Alzheimer's disease genetic risk score and neuroimaging in the FINGER lifestyle trial.

INTRODUCTION: We assessed a genetic risk score for Alzheimer's disease (AD-GRS) and apolipoprotein E (APOE4) in an exploratory neuroimaging substudy of the FINGER trial. METHODS: 1260 at-risk older individuals without dementia were randomized to multidomain lifestyle intervention or health advice. N = 126 participants underwent magnetic resonance imaging (MRI), and N = 47 positron emission tomography (PET) scans (Pittsburgh Compund B [PiB], Fluorodeoxyglucose) at baseline; N = 107 and N = 38 had repeated 2-year scans. RESULTS: The APOE4 allele, but not AD-GRS, was associated with baseline lower hippocampus volume (ß = -0.27, p = 0.001), greater amyloid deposition (ß = 0.48, p = 0.001), 2-year decline in hippocampus (ß = -0.27, p = 0.01), total gray matter volume (ß = -0.25, p = 0.01), and cortical thickness (ß = -0.28, p = 0.003). In analyses stratified by AD-GRS (below vs above median), the PiB composite score increased less in intervention versus control in the higher AD-GRS group (ß = -0.60, p = 0.03). DISCUSSION: AD-GRS and APOE4 may have different impacts on potential intervention effects on amyloid, that is, less accumulation in the higher-risk group (AD-GRS) versus lower-risk group (APOE). HIGHLIGHTS: First study of neuroimaging and AD genetics in a multidomain lifestyle intervention. Possible intervention effect on brain amyloid deposition may rely on genetic risk. AD-GRS and APOE4 allele may have different impacts on amyloid during intervention.

The Role of Brain Integrity in the Association between Occupational Complexity and Cognitive Performance in Subjects with Increased Risk of Dementia.

INTRODUCTION: Mechanisms underlying the positive association between occupational mental demands and late-life cognition are poorly understood. The objective of this study was to assess whether the association between occupational complexity and cognition is related to and moderated by brain integrity in individuals at risk for dementia. Brain integrity was appraised throughout structural measures (magnetic resonance imaging, MRI) and amyloid accumulation (Pittsburgh compound B (PiB)-positron emission tomography, PiB-PET). METHODS: Participants from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) neuroimaging sample - MRI (N = 126), PiB-PET (N = 41) - were included in a post hoc cross-sectional analysis. Neuroimaging parameters comprised the Alzheimer's disease signature (ADS) cortical thickness (FreeSurfer 5.3), medial temporal atrophy (MTA), and amyloid accumulation (PiB-PET). Cognition was assessed using the neuropsychological test battery. Occupational complexity with data, people, and substantive complexity were classified through the Dictionary of Occupational Titles. Linear regression models included cognition as dependent variable, and occupational complexity, measures of brain integrity, and their interaction terms as predictors. RESULTS: Occupational complexity with data and substantive complexity were associated with better cognition (overall cognition, executive function) when adjusting for ADS and MTA (independent association). Significant interaction effects between occupational complexity and brain integrity were also found, indicating that, for some indicators of brain integrity and cognition (e.g., overall cognition, processing speed), the positive association between occupational complexity and cognition occurred only among persons with higher brain integrity (moderated association). CONCLUSIONS: Among individuals at risk for dementia, occupational complexity does not seem to contribute toward resilience against neuropathology. These exploratory findings require validation in larger populations.

Change in CAIDE Dementia Risk Score and Neuroimaging Biomarkers During a 2-Year Multidomain Lifestyle Randomized Controlled Trial: Results of a Post-Hoc Subgroup Analysis.

