Medial prefrontal cortex 5-HT(2A) density is correlated with amygdala reactivity, response habituation, and functional coupling.

Feedback inhibition of the amygdala via medial prefrontal cortex (mPFC) is an important component in the regulation of complex emotional behaviors. The functional dynamics of this corticolimbic circuitry are, in part, modulated by serotonin (5-HT). Serotonin 2A (5-HT(2A)) receptors within the mPFC represent a potential molecular mechanism through which 5-HT can modulate this corticolimbic circuitry. We employed a multimodal neuroimaging strategy to explore the relationship between threat-related amygdala reactivity, assessed using blood oxygen level-dependent functional magnetic resonance imaging, and mPFC 5-HT(2A) density, assessed using [(18)F]altanserin positron emission tomography in 35 healthy adult volunteers. We observed a significant inverse relationship wherein greater mPFC 5-HT(2A) density was associated with reduced threat-related right amygdala reactivity. Remarkably, 25-37% of the variability in amygdala reactivity was explained by mPFC 5-HT(2A) density. We also observed a positive correlation between mPFC 5-HT(2A) density and the magnitude of right amygdala habituation. Furthermore, functional coupling between the amygdala and mPFC was positively correlated with 5-HT(2A) density suggesting that effective integration of emotionally salient information within this corticolimbic circuitry may be modulated, at least in part, by mPFC 5-HT(2A). Collectively, our results indicate that mPFC 5-HT(2A) is strongly associated with threat-related amygdala reactivity as well as its temporal habituation and functional coupling with prefrontal regulatory regions.

Consideration of optimal time window for Pittsburgh compound B PET summed uptake measurements.

UNLABELLED: The standardized uptake value ratio (SUVR, or summed tissue ratio) has been used effectively in Pittsburgh compound B (PiB) PET studies to distinguish subjects who have significant amyloid-beta deposition in their brain from those who do not. Relative to quantitative measurements, advantages of the SUVR are improved study feasibility and low test-retest variation; disadvantages include inherent bias (PiB retention overestimation) and potential for time-varying outcomes. The PiB SUVR has proven to be highly correlated with quantitative outcomes and to allow reliable detection of significant group differences (or effective contrasts). In this work, regional PiB SUVRs were examined across 9 time windows to select the window that provided the best trade-offs between bias, correlation, and effective contrast. METHODS: A total of 40 dynamic PiB PET studies were performed on controls (n = 16), patients with Alzheimer disease (AD; n = 11), and patients with mild cognitive impairment (MCI; n = 13) (555 MBq [15 mCi], 90-min scan, and arterial blood sampling). The SUVR was computed for five 20-min and four 30-min windows that spanned the 30- to 90-min postinjection period. The SUVRs were compared with Logan graphical distribution volume ratio (DVR) measurements (35-90 min), determined with arterial blood as input and without arterial blood as input (cerebellum as reference). RESULTS: Greater correlation and more bias were generally observed for the SUVR measurement at later times than at earlier times (relative to DVR). The effective contrast between the control and AD PiB SUVRs was slightly better for earlier data than for later data. The temporal dynamics of the SUVR measurement indicated greater stability in the measurement at 40 min after injection. CONCLUSION: The 50- to 70-min time window provided a good compromise between physiologic validity, stability, sensitivity, and clinical feasibility across the control, MCI, and AD subject data examined in this study. The 40- to 60-min period demonstrated many advantages and should be used in studies limited by low injected dose. Although more biased than the 40- to 60-min SUVR, the 50- to 70-min SUVR was thought to be optimal because of greater measurement stability, which may prove to be important for longitudinal multisite studies performed in control, MCI, and AD subjects that are not dose-limited.

Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer's disease.

