-2), phosphodiesterase-5 and 10 (PDE5, PDE10), and tropomyosin receptor kinase. Significant advances in neuroimaging have been made in the last 15 years. The use of 2-[F-18]-fluoro-2-deoxy-D-glucose (FDG) for quantification of regional cerebral glucose metabolism is well-established. Three tracers for beta-amyloid plaques have been approved by the Food and Drug Administration and European Medicines Agency. Several tracers for tau neurofibrillary tangles are already applied in clinical research. Since many novel agents are in the preclinical or experimental stage of development, further advances in nuclear medicine imaging can be expected in the near future. PET studies with established tracers and tracers for novel targets may result in early diagnosis and better classification of neurodegenerative disorders and in accurate monitoring of therapy trials which involve these targets. PET data have prognostic value and may be used to assess the response of the human brain to interventions, or to select the appropriate treatment strategy for an individual patient. (C) 2021 The Authors. Published by Elsevier Inc

Association of personality facets and cognition in the Lifelines population-based cohort study

Background: Personality traits have been associated with cognitive functioning and risk of cognitive decline. Fewer studies have investigated how personality facets are associated with cognition in large cohorts with a prospective design. Methods: The association between eight personality facets and cognition (speed measures reflecting psychomotor speed and visual attention; hit rate measures reflecting visual learning and working memory) was analyzed in middle-aged adults from the Lifelines cohort (N = 79911; age 43 ± 11 years). Results: High hostility, high vulnerability, low excitement seeking, and low competence were associated with worse cognitive performance on all tasks. Impulsivity-related facets had weak and differential associations, with self-discipline negatively associated with accuracy and deliberation negatively associated with speed. These associations remained largely unchanged when accounting for lifestyle factors (smoking, alcohol consumption, physical activity). The associations with cognition were stronger in older people for impulsiveness, deliberation, and hostility, while stronger in younger people for excitement seeking, self-discipline, and vulnerability. Conclusion: In a large population-based sample with a broad age range, the associations of personality facets with cognitive functioning had small effect sizes, were independent of lifestyle factors, and varied with age and among facets within the same personality domain. These findings highlight the importance of developmental stages and facet-level research in personality-cognition associations.</p

Effects of Interventions on Cerebral Perfusion in the Alzheimer's Disease Spectrum:A Systematic Review

Cerebral perfusion dysfunctions are seen in the early stages of Alzheimer’s disease (AD). We systematically reviewed the literature to investigate the effect of pharmacological and non-pharmacological interventions on cerebral hemodynamics in randomized controlled trials involving AD patients or Mild Cognitive Impairment (MCI) due to AD. Studies involving other dementia types were excluded. Data was searched in April 2021 on MEDLINE, Embase, and Web of Science. Risk of bias was assessed using Cochrane Risk of Bias Tool. A metasynthesis was performed separating results from MCI and AD studies. 31 studies were included and involved 310 MCI and 792 CE patients. The MCI studies (n = 8) included physical, cognitive, dietary, and pharmacological interventions. The AD studies (n = 23) included pharmacological, physical interventions, and phytotherapy. Cerebral perfusion was assessed with PET, ASL, Doppler, fNIRS, DSC-MRI, Xe-CT, and SPECT. Randomization and allocation concealment methods and subject characteristics such as AD-onset, education, and ethnicity were missing in several papers. Positive effects on hemodynamics were seen in 75 % of the MCI studies, and 52 % of the AD studies. Inserting cerebral perfusion outcome measures, together with established AD biomarkers, is fundamental to target all disease mechanisms and understand the role of cerebral perfusion in AD

Small vessel disease burden and functional brain connectivity in mild cognitive impairment

Background: The role of small vessel disease in the development of dementia is not yet completely understood. Functional brain connectivity has been shown to differ between individuals with and without cerebral small vessel disease. However, a comprehensive measure of small vessel disease quantifying the overall damage on the brain is not consistently used and studies using such measure in mild cognitive impairment individuals are missing.Method: Functional brain connectivity differences were analyzed between mild cognitive impairment individuals with absent or low (n = 34) and high (n = 34) small vessel disease burden using data from the Parelsnoer Institute, a Dutch multicenter study. Small vessel disease was characterized using an ordinal scale considering: lacunes, microbleeds, perivascular spaces in the basal ganglia, and white matter hyperintensities. Resting state functional MRI data using 3 Tesla scanners was analyzed with group-independent component analysis using the CONN toolbox.Results: Functional connectivity between areas of the cerebellum and between the cerebellum and the thalamus and caudate nucleus was higher in the absent or low small vessel disease group compared to the high small vessel disease group.Conclusion: These findings might suggest that functional connectivity of mild cognitive impairment individuals with low or absent small vessel disease burden is more intact than in mild cognitive impairment individuals with high small vessel disease. These brain areas are mainly responsible for motor, attentional and executive functions, domains which in previous studies were found to be mostly associated with small vessel disease markers. Our results support findings on the involvement of the cerebellum in cognitive functioning

