- Email: [email protected]
In vivo detection of cholinergic basal forebrain atrophy using cytoarchitectonic mappings and multimodal imaging approaches
P514
Featured Research Sessions: F3-02: The Cholinergic System in Alzheimer’s Disease Pathogenesis
any one of six ROIs or by exceeding the SUVR threshold in the global cortical region. Results: Twenty-one subjects were found to be PiB+, with age highly related to PiB+ status (p < 0.0001). For individuals age of 40 and older (N¼25), 72% were PiB+. Significant age-dependent increases in amyloid deposition were seen in all regions, with greatest increases seen in the anterior ventral striatum (R 2 ¼0.64). PiB+ subjects evidenced significantly lower mean scores on several neuropsychological measures, including executive/working memory, delayed recall, and attention/processing speed. These differences are hypothesized to become more pronounced at follow-up time points. Conclusions: This study offers an important opportunity to study the preclinical manifestations of AD. Follow-up assessments at 30-month intervals may not only provide information that could affect early detection, prevention, and treatment of AD for individuals with DS, but also may offer information that will prove extremely useful for the general population.
in MCI and only declines in clinical AD, when PiB binding and soluble beta-amyloid 42 levels are substantially elevated compared to MCI. Moreover, amyloid deposition failed to induce cholinergic cortical neuronal degeneration in APP and triple transgenic mouse models of AD. Increased cortical levels of proNGF and a decrease in TrkA suggest a shift away from cell survival to apoptotic proNGF signaling. Interestingly, this switch to cell death mechanisms did not occur in the hippocampus during prodromal AD. Conclusions: Together these data suggest that CBF system dysregulation is not uniform, the system is neuroplastic, pretangle pathology plays a key role in cognitive impairment, amyloid deposition may not be toxic early on and there is a shift from cell survival to cell death trophic factor signaling in MCI. F3-02-02
Table 1 Subject Demographics (N¼ 56) N(%) Gender Male Female Race White Black Asian American Indian/Alaskan Native Native Hawaiian/Pacific Islander Other Ethnicity Hispanic Age at Screening (yrs) PPVT age equivalent (months) PPVT standard score
28 (50%) 28 (50%) 54 (96.4%) 0 ( 0%) 0 (0%) 1 (1.8%) 0 (0%) 1 (1.8%) 0 (0%) Mean (sd)
Range
38.9 (6.5) 92.3 (34.1) 54.9 (16.6)
30.0-50.0 30-179 20-89
FEATURED RESEARCH SESSIONS: F3-02 THE CHOLINERGIC SYSTEM IN ALZHEIMER’S DISEASE PATHOGENESIS F3-02-01
CHOLINERGIC DYSREGULATION IN PRODROMAL ALZHEIMER’S DISEASE
Elliott Mufson, Rush University, Chicago, Illinois, United States. Contact e-mail: [email protected] Background: The cholinergic hypothesis of geriatric memory dysfunction led to the development of FDA-approved anticholinesterase drugs to maintain this system in AD patients. The importance of defining the status of the cholinergic basal forebrain cortical projection system in subjects with prodromal AD who are at risk for developing AD continues to be of great clinical and translational interest. Methods: The findings presented are derived from molecular and cellular neuropathologic investigations of people who died with a premortem clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI) and Alzheimer’s disease (AD) as well as from AD transgenic animal studies. Results: Clinical pathologic investigations revealed that CBF neurons maintain their cholinergic neuronal phenotype despite exhibiting pretangles, which correlate with cognitive impairment and an altered ratio of 3 repeat to 4 repeat tau in the MCI brain. Interestingly, the cortical cholinergic system displays an upregulation of choline acetyltransferease (ChAT) activity in the frontal cortex and hippocampus suggesting early reparative mechanisms during prodromal AD. Moreover, despite the early accumulation of amyloid burden in the precuneus component of the default memory network, cholinergic enzyme activity remains stable
IN VIVO DETECTION OF CHOLINERGIC BASAL FOREBRAIN ATROPHY USING CYTOARCHITECTONIC MAPPINGS AND MULTIMODAL IMAGING APPROACHES