The positron emission tomography (PET) radiotracer Pittsburgh Compound-B (PiB) binds with high affinity to beta-pleated sheet aggregates of the amyloid-beta (Abeta) peptide in vitro. The in vivo retention of PiB in brains of people with Alzheimer's disease shows a regional distribution that is very similar to distribution of Abeta deposits observed post-mortem. However, the basis for regional variations in PiB binding in vivo, and the extent to which it binds to different types of Abeta-containing plaques and tau-containing neurofibrillary tangles (NFT), has not been thoroughly investigated. The present study examined 28 clinically diagnosed and autopsy-confirmed Alzheimer's disease subjects, including one Alzheimer's disease subject who had undergone PiB-PET imaging 10 months prior to death, to evaluate region- and substrate-specific binding of the highly fluorescent PiB derivative 6-CN-PiB. These data were then correlated with region-matched Abeta plaque load and peptide levels, [(3)H]PiB binding in vitro, and in vivo PET retention levels. We found that in Alzheimer's disease brain tissue sections, the preponderance of 6-CN-PiB binding is in plaques immunoreactive to either Abeta42 or Abeta40, and to vascular Abeta deposits. 6-CN-PiB labelling was most robust in compact/cored plaques in the prefrontal and temporal cortices. While diffuse plaques, including those in caudate nucleus and presubiculum, were less prominently labelled, amorphous Abeta plaques in the cerebellum were not detectable with 6-CN-PiB. Only a small subset of NFT were 6-CN-PiB positive; these resembled extracellular 'ghost' NFT. In Alzheimer's disease brain tissue homogenates, there was a direct correlation between [(3)H]PiB binding and insoluble Abeta peptide levels. In the Alzheimer's disease subject who underwent PiB-PET prior to death, in vivo PiB retention levels correlated directly with region-matched post-mortem measures of [(3)H]PiB binding, insoluble Abeta peptide levels, 6-CN-PiB- and Abeta plaque load, but not with measures of NFT. These results demonstrate, in a typical Alzheimer's disease brain, that PiB binding is highly selective for insoluble (fibrillar) Abeta deposits, and not for neurofibrillary pathology. The strong direct correlation of in vivo PiB retention with region-matched quantitative analyses of Abeta plaques in the same subject supports the validity of PiB-PET imaging as a method for in vivo evaluation of Abeta plaque burden.

Amyloid deposition begins in the striatum of presenilin-1 mutation carriers from two unrelated pedigrees.

The amyloid cascade hypothesis suggests that the aggregation and deposition of amyloid-beta protein is an initiating event in Alzheimer's disease (AD). Using amyloid imaging technology, such as the positron emission tomography (PET) agent Pittsburgh compound-B (PiB), it is possible to explore the natural history of preclinical amyloid deposition in people at high risk for AD. With this goal in mind, asymptomatic (n = 5) and symptomatic (n = 5) carriers of presenilin-1 (PS1) mutations (C410Y or A426P) that lead to early-onset AD and noncarrier controls from both kindreds (n = 2) were studied with PiB-PET imaging and compared with sporadic AD subjects (n = 12) and controls from the general population (n = 18). We found intense and focal PiB retention in the striatum of all 10 PS1 mutation carriers studied (ages 35-49 years). In most PS1 mutation carriers, there also were increases in PiB retention compared with controls in cortical brain areas, but these increases were not as great as those observed in sporadic AD subjects. The two PS1 mutation carriers with a clinical diagnosis of early-onset AD did not show the typical regional pattern of PiB retention observed in sporadic AD. Postmortem evaluation of tissue from two parents of PS1C410Y subjects in this study confirmed extensive striatal amyloid deposition, along with typical cortical deposition. The early, focal striatal amyloid deposition observed in these PS1 mutation carriers is often is not associated with clinical symptoms.

Characterizing regional correlation, laterality and symmetry of amyloid deposition in mild cognitive impairment and Alzheimer's disease with Pittsburgh Compound B.

We evaluated the region-to-region correlation, laterality and asymmetry of amyloid deposition in subjects with mild cognitive impairment (MCI) or Alzheimer's disease (AD) using the amyloid tracer, Pittsburgh Compound B (PiB). Seventeen subjects, including 7 with MCI (MMSE 26.7+/-2.4) and 10 with AD (MMSE of 24.8+/-2.7) underwent PiB imaging. Measures of laterality (i.e., group-wise predilection for right or left) and asymmetry (i.e., group-wise predilection for unequal PiB retention between the two hemispheres) were calculated for 17 Regions of Interest (ROIs). Regional correlations were calculated along with within-group and between-groups statistical analyses of laterality and asymmetry metrics. The median correlation between PiB retention across all pairs of ROIs was 0.65, with highest correlations found in areas of highest PiB retention (r=0.74). Overall, PiB retention was symmetric bilaterally, but there was PiB laterality in MCI in dorsal frontal cortex [(t(6)=3.05, p=0.02, L>R] and sensory-motor area [t(6)=3.10, p=0.02, L>R] and in AD in the occipital pole (t(9)=-2.63, p=0.03, R>L). The most significant asymmetries in PiB retention were found in sub-cortical white matter (t(6)=3.99, p=0.01) and middle precuneus [(t(6)=3.57, p=0.01] in MCI, and in lateral temporal cortex (t(9)=3.02, p=0.01) and anterior ventral striatum [t(9)=2.37, p=0.04] in AD. No group differences (AD versus MCI) were detected in laterality [F (1, 15)=0.15, p=0.7] or asymmetry [F (1, 15)=0.7, p=0.42].