The CAIDE (Cardiovascular Risk Factors, Aging and Dementia) Risk Score is a validated tool estimating dementia risk. It was previously associated with imaging biomarkers. However, associations between dementia risk scores (including CAIDE) and dementia-related biomarkers have not been studied in the context of an intervention. This study investigated associations between change in CAIDE score and change in neuroimaging biomarkers (brain magnetic resonance imaging [MRI] and Pittsburgh Compound B-positron emission tomography [PiB-PET] measures) during the 2-year Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) (post-hoc analyses). FINGER targeted at-risk older adults, aged 60-77 years, from the general population. Participants were randomized to either multidomain intervention (diet, exercise, cognitive training, and vascular risk management) or control group (general health advice). Neuroimaging (MRI and PiB-PET) data from baseline and 2-year visits were used. A toal of 112 participants had repeated brain MRI measures (hippocampal, total gray matter, and white matter lesion volumes, and Alzheimer's disease signature cortical thickness). Repeated PiB-PET scans were available for 39 participants. Reduction in CAIDE score (indicating lower dementia risk) during the intervention was associated with less decline in hippocampus volume in the intervention group, but not the control group (Randomization group × CAIDE change interaction ß coefficient = -0.40, p = .02). Associations for other neuroimaging measures were not significant. The intervention may have benefits on hippocampal volume in individuals who succeed in improving their overall risk level as indicated by a reduction in CAIDE score. This exploratory finding requires further testing and validation in larger studies.

27-Hydroxycholesterol, cognition, and brain imaging markers in the FINGER randomized controlled trial.

BACKGROUND: 27-Hydroxycholesterol (27-OH), the main circulating oxysterol in humans and the potential missing link between peripheral hypercholesterolemia and Alzheimer's disease (AD), has not been investigated previously in relation to cognition and neuroimaging markers in the context of preventive interventions. METHODS: The 2-year Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) included older individuals (60-77 years) at increased risk for dementia but without dementia or substantial cognitive impairment from the general population. Participants were randomized to a multidomain intervention (diet, exercise, cognitive training, and vascular risk management) or control group (general health advice) in a 1:1 ratio. Outcome assessors were masked to group allocation. This FINGER exploratory sub-study included 47 participants with measures of 27-OH, cognition, brain MRI, brain FDG-PET, and PiB-PET. Linear regression models were used to assess the cross-sectional and longitudinal associations between 27-OH, cognition, and neuroimaging markers, considering several potential confounders/intervention effect modifiers. RESULTS: 27-OH reduction during the intervention was associated with improvement in cognition (especially memory). This was not observed in the control group. The intervention reduced 27-OH particularly in individuals with the highest 27-OH levels and younger age. No associations were found between changes in 27-OH levels and neuroimaging markers. However, at baseline, a higher 27-OH was associated with lower total gray matter and hippocampal volume, and lower cognitive scores. These associations were unaffected by total cholesterol levels. While sex seemed to influence associations at baseline, it did not affect longitudinal associations. CONCLUSION: 27-OH appears to be a marker not only for dementia/AD risk, but also for monitoring the effects of preventive interventions on cholesterol metabolism. TRIAL REGISTRATION: ClinicalTrials.gov , NCT01041989 . Registered on 4 January 2010.

White Matter Changes on Diffusion Tensor Imaging in the FINGER Randomized Controlled Trial.

BACKGROUND: Early pathological changes in white matter microstructure can be studied using the diffusion tensor imaging (DTI). It is not only important to study these subtle pathological changes leading to cognitive decline, but also to ascertain how an intervention would impact the white matter microstructure and cognition in persons at-risk of dementia. OBJECTIVES: To study the impact of a multidomain lifestyle intervention on white matter and cognitive changes during the 2-year Finnish Geriatric Intervention Study to prevent Cognitive Impairment and Disability (FINGER), a randomized controlled trial in at-risk older individuals (age 60-77 years) from the general population. METHODS: This exploratory study consisted of a subsample of 60 FINGER participants. Participants were randomized to either a multidomain intervention (diet, exercise, cognitive training, and vascular risk management, n = 34) or control group (general health advice, n = 26). All underwent baseline and 2-year brain DTI. Changes in fractional anisotropy (FA), diffusivity along domain (F1) and non-domain (F2) diffusion orientations, mean diffusivity (MD), axial diffusivity (AxD), radial diffusivity (RD), and their correlations with cognitive changes during the 2-year multidomain intervention were analyzed. RESULTS: FA decreased, and cognition improved more in the intervention group compared to the control group (p < 0.05), with no significant intergroup differences for changes in F1, F2, MD, AxD, or RD. The cognitive changes were significantly positively related to FA change, and negatively related to RD change in the control group, but not in the intervention group. CONCLUSION: The 2-year multidomain FINGER intervention may modulate white matter microstructural alterations.