Michel Grothe, German Center for Neurodegenerative Diseases, Rostock, Germany. Contact e-mail: [email protected] Background: Post-mortem histopathological examinations of human brain specimens have provided substantial evidence for basal forebrain cholinergic system (BFCS) changes in Alzheimer’s disease (AD) dementia. In-vivo imaging markers of BFCS changes would greatly facilitate the investigation of the cholinergic deficit in predementia stages of AD. The recent development of stereotactic cytoarchitectonic maps enables the indirect localization of the cholinergic BF in multimodal imaging approaches. Methods: Using the BFCS cytoarchitectonic maps for automated morphometric analysis in high-resolution structural MRI scans, we assessed volumetric changes in this system in a large number (N>800) of subjects, including AD patients, subjects with Mild Cognitive Impairment (MCI), as well as cognitively normal controls. Volumetric measures of the BFCS were evaluated for their diagnostic utility in predementia and clinically manifest stages of AD and neuropsychometric examinations were used to assess cognitive correlates of BFCS degeneration. Using AV45- and FDG-PET scans from the ADNI2 database, we assessed associations between BFCS degeneration and cortical changes in amyloid deposition and hypometabolism, respectively, in the prodromal phase of AD. Results: The findings suggest that BFCS volume is particularly vulnerable to degeneration in advanced age and the presence of prodromal AD has an additional effect on BFCS volume loss. In clinically manifest stages of AD the diagnostic accuracy of BFCS volume is comparable to that of hippocampus volume, whereas in subjects with MCI hippocampus atrophy is more pronounced than BFCS atrophy. However, in the predementia phase of AD BFCS volume is more closely associated with AV45-PET measured amyloid deposition, suggesting a higher specificity for AD pathology in predemented subjects. BFCS atrophy correlates with performance decline in tests of both memory and attention/executive function in MCI. Regression analyses in FDG-PET scans indicate that the differential effect of BFCS atrophy on cognitive function is mediated by its association with hypometabolism in distinct cortical networks underlying these specific cognitive functions. Conclusions: Through the wide availability of structural MRI scans, in-vivo BFCS volumetry is well suited to complement laborious postmortem evaluations, especially facilitating the assessment of BFCS changes in predementia AD. Given the indirect nature of the measurement, histopathologic correlates of BFCS volume reductions remain to be elucidated in more detail. F3-02-03
IMAGING OF a4b2 NICOTINIC ACETYLCHOLINE RECEPTORS IN NEURODEGENERATIVE DISORDERS USING 2-[18F]F-A85380 AND [18F] FLUBATINE
Osama Sabri, University of Leipzig, Leipzig, Germany. Contact e-mail: [email protected] Background: The loss of a4ß2-nicotinic acetylcholine receptors (nAChRs) may predict cognitive deterioration at an early-stage in
Featured Research Sessions: F3-02: The Cholinergic System in Alzheimer’s Disease Pathogenesis
any one of six ROIs or by exceeding the SUVR threshold in the global cortical region. Results: Twenty-one subjects were found to be PiB+, with age highly related to PiB+ status (p < 0.0001). For individuals age of 40 and older (N¼25), 72% were PiB+. Significant age-dependent increases in amyloid deposition were seen in all regions, with greatest increases seen in the anterior ventral striatum (R 2 ¼0.64). PiB+ subjects evidenced significantly lower mean scores on several neuropsychological measures, including executive/working memory, delayed recall, and attention/processing speed. These differences are hypothesized to become more pronounced at follow-up time points. Conclusions: This study offers an important opportunity to study the preclinical manifestations of AD. Follow-up assessments at 30-month intervals may not only provide information that could affect early detection, prevention, and treatment of AD for individuals with DS, but also may offer information that will prove extremely useful for the general population.