Imaging Alzheimer pathology in late-life depression with PET and Pittsburgh Compound-B.

There is increasing evidence for an empiric link between late-life depression and Alzheimer disease (AD). The neuropathology of AD, previously only confirmed at autopsy, may now be detectable in vivo using selective imaging ligands for beta-amyloid. Positron emission tomography (PET) with [11C] 6-OH-BTA-1 [Pittsburgh Compound-B (PiB)] has shown high tracer retention in cortical areas in patients with clinical diagnoses of probable AD and low retention in age-matched controls. We also previously reported variable PiB retention in patients with mild cognitive impairment (MCI). In this study, we used PiB-PET to evaluate whether amyloid is present in elders with treated major depression, many of whom have persistent cognitive impairment. We evaluated 9 subjects with remitted major depression [3M: 6F, mean (SD) age=71.8(5.7) y]. Seven of the 9 depressed subjects also met criteria for the diagnosis of MCI. PiB-PET data from healthy elders [n=8; mean (SD) age=71.5(3.0) y] were used for comparison. PET was acquired with arterial sampling and PiB retention was quantified using magnetic resonance imaging-guided cortical regions and graphical analysis of time-activity data; arterial line failure led to exclusion of 1 depressed subject. The data demonstrated variably elevated PiB retention. PiB retention in the 2 depressed subjects with normal cognitive ability was in the range of nondepressed cognitively normal subjects. PiB retention in 3 of the 6 depressed subjects with MCI fell in the range of subjects with AD. PiB retention in the remaining 3 depressed subjects with cooccurring MCI was variable and generally was intermediate to the other subjects. Our findings are consistent with and supportive of the hypothesis that depression may herald the development of AD in some individuals.

Exaggerated 5-HT1A but normal 5-HT2A receptor activity in individuals ill with anorexia nervosa.

BACKGROUND: Many studies have found disturbances of serotonin (5-HT) activity in anorexia nervosa (AN). Because little is known about 5-HT receptor function in AN, positron emission tomography (PET) imaging with 5-HT receptor-specific radioligands was used to characterize 5-HT1A and 5-HT2A receptors. METHODS: Fifteen women ill with AN (ILL AN) were compared with 29 healthy control women (CW); PET and [11C]WAY100635 were used to assess binding potential (BP) of the 5-HT1A receptor, and [18F]altanserin was used to assess postsynaptic 5-HT2A receptor BP. [15O] water and PET were used to assess cerebral blood flow. RESULTS: The ILL AN women had a highly significant (30%-70%) increase in [11C]WAY100635 BP in prefrontal and lateral orbital frontal regions, mesial and lateral temporal lobes, parietal cortex, and dorsal raphe nuclei compared with CW. The [18F]altanserin BP was normal in ILL AN but was positively and significantly related to harm avoidance in suprapragenual cingulate, frontal, and parietal regions. Cerebral blood flow was normal in ILL AN women. CONCLUSIONS: Increased activity of 5-HT1A receptor activity may help explain poor response to 5-HT medication in ILL AN. This study extends data suggesting that 5-HT function, and, specifically, the 5-HT2A receptor, is related to anxiety in AN.

Serotonin transporter binding after recovery from eating disorders.