Detecting Amyloid Positivity in Elderly With Increased Risk of Cognitive Decline.

The importance of early interventions in Alzheimer's disease (AD) emphasizes the need to accurately and efficiently identify at-risk individuals. Although many dementia prediction models have been developed, there are fewer studies focusing on detection of brain pathology. We developed a model for identification of amyloid-PET positivity using data on demographics, vascular factors, cognition, APOE genotype, and structural MRI, including regional brain volumes, cortical thickness and a visual medial temporal lobe atrophy (MTA) rating. We also analyzed the relative importance of different factors when added to the overall model. The model used baseline data from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) exploratory PET sub-study. Participants were at risk for dementia, but without dementia or cognitive impairment. Their mean age was 71 years. Participants underwent a brain 3T MRI and PiB-PET imaging. PiB images were visually determined as positive or negative. Cognition was measured using a modified version of the Neuropsychological Test Battery. Body mass index (BMI) and hypertension were used as cardiovascular risk factors in the model. Demographic factors included age, gender and years of education. The model was built using the Disease State Index (DSI) machine learning algorithm. Of the 48 participants, 20 (42%) were rated as Aß positive. Compared with the Aß negative group, the Aß positive group had a higher proportion of APOE ε4 carriers (53 vs. 14%), lower executive functioning, lower brain volumes, and higher visual MTA rating. AUC [95% CI] for the complete model was 0.78 [0.65-0.91]. MRI was the most effective factor, especially brain volumes and visual MTA rating but not cortical thickness. APOE was nearly as effective as MRI in improving detection of amyloid positivity. The model with the best performance (AUC 0.82 [0.71-0.93]) was achieved by combining APOE and MRI. Our findings suggest that combining demographic data, vascular risk factors, cognitive performance, APOE genotype, and brain MRI measures can help identify Aß positivity. Detecting amyloid positivity could reduce invasive and costly assessments during the screening process in clinical trials.

Association of Peripheral Insulin Resistance and Other Markers of Type 2 Diabetes Mellitus with Brain Amyloid Deposition in Healthy Individuals at Risk of Dementia.

We explored the association of type 2 diabetes related blood markers with brain amyloid accumulation on PiB-PET scans in 41 participants from the FINGER PET sub-study. We built logistic regression models for brain amyloid status with12 plasma markers of glucose and lipid metabolism, controlled for diabetes and APOEɛ4 carrier status. Lower levels of insulin, insulin resistance index (HOMA-IR), C-peptide, and plasminogen activator (PAI-1) were associated with amyloid positive status, although the results were not significant after adjusting for multiple testing. None of the models found evidence for associations between amyloid status and fasting glucose or HbA1c.

Bupropion Causes Misdiagnosis in Brain Dopamine Transporter Imaging for Parkinsonism.

OBJECTIVE: The objective of this study was to report long-lasting effects of bupropion on brain dopamine transporter (DAT) in a patient with depression and parkinsonism. METHODS: The patient was a 52-year old man who had been treated with 150 mg/d of bupropion for depression. The patient developed cognitive problems, bradykinesia, and reduced stride length for which he was scanned with [I]FP-CIT single photon emission computed tomography after the recommended 1-week discontinuation of bupropion. Levodopa treatment trial was initiated without a response. Eleven months later, the patient was scanned for a second time after a 1-month stoppage of bupropion. RESULTS: The first scan was abnormal with left putamen specific binding ratio of 1.99 (SDs from the reference value mean, -2.40), right putamen of 2.27 (SD, -1.84), left caudate of 2.33 (SD, -2.26), and right caudate of 2.29 (SD, -2.18). The second scan (after 1-month discontinuation) was normal, and specific binding ratios had increased from 5.2% to 31.7% in all striatal regions as compared with the first scan. Brain magnetic resonance imaging and [F]fluorodeoxyglucose positron emission tomography imaging were normal, and there was no levodopa response or other features supporting neurodegenerative parkinsonism. CONCLUSIONS: Bupropion has previously generally been discontinued 1 week prior DAT imaging, which meets the recommended, albeit arbitrary, time interval of 5 plasma clearance half-lives before the scan. One-week discontinuation of bupropion before DAT imaging may be insufficiently short. Our case shows that longer medication washout and rescan may be needed when there is contradiction between the imaging result and clinical outcome in patients with medications affecting DAT binding.