Small vessel disease burden and functional brain connectivity in mild cognitive impairment

Background: The role of small vessel disease in the development of dementia is not yet completely understood. Functional brain connectivity has been shown to differ between individuals with and without cerebral small vessel disease. However, a comprehensive measure of small vessel disease quantifying the overall damage on the brain is not consistently used and studies using such measure in mild cognitive impairment individuals are missing.Method: Functional brain connectivity differences were analyzed between mild cognitive impairment individuals with absent or low (n = 34) and high (n = 34) small vessel disease burden using data from the Parelsnoer Institute, a Dutch multicenter study. Small vessel disease was characterized using an ordinal scale considering: lacunes, microbleeds, perivascular spaces in the basal ganglia, and white matter hyperintensities. Resting state functional MRI data using 3 Tesla scanners was analyzed with group-independent component analysis using the CONN toolbox.Results: Functional connectivity between areas of the cerebellum and between the cerebellum and the thalamus and caudate nucleus was higher in the absent or low small vessel disease group compared to the high small vessel disease group.Conclusion: These findings might suggest that functional connectivity of mild cognitive impairment individuals with low or absent small vessel disease burden is more intact than in mild cognitive impairment individuals with high small vessel disease. These brain areas are mainly responsible for motor, attentional and executive functions, domains which in previous studies were found to be mostly associated with small vessel disease markers. Our results support findings on the involvement of the cerebellum in cognitive functioning

Effects of interventions on cerebral perfusion in the Alzheimer's disease spectrum : a systematic review

Cerebral perfusion dysfunctions are seen in the early stages of Alzheimer’s disease (AD). We systematically reviewed the literature to investigate the effect of pharmacological and non-pharmacological interventions on cerebral hemodynamics in randomized controlled trials involving AD patients or Mild Cognitive Impairment (MCI) due to AD. Studies involving other dementia types were excluded. Data was searched in April 2021 on MEDLINE, Embase, and Web of Science. Risk of bias was assessed using Cochrane Risk of Bias Tool. A metasynthesis was performed separating results from MCI and AD studies. 31 studies were included and involved 310 MCI and 792 CE patients. The MCI studies (n = 8) included physical, cognitive, dietary, and pharmacological interventions. The AD studies (n = 23) included pharmacological, physical interventions, and phytotherapy. Cerebral perfusion was assessed with PET, ASL, Doppler, fNIRS, DSC-MRI, Xe-CT, and SPECT. Randomization and allocation concealment methods and subject characteristics such as AD-onset, education, and ethnicity were missing in several papers. Positive effects on hemodynamics were seen in 75 % of the MCI studies, and 52 % of the AD studies. Inserting cerebral perfusion outcome measures, together with established AD biomarkers, is fundamental to target all disease mechanisms and understand the role of cerebral perfusion in AD

Small vessel disease burden and functional brain connectivity in mild cognitive impairment

Abstract: Background: The role of small vessel disease in the development of dementia is not yet completely understood. Functional brain connectivity has been shown to differ between individuals with and without cerebral small vessel disease. However, a comprehensive measure of small vessel disease quantifying the overall damage on the brain is not consistently used and studies using such measure in mild cognitive impairment individuals are missing.Method: Functional brain connectivity differences were analyzed between mild cognitive impairment individuals with absent or low (n = 34) and high (n = 34) small vessel disease burden using data from the Parelsnoer Institute, a Dutch multicenter study. Small vessel disease was characterized using an ordinal scale considering: lacunes, microbleeds, perivascular spaces in the basal ganglia, and white matter hyperintensities. Resting state functional MRI data using 3 Tesla scanners was analyzed with group-independent component analysis using the CONN toolbox.Results: Functional connectivity between areas of the cerebellum and between the cerebellum and the thalamus and caudate nucleus was higher in the absent or low small vessel disease group compared to the high small vessel disease group.Conclusion: These findings might suggest that functional connectivity of mild cognitive impairment individuals with low or absent small vessel disease burden is more intact than in mild cognitive impairment individuals with high small vessel disease. These brain areas are mainly responsible for motor, attentional and executive functions, domains which in previous studies were found to be mostly associated with small vessel disease markers. Our results support findings on the involvement of the cerebellum in cognitive functioning