RATIONALE: Several lines of evidence suggest that altered serotonin (5-HT) function persists after recovery from anorexia nervosa (AN) and bulimia nervosa (BN). OBJECTIVES: We compared 11 subjects who recovered (>1 year normal weight, regular menstrual cycles, no binging or purging) from restricting-type AN (REC RAN), 7 who recovered from bulimia-type AN (REC BAN), 9 who recovered from BN (REC BN), and 10 healthy control women (CW). MATERIALS AND METHODS: Positron emission tomography (PET) imaging with [11C]McN5652 was used to assess the 5-HT transporter (5-HTT). For [11C]McN5652, distribution volume (DV) values were determined using a two-compartment, three-parameter tracer kinetic model, and specific binding was assessed using the binding potential (BP, BP=DVregion of interest/DVcerebellum-1). RESULTS: After correction for multiple comparisons, the four groups showed significant (p<0.05) differences for [11C]McN5652 BP values for the dorsal raphe and antero-ventral striatum (AVS). Post-hoc analysis revealed that REC RAN had significantly increased [11C]McN5652 BP compared to REC BAN in these regions. CONCLUSIONS: Divergent 5-HTT activity in subtypes of eating disorder subjects may provide important insights as to why these groups have differences in affective regulation and impulse control.

Stroke onset time using sodium MRI in rat focal cerebral ischemia.

BACKGROUND AND PURPOSE: Thrombolytic therapy with intravenous tPA must be administered within 3 hours after stroke onset. However, stroke onset time cannot be established in 20% to 45% of potential patients. We propose that the rate of increase of the brain concentration of sodium ([Na+]br) after stroke, monitored using sodium MRI in a rat model of cortical ischemia, is linear in each individual animal, can locate the ischemic region, and can be used to estimate onset time. METHODS: After induction of focal cortical ischemia in rats under isoflurane anesthesia, [Na+]br time course maps were acquired continuously on a 3 T whole body scanner from 2 to 7 hours after occlusion followed by T2-weighted proton images. Microtubule-associated protein-2 immunostained brain sections were used to verify the location of the infarct. RESULTS: The ischemic region identified with microtubule-associated protein-2 corresponded to the region of maximum [Na+]br increase (P<0.001; n=5), and all of the animals demonstrated high linearity. [Na+]br increased at a mean rate of 25+/-4.7%/h in ischemic tissue (P=0.013) but not in normal cortex (1.0+/-1.1%/h; P=0.42). The mean onset time error was 1+/-4 minutes (n=4). CONCLUSIONS: These results of sodium MRI show that the region of maximum [Na+]br increase corresponds to the ischemic region. Although [Na+]br increases at a different rate in each animal, the increase is linear, and, therefore, onset time can be estimated. These findings suggest that this method can be used as a ticking clock to estimate time elapsed after vascular occlusion.

Normal brain tissue volumes after long-term recovery in anorexia and bulimia nervosa.

BACKGROUND: Individuals who are ill with anorexia (AN) and bulimia nervosa (BN) often have increased cerebrospinal fluid (CSF) volumes and decreased total gray and white matter volumes. It is unclear whether such disturbances persist after recovery from an eating disorder. METHODS: Magnetic resonance imaging was performed on 40 women who were long-term recovered (>1 year no binging, purging, or restricting behaviors, normal weight, and menstrual cycles, not on medication) from restricting or binge/purging type AN or BN and 31 healthy control women (CW). Voxel-based morphometry (VBM) was used for data analysis. RESULTS: Recovered AN and BN subgroups were similar to CW in terms of cerebrospinal fluid (CSF) volume as well as total or regional gray or white matter volume. CONCLUSIONS: These findings suggest that structural brain abnormalities are reversible in individuals with eating disorders after long-term recovery.

Altered brain serotonin 5-HT1A receptor binding after recovery from anorexia nervosa measured by positron emission tomography and [carbonyl11C]WAY-100635.