Brain volumes and cortical thickness on MRI in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER).

BACKGROUND: The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) was a multicenter randomized controlled trial that reported beneficial effects on cognition for a 2-year multimodal intervention (diet, exercise, cognitive training, vascular risk monitoring) versus control (general health advice). This study reports exploratory analyses of brain MRI measures. METHODS: FINGER targeted 1260 older individuals from the general Finnish population. Participants were 60-77 years old, at increased risk for dementia but without dementia/substantial cognitive impairment. Brain MRI scans were available for 132 participants (68 intervention, 64 control) at baseline and 112 participants (59 intervention, 53 control) at 2 years. MRI measures included regional brain volumes, cortical thickness, and white matter lesion (WML) volume. Cognition was assessed at baseline and 1- and 2-year visits using a comprehensive neuropsychological test battery. We investigated the (1) differences between the intervention and control groups in change in MRI outcomes (FreeSurfer 5.3) and (2) post hoc sub-group analyses of intervention effects on cognition in participants with more versus less pronounced structural brain changes at baseline (mixed-effects regression models, Stata 12). RESULTS: No significant differences between the intervention and control groups were found on the changes in MRI measures. Beneficial intervention effects on processing speed were more pronounced in individuals with higher baseline cortical thickness in Alzheimer's disease signature areas (composite measure of entorhinal, inferior and middle temporal, and fusiform regions). The randomization group × time × cortical thickness interaction coefficient was 0.198 (p = 0.021). A similar trend was observed for higher hippocampal volume (group × time × hippocampus volume interaction coefficient 0.1149, p = 0.085). CONCLUSIONS: The FINGER MRI exploratory sub-study did not show significant differences between the intervention and control groups on changes in regional brain volumes, regional cortical thicknesses, or WML volume after 2 years in at-risk elderly without substantial impairment. The cognitive benefits on processing speed of the FINGER intervention may be more pronounced in individuals with fewer structural brain changes on MRI at baseline. This suggests that preventive strategies may be more effective if started early, before the occurrence of more pronounced structural brain changes. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01041989 . Registered January 5, 2010.

Brain amyloid load and its associations with cognition and vascular risk factors in FINGER Study.

OBJECTIVE: To investigate brain amyloid pathology in a dementia-risk population defined as cardiovascular risk factors, aging, and dementia risk (CAIDE) score of at least 6 but with normal cognition and to examine associations between brain amyloid load and cognitive performance and vascular risk factors. METHODS: A subgroup of 48 individuals from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) main study participated in brain 11C-Pittsburgh compound B (PiB)-PET imaging, brain MRI, and neuropsychological assessment at the beginning of the study. Lifestyle/vascular risk factors were determined as body mass index, blood pressure, total and low-density lipoprotein cholesterol, and glucose homeostasis model assessment. White matter lesions were visually rated from MRIs by a semiquantitative Fazekas score. RESULTS: Twenty participants (42%) had a positive PiB-PET on visual analysis. The PiB-positive group performed worse in executive functioning tests, included more participants with APOE ε4 allele (50%), and showed slightly better glucose homeostasis compared to PiB-negative participants. PiB-positive and -negative participants did not differ significantly in other cognitive domain scores or other vascular risk factors. There was no significant difference in Fazekas score between the PiB groups. CONCLUSIONS: The high percentage of PiB-positive participants provides evidence of a successful recruitment process of the at-risk population in the main FINGER intervention trial. The results suggest a possible association between early brain amyloid accumulation and decline in executive functions. APOE ε4 was clearly associated with amyloid positivity, but no other risk factor was found to be associated with positive PiB-PET.

Associations of CAIDE Dementia Risk Score with MRI, PIB-PET measures, and cognition.

