Mean Cortical Binding Potential Research Articles

Neuroinflammation and amyloid deposition in the progression of mixed Alzheimer and vascular dementia

BackgroundAlzheimer’s disease (AD) and vascular contributions to cognitive impairment and dementia (VCID) pathologies coexist in patients with cognitive impairment. Abnormal amyloid beta (Aβ) deposition is the hallmark pathologic biomarker for AD. Neuroinflammation may be a pathophysiological mechanism in both AD and VCID. In this study, we aimed to understand the role of neuroinflammation and Aβ deposition in white matter hyperintensities (WMH) progression and cognitive decline over a decade in patients with mixed AD and VCID pathologies. MethodsTwenty-four elderly participants (median [interquartile range] age 78 [64.8, 83] years old, 14 female) were recruited from the Knight Alzheimer Disease Research Center. 11C-PK11195 standard uptake value ratio (SUVR) and 11C-PiB mean cortical binding potential (MCBP) were used to evaluate neuroinflammation and Aβ deposition in-vivo, respectively. Fluid-attenuated inversion recovery MR images were acquired to obtain baseline WMH volume and its progression over 11.5 years. Composite cognitive scores (global, processing speed and memory) were computed at baseline and follow-up over 7.5 years. Multiple linear regression models evaluated the association between PET biomarkers (11C-PK11195 SUVR and 11C-PiB MCBP) and baseline WMH volume and cognitive function. Moreover, linear mixed-effects models evaluated whether PET biomarkers predicted greater WMH progression or cognitive decline over a decade. ResultsFifteen participants (62.5%) had mixed AD (positive PiB) and VCID (at least one vascular risk factor) pathologies. Elevated 11C-PK11195 SUVR, but not 11C-PiB MCBP, was associated with greater baseline WMH volume and predicted greater WMH progression. Elevated 11C-PiB MCBP was associated with baseline memory and global cognition. Elevated 11C-PK11195 SUVR and elevated 11C-PiB MCBP independently predicted greater global cognition and processing speed declines. No association was found between 11C-PK11195 SUVR and 11C-PiB MCBP. ConclusionsNeuroinflammation and Aβ deposition may represent two distinct pathophysiological pathways, and both independently contributed to the progression of cognitive impairment in mixed AD and VCID pathologies. Neuroinflammation, but not Aβ deposition, contributed to WMH volume and progression.

Associations of Stages of Objective Memory Impairment with Cerebrospinal Fluid and Neuroimaging Biomarkers of Alzheimer's Disease.

To investigate cerebrospinal fluid (CSF) and neuroimaging correlates of Stages of Objective Memory Impairment (SOMI) based on Free and Cued Selective Reminding Test (FCSRT) performance, and to evaluate the effect of APOE ε4 status on this relationship. Data from 586 cognitively unimpaired individuals who had FCSRT, CSF, and volumetric magnetic resonance imaging (MRI) measures available was used. We compared CSF measures of β-amyloid (Aβ42/Aβ40 ratio), phosphorylated tau (p-Tau181), total tau (t-Tau), hippocampal volume, and PIB-PET mean cortical binding potential with partial volume correction (MCBP) among SOMI groups in the whole sample and in subsamples stratified by APOE ε4 status. Participants had a mean age of 67.4 (SD=9.1) years, had 16.1 (SD=2.6) years of education, 57.0% were female, and 33.8% were APOE ε4 positive. In the entire sample, there was no significant difference between SOMI stages in Aβ42/Aβ40 ratio, p-Tau181, t-Tau, or PIB-PET MCBP when adjusted for age, sex, and education. However, higher SOMI stages had smaller hippocampal volume (F=3.29, p=0.020). In the stratified sample based on APOE ε4 status, in APOE ε4 positive individuals, higher SOMI stages had higher p-Tau181 (F=2.94, p=0.034) higher t-Tau (F=3.41, p=0.019), and smaller hippocampal volume (F=5.78, p<0.001). There were no significant differences in CSF or imaging biomarkers between SOMI groups in the APOE ε4 negative subsample. Cognitively normal older individuals with higher SOMI stages have higher in-vivo tau and neurodegenerative pathology only in APOE ε4 carriers. These original results indicate the potential usefulness of the SOMI staging system in assessing of tau and neurodegenerative pathology.