CONTEXT: Previous studies have shown that women with anorexia nervosa (AN), when ill and after recovery, have alterations of serotonin (5-HT) neuronal activity and core eating disorder symptoms, such as anxiety. OBJECTIVE: To further characterize the 5-HT system in AN, we investigated 5-HT1A receptor activity using positron emission tomography imaging because this receptor is implicated in anxiety and feeding behavior. DESIGN, SETTING, AND PARTICIPANTS: To avoid the confounding effects of malnutrition, we studied 13 women who had recovered from restricting-type AN (mean age, 23.3 +/- 5.2 years) and 12 women who had recovered from bulimia-type AN (mean age, 28.6 +/- 7.3 years) (>1 year normal weight, regular menstrual cycles, no bingeing or purging). These subjects were compared with 18 healthy control women (mean age, 25.1 +/- 5.8 years). Intervention The 5-HT1A receptor binding was measured using positron emission tomography imaging and a specific 5-HT1A receptor antagonist, [carbonyl-11C]WAY-100635. MAIN OUTCOME MEASURE: Specific 5-HT1A receptor binding was assessed using the binding potential measure. Binding potential values were derived using both the Logan graphical method and compartmental modeling. The binding potential in a region of interest was calculated with the formula: binding potential = distribution volume of the region of interest minus distribution volume of the cerebellum. RESULTS: Women recovered from bulimia-type AN had significantly (P<.05) increased [11C]WAY-100635 binding potential in cingulate, lateral and mesial temporal, lateral and medial orbital frontal, parietal, and prefrontal cortical regions and in the dorsal raphe compared with control women. No differences were found for women recovered from restricting-type AN relative to controls. For women recovered from restricting-type AN, the 5-HT1A postsynaptic receptor binding in mesial temporal and subgenual cingulate regions was positively correlated with harm avoidance. CONCLUSIONS: We observed increased 5-HT1A receptor binding in women who had recovered from bulimia-type AN but not restricting-type AN. However, 5-HT1A receptor binding was associated with a measure of anxiety in women recovered from restricting-type AN. These data add to a growing body of evidence showing that altered serotonergic function and anxiety symptoms persist after recovery from AN. These psychobiological alterations may be trait related and may contribute to the pathogenesis of AN.

Increased dopamine D2/D3 receptor binding after recovery from anorexia nervosa measured by positron emission tomography and [11c]raclopride.

BACKGROUND: Several lines of evidence support the possibility that disturbances of dopamine (DA) function could contribute to alterations of weight, feeding, motor activity, and reward in anorexia nervosa (AN). METHODS: To assess possibly trait-related disturbances but avoid confounding effects of malnutrition, 10 women who were recovered from AN (REC AN) were compared with 12 healthy control women (CW). Positron emission tomography with [(11)C]raclopride was used to assess DA D2/D3 receptor binding. RESULTS: The women who were recovered from AN had significantly higher [(11)C]raclopride binding potential in the antero-ventral striatum than CW. For REC AN, [(11)C]raclopride binding potential was positively related to harm avoidance in the dorsal caudate and dorsal putamen. CONCLUSIONS: These data lend support for the possibility that decreased intrasynaptic DA concentration or increased D2/D3 receptor density or affinity is associated with AN and might contribute to the characteristic harm avoidance or increased physical activity found in AN. Most intriguing is the possibility that individuals with AN might have a DA related disturbance of reward mechanisms contributing to altered hedonics of feeding behavior and their ascetic, anhedonic temperament.

Kinetic modeling of amyloid binding in humans using PET imaging and Pittsburgh Compound-B.

A valid quantitative imaging method for the measurement of amyloid deposition in humans could improve Alzheimer's disease (AD) diagnosis and antiamyloid therapy assessment. Our group developed Pittsburgh Compound-B (PIB), an amyloid-binding radiotracer, for positron emission tomography (PET). The current study was aimed to further validate PIB PET through quantitative imaging (arterial input) and inclusion of subjects with mild cognitive impairment (MCI). Pittsburgh Compound-B studies were performed in five AD, five MCI, and five control subjects and five subjects were retested within 20 days. Magnetic resonance images were acquired for partial volume correction and region-of-interest definition (e.g., posterior cingulate: PCG; cerebellum: CER). Data were analyzed using compartmental and graphical approaches. Regional distribution volume (DV) values were normalized to the reference region (CER) to yield DV ratios (DVRs). Good agreement was observed between compartmental and Logan DVR values (e.g., PCG: r=0.89, slope=0.91); the Logan results were less variable. Nonspecific PIB retention was similar across subjects (n=15, Logan CER DV: 3.63+/-0.48). Greater retention was observed in AD cortical areas, relative to controls (P<0.05). The PIB retention in MCI subjects appeared either 'AD-like' or 'control-like'. The mean test/retest variation was approximately 6% in primary areas-of-interest. The Logan analysis was the method-of-choice for the PIB PET data as it proved stable, valid, and promising for future larger studies and voxel-based statistical analyses. This study also showed that it is feasible to perform quantitative PIB PET imaging studies that are needed to validate simpler methods for routine use across the AD disease spectrum.

Simplified quantification of Pittsburgh Compound B amyloid imaging PET studies: a comparative analysis.