BACKGROUND: CAIDE Dementia Risk Score is the first validated tool for estimating dementia risk based on a midlife risk profile. OBJECTIVES: This observational study investigated longitudinal associations of CAIDE Dementia Risk Score with brain MRI, amyloid burden evaluated with PIB-PET, and detailed cognition measures. METHODS: FINGER participants were at-risk elderly without dementia. CAIDE Risk Score was calculated using data from previous national surveys (mean age 52.4 years). In connection to baseline FINGER visit (on average 17.6 years later, mean age 70.1 years), 132 participants underwent MRI scans, and 48 underwent PIB-PET scans. All 1,260 participants were cognitively assessed (Neuropsychological Test Battery, NTB). Neuroimaging assessments included brain cortical thickness and volumes (Freesurfer 5.0.3), visually rated medial temporal atrophy (MTA), white matter lesions (WML), and amyloid accumulation. RESULTS: Higher CAIDE Dementia Risk Score was related to more pronounced deep WML (OR 1.22, 95% CI 1.05-1.43), lower total gray matter (ß-coefficient -0.29, p = 0.001) and hippocampal volume (ß-coefficient -0.28, p = 0.003), lower cortical thickness (ß-coefficient -0.19, p = 0.042), and poorer cognition (ß-coefficients -0.31 for total NTB score, -0.25 for executive functioning, -0.33 for processing speed, and -0.20 for memory, all p < 0.001). Higher CAIDE Dementia Risk Score including APOE genotype was additionally related to more pronounced MTA (OR 1.15, 95% CI 1.00-1.30). No associations were found with periventricular WML or amyloid accumulation. CONCLUSIONS: The CAIDE Dementia Risk Score was related to indicators of cerebrovascular changes and neurodegeneration on MRI, and cognition. The lack of association with brain amyloid accumulation needs to be verified in studies with larger sample sizes.

Long-Term Interrelationship between Brain Metabolism and Amyloid Deposition in Mild Cognitive Impairment.

The aim of this longitudinal positron emission tomography (PET) study was to evaluate the interrelationship between brain metabolism and amyloid accumulation during the disease process from mild cognitive impairment (MCI) to Alzheimer's disease (AD). Nine MCI patients, who converted to AD between two and five years, and nine healthy subjects underwent [11C]PIB and [18F]FDG PET scans at baseline and at 5 years. [11C]PIB uptake was clearly higher in MCI patients at baseline compared to controls and spread extensively to the cerebral cortex during the conversion to AD. [18F]FDG uptake was reduced especially in the temporal-parietal regions in MCI compared to controls at baseline, and widely over the cortex at the 5-year follow-up. The reduction in metabolism during the follow-up was significant in the posterior brain regions. In addition, brain amyloid load was positively associated with metabolism in posterior brain regions in MCI, but not after conversion to AD. The results suggest that there are interactions between brain amyloid accumulation and metabolism during the AD process, including a possible compensatory upregulation of posterior brain metabolism in the early phase.

Reproducibility of automated simplified voxel-based analysis of PET amyloid ligand [11C]PIB uptake using 30-min scanning data.

PURPOSE: Positron emission tomography (PET) with 11C-labelled Pittsburgh compound B ([11C]PIB) enables the quantitation of beta-amyloid accumulation in the brain of patients with Alzheimer's disease (AD). Voxel-based image analysis techniques conducted in a standard brain space provide an objective, rapid and fully automated method to analyze [11C]PIB PET data. The purpose of this study was to evaluate both region- and voxel-level reproducibility of automated and simplified [11C]PIB quantitation when using only 30 min of imaging data. METHODS: Six AD patients and four healthy controls were scanned twice with an average interval of 6 weeks. To evaluate the feasibility of short scanning (convenient for AD patients), [11C]PIB uptake was quantitated using 30 min of imaging data (60 to 90 min after tracer injection) for region-to-cerebellum ratio calculations. To evaluate the reproducibility, a test-retest design was used to derive absolute variability (VAR) estimates and intraclass correlation coefficients at both region-of-interest (ROI) and voxel level. RESULTS: The reproducibility both at the region level (VAR 0.9-5.5%) and at the voxel level (VAR 4.2-6.4%) was good to excellent. Based on the variability estimates obtained, power calculations indicated that 90% power to obtain statistically significant difference can be achieved using a sample size of five subjects per group when a 15% change from baseline (increase or decrease) in [11C]PIB accumulation in the frontal cortex is anticipated in one group compared to no change in another group. CONCLUSION: Our results showed that an automated analysis method based on an efficient scanning protocol provides reproducible results for [11C]PIB uptake and appears suitable for PET studies aiming at the quantitation of amyloid accumulation in the brain of AD patients for the evaluation of progression and treatment effects.