in MCI and only declines in clinical AD, when PiB binding and soluble beta-amyloid 42 levels are substantially elevated compared to MCI. Moreover, amyloid deposition failed to induce cholinergic cortical neuronal degeneration in APP and triple transgenic mouse models of AD. Increased cortical levels of proNGF and a decrease in TrkA suggest a shift away from cell survival to apoptotic proNGF signaling. Interestingly, this switch to cell death mechanisms did not occur in the hippocampus during prodromal AD. Conclusions: Together these data suggest that CBF system dysregulation is not uniform, the system is neuroplastic, pretangle pathology plays a key role in cognitive impairment, amyloid deposition may not be toxic early on and there is a shift from cell survival to cell death trophic factor signaling in MCI. F3-02-02
Table 1 Subject Demographics (N¼ 56) N(%) Gender Male Female Race White Black Asian American Indian/Alaskan Native Native Hawaiian/Pacific Islander Other Ethnicity Hispanic Age at Screening (yrs) PPVT age equivalent (months) PPVT standard score
28 (50%) 28 (50%) 54 (96.4%) 0 ( 0%) 0 (0%) 1 (1.8%) 0 (0%) 1 (1.8%) 0 (0%) Mean (sd)
Range
38.9 (6.5) 92.3 (34.1) 54.9 (16.6)
30.0-50.0 30-179 20-89
FEATURED RESEARCH SESSIONS: F3-02 THE CHOLINERGIC SYSTEM IN ALZHEIMER’S DISEASE PATHOGENESIS F3-02-01
CHOLINERGIC DYSREGULATION IN PRODROMAL ALZHEIMER’S DISEASE
Elliott Mufson, Rush University, Chicago, Illinois, United States. Contact e-mail: [email protected] Background: The cholinergic hypothesis of geriatric memory dysfunction led to the development of FDA-approved anticholinesterase drugs to maintain this system in AD patients. The importance of defining the status of the cholinergic basal forebrain cortical projection system in subjects with prodromal AD who are at risk for developing AD continues to be of great clinical and translational interest. Methods: The findings presented are derived from molecular and cellular neuropathologic investigations of people who died with a premortem clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI) and Alzheimer’s disease (AD) as well as from AD transgenic animal studies. Results: Clinical pathologic investigations revealed that CBF neurons maintain their cholinergic neuronal phenotype despite exhibiting pretangles, which correlate with cognitive impairment and an altered ratio of 3 repeat to 4 repeat tau in the MCI brain. Interestingly, the cortical cholinergic system displays an upregulation of choline acetyltransferease (ChAT) activity in the frontal cortex and hippocampus suggesting early reparative mechanisms during prodromal AD. Moreover, despite the early accumulation of amyloid burden in the precuneus component of the default memory network, cholinergic enzyme activity remains stable
IN VIVO DETECTION OF CHOLINERGIC BASAL FOREBRAIN ATROPHY USING CYTOARCHITECTONIC MAPPINGS AND MULTIMODAL IMAGING APPROACHES
Michel Grothe, German Center for Neurodegenerative Diseases, Rostock, Germany. Contact e-mail: [email protected] Background: Post-mortem histopathological examinations of human brain specimens have provided substantial evidence for basal forebrain cholinergic system (BFCS) changes in Alzheimer’s disease (AD) dementia. In-vivo imaging markers of BFCS changes would greatly facilitate the investigation of the cholinergic deficit in predementia stages of AD. The recent development of stereotactic cytoarchitectonic maps enables the indirect localization of the cholinergic BF in multimodal imaging approaches. Methods: Using the BFCS cytoarchitectonic maps for automated morphometric analysis in high-resolution structural MRI scans, we assessed volumetric changes in this system in a large number (N>800) of subjects, including AD patients, subjects with Mild Cognitive Impairment (MCI), as well as cognitively normal controls. Volumetric measures of the BFCS were evaluated for their diagnostic utility in predementia and clinically manifest stages of AD and neuropsychometric examinations were used to assess cognitive correlates of BFCS degeneration. Using AV45- and FDG-PET scans from the ADNI2 database, we assessed associations between BFCS degeneration and cortical changes in amyloid deposition and hypometabolism, respectively, in the prodromal phase of AD. Results: The findings suggest that BFCS volume is particularly vulnerable to degeneration in advanced age and the presence of prodromal AD has an additional effect on BFCS volume loss. In clinically manifest stages of AD the diagnostic accuracy of BFCS volume is comparable to that of hippocampus volume, whereas in subjects with MCI hippocampus atrophy is more pronounced than BFCS atrophy. However, in the predementia phase of AD BFCS volume is more closely associated with AV45-PET measured amyloid deposition, suggesting a higher specificity for AD pathology in predemented subjects. BFCS atrophy correlates with performance decline in tests of both memory and attention/executive function in MCI. Regression analyses in FDG-PET scans indicate that the differential effect of BFCS atrophy on cognitive function is mediated by its association with hypometabolism in distinct cortical networks underlying these specific cognitive functions. Conclusions: Through the wide availability of structural MRI scans, in-vivo BFCS volumetry is well suited to complement laborious postmortem evaluations, especially facilitating the assessment of BFCS changes in predementia AD. Given the indirect nature of the measurement, histopathologic correlates of BFCS volume reductions remain to be elucidated in more detail. F3-02-03
IMAGING OF a4b2 NICOTINIC ACETYLCHOLINE RECEPTORS IN NEURODEGENERATIVE DISORDERS USING 2-[18F]F-A85380 AND [18F] FLUBATINE
Osama Sabri, University of Leipzig, Leipzig, Germany. Contact e-mail: [email protected] Background: The loss of a4ß2-nicotinic acetylcholine receptors (nAChRs) may predict cognitive deterioration at an early-stage in