UNLABELLED: PET studies have been performed using the amyloid binding radiotracer Pittsburgh Compound B (PIB). Previous quantitative analyses using arterial blood showed that the Logan graphical analysis using 90 min of emission data (ART90) provided a reliable measure of PIB retention. This work reports on simplified methods of analysis for human PIB imaging. METHODS: PIB PET scans were conducted in 24 subjects (6 Alzheimer's disease [AD], 10 mild cognitive impairment [MCI], 8 controls) with arterial blood sampling. Retest scans were performed on 8 subjects (3 AD, 1 MCI, 4 controls) within 28 d. Data were analyzed over 60 and 90 min using the Logan analysis and (a) metabolite-corrected input functions based on arterial plasma (ART60, ART90), (b) carotid artery time-activity data with a population average metabolite correction (CAR60, CAR90); and (c) cerebellar reference tissue (CER60, CER90). Data also were analyzed using the simplified reference tissue method (SRTM60, SRTM90) and a single-scan method based on late-scan ratios of standardized uptake values (SUVR60, SUVR90). RESULTS: All methods of analysis examined effectively discerned regional differences between AD and control subjects in amyloid-laden cortical regions, although the performance of the simplified methods varied in terms of bias, test-retest variability, intersubject variability, and effect size. CAR90 best agreed with ART90 distribution volume ratio (DVR) measures across brain regions and subject groups and demonstrated satisfactory test-retest variability (+/-7.1% across regions). CER90 and CER60 showed negative biases relative to ART90 in high-DVR subjects but had the lowest test-retest variability. The single-scan SUV-based methods showed the largest effect sizes for AD and control group differences and performed well in terms of intersubject and test-retest variability. CONCLUSION: Of the simplified methods for PIB analysis examined, CAR90 provided DVR measures that were most comparable to ART90; CER90 was the most reproducible and SUVR90 produced the largest effect size. All simplified methods were effective at distinguishing AD and control differences and may be effectively used in the analysis of PIB. SUVR60 data can be obtained with as little as 20 min of PET emission data collection. The relative strengths and limitations of each method must be considered for each experimental design.

Serotonin 1A receptor binding and treatment response in late-life depression.

Depression in late life carries an increased risk of dementia and brittle response to treatment. There is growing evidence to support a key role of the serotonin type 1A (5-HT(1A)) receptor as a regulator of treatment response, particularly the 5-HT(1A) autoreceptor in the dorsal raphe nucleus (DRN). We used [11C]WAY 100635 and positron emission tomography (PET) to test our hypothesis that 5-HT(1A) receptor binding in the DRN and prefrontal cortex is altered in elderly depressives and that these measures relate to treatment responsivity. We studied 17 elderly subjects with untreated (nonpsychotic, nonbipolar) major depression (four men, 13 women; mean age: 71.4+/-5.9) and 17 healthy control subjects (eight men, nine women; mean age: 70.0+/-6.7). Patients were subsequently treated with paroxetine as part of a clinical trial of maintenance therapies in geriatric depression. [11C]WAY 100635 PET imaging was acquired and binding potential (BP) values derived using compartmental modeling. We observed significantly diminished [11C]WAY 100635 binding in the DRN in depressed (BP = 2.31+/-0.90) relative to control (BP = 3.69+/-1.56) subjects (p = 0.0016). Further, the DRN BP was correlated with pretreatment Hamilton Depression Rating Scores (r = 0.60, p = 0.014) in the depressed cohort. A trend level correlation between DRN binding and time to remission (r = 0.52, p = 0.067) was observed in the 14 depressed patients for whom these data were available. Our finding of decreased [11C]WAY 100635 binding in the brainstem region of the DRN in elderly depressed patients supports evidence of altered 5-HT(1A) autoreceptor function in depression. Further, this work indicates that dysfunction in autoreceptor activity may play a central role in the mechanisms underlying treatment response to selective serotonin reuptake inhibitors in late-life depression.

Assessment of parameter settings for SPM5 spatial normalization of structural MRI data: application to type 2 diabetes.