Posterior cortical atrophy: a rare form of dementia with in vivo evidence of amyloid-beta accumulation.

Posterior cortical atrophy (PCA) is a rare form of degenerative dementia, which is characterized by progressive atrophy of occipital and parietal cortical areas. It usually manifests as increasing difficulties of visuoperceptive abilities. Later on, memory and other cognitive functions are involved. Various pathologies have been associated with clinical PCA presentation, but most of the patients with autopsy have had Alzheimer-type pathology. Thus, PCA has been considered to be a rare form of Alzheimer-type dementia with unusual pathological distribution. Here we describe a patient who had a typical clinical course for this syndrome and who showed a positive accumulation of amyloid-beta in posterior areas studied with positron emission tomography.

Regional analysis of FDG and PIB-PET images in normal aging, mild cognitive impairment, and Alzheimer's disease.

OBJECTIVE: The objective of the study is to compare the diagnostic value of regional sampling of the cerebral metabolic rate of glucose metabolism (MRglc) using [18F]-fluoro-2-deoxyglucose ([18F]FDG)-positron emission tomography (PET) and amyloid-beta pathology using Pittsburgh Compound-B ([11C]PIB)-PET in the evaluation of patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) compared to normal elderly (NL). MATERIALS AND METHODS: AD patients, 7 NL, 13 MCI, and 17, received clinical, neuropsychological, magnetic resonance imaging (MRI), FDG, and PIB-PET exams. Parametric images of PIB uptake and MRglc were sampled using automated regions-of-interest (ROI). RESULTS: AD showed global MRglc reductions, and MCI showed reduced hippocampus (HIP) and inferior parietal lobe (IP) MRglc compared to NL. On PIB, AD patients showed significantly increased uptake in the middle frontal gyrus (MFG), posterior cingulate cortex (PCC), and IP (ps < 0.05). PIB uptake in MCI subjects was either AD or NL-like. HIP MRglc and MFG PIB uptake were the best discriminators of NL from MCI and NL from AD. These two best measures showed high diagnostic agreement for AD (94%) and poor agreement for MCI (54%). For the NL vs. MCI discrimination, combining the two best measures increased the accuracy for PIB (75%) and for FDG (85%) to 90%. CONCLUSION: For AD, the pattern of regional involvement for FDG and PIB differ, but both techniques show high diagnostic accuracy and 94% case by case agreement. In the classification of NL and MCI, FDG is superior to PIB, but there is only 54% agreement at a case level. Combining the two modalities improves the diagnostic accuracy for MCI.

Carbon 11-labeled pittsburgh compound B positron emission tomographic amyloid imaging in patients with APP locus duplication.

OBJECTIVE: To investigate amyloid accumulation by carbon 11-labeled Pittsburgh Compound B (11C-PiB) in hereditary cerebral amyloid angiopathy and APP locus duplication. DESIGN, SETTING, AND PATIENTS: Positron emission tomography with 11C-PiB and magnetic resonance imaging were performed for 2 patients, 49-year-old and 60-year-old siblings with APP locus duplication, with hereditary Alzheimer disease and cerebral amyloid angiopathy. MAIN OUTCOME MEASURE: Change in 11C-PiB uptake. RESULTS: Uptake of 11C-PiB was increased especially in the striatum (caudate nucleus to 225% and 280% of the control mean and putamen to 166% and 185% of the control mean) and in the posterior cingulate (to 168% and 198% of the control mean), and it was marginally increased in other cortical brain areas. The pattern of increased 11C-PiB uptake was different from that seen in sporadic Alzheimer disease. CONCLUSIONS: Amyloid imaging with 11C-PiB positron emission tomography is a useful tool for detecting in vivo amyloid accumulation in patients with hereditary cerebral amyloid angiopathy. However, the pattern of 11C-PiB accumulation differs between patients with typical AD and patients with APP locus duplication.

Cognitive reserve hypothesis: Pittsburgh Compound B and fluorodeoxyglucose positron emission tomography in relation to education in mild Alzheimer's disease.