Spatial normalization is the process of standardizing images of different subjects into the same anatomical space. The goal of this work was to assess standard and unified methods in SPM5 for the normalization of structural magnetic resonance imaging (MRI) data acquired in mid-life/elderly subjects with diabetes. In this work, we examined the impact of different parameters (i.e. nonlinear frequency cutoff, nonlinear regularization and nonlinear iterations) on the normalization, in terms of the residual variability. Total entropy was used to assess the residual anatomical variability after spatial normalization in a sample of 14 healthy mid-life/elderly control subjects and 24 mid-life/elderly subjects with type 2 diabetes. Spatial normalization was performed using default settings and by varying a single parameter or a combination of parameters. Descriptive statistics and nonparametric tests were used to examine differences in total entropy. Statistical parametric mapping analyses were performed to evaluate the influence of parameter settings on the spatial normalization. Total entropy results and SPM analyses suggest that the best parameters for the spatial normalization of mid-life/elderly image data to the MNI template, when applying the standard approach, correspond to the default cutoff (25 mm), heavy regularization, and the default number of nonlinear iterations (16). On the other hand, when applying the unified approach, the default parameters were the best for spatial normalization of mid-life/elderly image data to the MNI priors. These findings are relevant for studies of structural brain alterations that may occur in normal aging, chronic medical conditions, neuropsychiatric disorders, and neurodegenerative disorders.

Frequent amyloid deposition without significant cognitive impairment among the elderly.

OBJECTIVE: To characterize the prevalence of amyloid deposition in a clinically unimpaired elderly population, as assessed by Pittsburgh Compound B (PiB) positron emission tomography (PET) imaging, and its relationship to cognitive function, measured with a battery of neuropsychological tests. DESIGN: Subjects underwent cognitive testing and PiB PET imaging (15 mCi for 90 minutes with an ECAT HR+ scanner). Logan graphical analysis was applied to estimate regional PiB retention distribution volume, normalized to a cerebellar reference region volume, to yield distribution volume ratios (DVRs). SETTING: University medical center. PARTICIPANTS: From a community-based sample of volunteers, 43 participants aged 65 to 88 years who did not meet diagnostic criteria for Alzheimer disease or mild cognitive impairment were included. MAIN OUTCOME MEASURES: Regional PiB retention and cognitive test performance. RESULTS: Of 43 clinically unimpaired elderly persons imaged, 9 (21%) showed evidence of early amyloid deposition in at least 1 brain area using an objectively determined DVR cutoff. Demographic characteristics did not differ significantly between amyloid-positive and amyloid-negative participants, and neurocognitive performance was not significantly worse among amyloid-positive compared with amyloid-negative participants. CONCLUSIONS: Amyloid deposition can be identified among cognitively normal elderly persons during life, and the prevalence of asymptomatic amyloid deposition may be similar to that of symptomatic amyloid deposition. In this group of participants without clinically significant impairment, amyloid deposition was not associated with worse cognitive function, suggesting that an elderly person with a significant amyloid burden can remain cognitively normal. However, this finding is based on relatively small numbers and needs to be replicated in larger cohorts. Longitudinal follow-up of these subjects will be required to support the potential of PiB imaging to identify preclinical Alzheimer disease, or, alternatively, to show that amyloid deposition is not sufficient to cause Alzheimer disease within some specified period.

Evaluation of voxel-based methods for the statistical analysis of PIB PET amyloid imaging studies in Alzheimer's disease.

Deposition of amyloid plaques is believed to be a central event in the development of Alzheimer's disease (AD). The present study was undertaken to evaluate statistical methods for the assessment of group differences in retention of an amyloid imaging agent, PIB, throughout the brain and to compare these results to FDG studies of glucose metabolism performed in the same subjects on the same day. PET studies were performed in 10 mild to moderate AD and 11 control subjects. Parametric images of PIB retention (over 90 min post-injection) were generated using the Logan graphical analysis with cerebellar (CER, reference region) data as input. FDG parametric images were created by summing the uptake over 40-60 min post-injection and normalizing that to the CER to give a standardized uptake value ratio. Data were compared using parametric (SPM) and non-parametric (SnPM) statistical methods with familywise error (FWE) and false discovery rate (FDR) corrections. PIB results were consistent with previous regional results as AD subjects showed highly significant retention in frontal, parietal, temporal, and posterior cingulate cortices (FDR-corrected p<1.4e-10). FDG results showed regions of marginally significant decreases in uptake in AD subjects (frontal, parietal, temporal, posterior cingulate cortices: FDR-corrected p<0.1) consistent with previous studies. Relative to FDG, the PIB analyses were of greater statistical significance and larger spatial extent. Additionally, the PIB analyses retained significance after both FWE and FDR corrections. These results indicate that voxel-based methods will be useful for future larger longitudinal studies of amyloid deposition that could improve AD diagnosis and anti-amyloid therapy assessment.