OBJECTIVE: The reduced risk for Alzheimer's disease (AD) in high-educated individuals has been proposed to reflect brain cognitive reserve, which would provide more efficient compensatory mechanisms against the underlying pathology, and thus delayed clinical expression. Our aim was to find possible differences in brain amyloid ligand 11C-labeled Pittsburgh Compound B ([11C]PIB) uptake and glucose metabolism in high- and low-educated patients with mild AD. METHODS: Twelve high-educated and 13 low-educated patients with the same degree of cognitive deterioration were studied with PET using [11C]PIB and 18F-fluorodeoxyglucose as ligands. The between-group differences were analyzed with voxel-based statistical method, and quantitative data were obtained with automated region-of-interest analysis. RESULTS: High-educated patients showed increased [11C]PIB uptake in the lateral frontal cortex compared with low-educated patients. Moreover, high-educated patients had significantly lower glucose metabolic rate in the temporoparietal cortical regions compared with low-educated patients. INTERPRETATION: Our results suggesting more advanced pathological and functional brain changes in high-educated patients with mild AD are in accordance with the brain cognitive reserve hypothesis and point out the importance of development of reliable markers of underlying AD pathology for early AD diagnostics.

Brain white matter expansion in human obesity and the recovering effect of dieting.

CONTEXT AND OBJECTIVE: Obesity is associated with several metabolic abnormalities. Recent studies suggest that obesity also affects brain function and is a risk factor for some degenerative brain diseases. The objective of this study was to examine the effects of weight gain and weight loss on brain gray and white matter structure. We hypothesized that possible differences seen in the brains of obese subjects would disappear or diminish after an intensive dieting period. METHODS: In part I of the study, we scanned with magnetic resonance imaging 16 lean (mean body mass index, 22 kg/m(2)) and 30 obese (mean body mass index, 33 kg/m(2)) healthy subjects. In part II, 16 obese subjects continued with a very low-calorie diet for 6 wk, after which they were scanned again. Regional brain white and gray matter volumes were calculated using voxel-based morphometry. RESULTS: White matter volumes were greater in obese subjects, compared with lean subjects in several basal brain regions, and obese individuals showed a positive correlation between white matter volume in basal brain structures and waist to hip ratio. The detected white matter expansion was partially reversed by dieting. Regional gray matter volumes did not differ significantly in obese and lean subjects, and dieting did not affect gray matter. CONCLUSIONS: The precise mechanism for the discovered white matter changes remains unclear, but the present study demonstrates that obesity and dieting are associated with opposite changes in brain structure. It is not excluded that white matter expansion in obesity has a role in the neuropathogenesis of degenerative brain diseases.

Age-related loss of extrastriatal dopamine D(2) -like receptors in women.

Positron emission tomography (PET) studies have indicated that the in vivo availability of dopamine D(2) -like receptors declines with age in the human brain. Most of the studies have been carried out with healthy male subjects, or with subject groups containing both sexes. The authors have recently demonstrated that the availability of D(2) -like receptors in the frontal cortex is higher in women than in men. The present study was aimed to further examine this phenomenon. Thirty-seven healthy women (age range 22-78 years) were examined with PET and [(11) C]FLB 457, a high-affinity tracer for the extrastriatal D(2) -like receptors. A negative relationship between age and dopamine D(2) -like receptor availability was seen in the frontal cortex (decrease of 12% per decade of life), the temporal cortex (9%) and the thalamus (6%). A non-linear s-shape association explained the relationship only in the frontal cortex, while in other regions the association was linear. Neither oestradiol nor progesterone levels had a significant relationship with the [(11) C]FLB 457 uptake in any of the brain regions studied after the effect of age was partialled out. The results indicate that: (i) the extrastriatal D(2) -like receptor availability decreases with age in healthy women with the fastest rate in the frontal cortex and with the overall rate close to the rate reported in healthy men; (ii) around midlife (age 40-60 years) in women, the frontal receptor decline plateaus while the decline continues to be linear in other extrastriatal brain regions; and (iii) serum oestradiol or progesterone levels are not associated with cortical or thalamic D(2) -like receptor availability in women. The results may prove to be important in studies where the biochemical basis of clinical sex differences is examined in patients with dopamine-related neuropsychiatric disorders.