Functional genomic analyses uncover APOE-mediated regulation\xa0of\xa0brain and cerebrospinal fluid beta-amyloid levels in Parkinson disease

Alpha-synuclein is the main protein component of Lewy bodies, the pathological hallmark of Parkinson’s disease. However, genetic modifiers of cerebrospinal fluid (CSF) alpha-synuclein levels remain unknown. The use of CSF levels of amyloid beta1–42, total tau, and phosphorylated tau181 as quantitative traits in genetic studies have provided novel insights into Alzheimer’s disease pathophysiology. A systematic study of the genomic architecture of CSF biomarkers in Parkinson’s disease has not yet been conducted. Here, genome-wide association studies of CSF biomarker levels in a cohort of individuals with Parkinson’s disease and controls (N = 1960) were performed. PD cases exhibited significantly lower CSF biomarker levels compared to controls. A SNP, proxy for APOE ε4, was associated with CSF amyloid beta1–42 levels (effect = − 0.5, p = 9.2 × 10−19). No genome-wide loci associated with CSF alpha-synuclein, total tau, or phosphorylated tau181 levels were identified in PD cohorts. Polygenic risk score constructed using the latest Parkinson’s disease risk meta-analysis were associated with Parkinson’s disease status (p = 0.035) and the genomic architecture of CSF amyloid beta1–42 (R2 = 2.29%; p = 2.5 × 10−11). Individuals with higher polygenic risk scores for PD risk presented with lower CSF amyloid beta1–42 levels (p = 7.3 × 10−04). Two-sample Mendelian Randomization revealed that CSF amyloid beta1–42 plays a role in Parkinson’s disease (p = 1.4 × 10−05) and age at onset (p = 7.6 × 10−06), an effect mainly mediated by variants in the APOE locus. In a subset of PD samples, the APOE ε4 allele was associated with significantly lower levels of CSF amyloid beta1–42 (p = 3.8 × 10−06), higher mean cortical binding potentials (p = 5.8 × 10−08), and higher Braak amyloid beta score (p = 4.4 × 10−04). Together these results from high-throughput and hypothesis-free approaches converge on a genetic link between Parkinson’s disease, CSF amyloid beta1–42, and APOE.

Amyloid Imaging, Cerebrospinal Fluid Biomarkers Predict Driving Performance Among Cognitively Normal Individuals.

Postmortem brain studies of older drivers killed in car accidents indicate that many had Alzheimer disease (AD) neuropathologic changes. We examined whether AD biomarkers are related to driving performance among cognitively normal older adults. Individuals with normal cognition, aged 65+ years, and driving at least once per week, were recruited. Participants (N=129) took part in clinical assessments, a driving test, and positron emission tomography imaging with Pittsburgh compound B (PIB) and/or cerebrospinal fluid (CSF) collection. General linear models tested whether the number of driving errors differed as a function of each of the biomarker variables (mean cortical binding potential for PIB, and CSF Aβ42, tau, ptau181, tau/Aβ42, ptau181/Aβ42). Higher ratios of CSF tau/Aβ42, ptau181/Aβ42, and PIB mean cortical binding potential, were associated with more driving errors (P<0.05). Preclinical AD may have subtle cognitive and functional effects, which alone may go unnoticed. However, when combined, these changes may impact complex behaviors such as driving.

Lower body mass index is associated with greater Alzheimer pathology in asymptomatic individuals

Pathophysiology (SNAP), a normal or an unclassified group (Table 1). Longitudinal progression to CDR>0 was modeled using survival analyses. Results: Controlling for appropriate covariates, correlations between CSF Ab 42 and the mean cortical PIB binding potential (MCBP) were significant (r1⁄4-.39, p<.0001), while the relationships between adjusted hippocampal volume and CSF (r1⁄4.04, p1⁄4.52) and ptau (r1⁄4.03, p1⁄4.62) were not (Figures 1 & 2). Individuals classified as Stage 2 and 3 were at an elevated risk of later dementia relative to those in Stage 0. (Figures 3-5). Conclusions:The NIA-AA preclinical stages successfully stratify dementia risk using both CSF and neuroimaging biomarkers. Measures of amyloid were highly congruent, while measures of neurodegeneration were often incongruent. This suggests that such markers cannot be used interchangeably to represent the same pathology.

Cognitive reserve and β-amyloid pathology in Parkinson disease.

Dementia in Parkinson disease (PD) is associated with abnormal accumulation of proteins, including β-amyloid, in cortical regions. High cognitive reserve capacity may protect cognition from β-amyloid and delay the onset of dementia. We tested the cognitive reserve theory in PD by determining whether educational attainment, a proxy for cognitive reserve, modifies the correlation between cortical β-amyloid accumulation and cognitive impairment. PD participants (N = 155) underwent MRI to quantify brain volume and [(11)C] PiB PET imaging to quantify fibrillar β-amyloid deposition. Mean cortical binding potentials (MCBP) were calculated for each participant, with higher scores indicating more fibrillar β-amyloid. Global cognitive function was assessed using the Clinical Dementia Rating (CDR) and Mini-Mental State Examination (MMSE). Multiple linear regression analysis was used to determine whether education modified the relationship between MCBP and cognitive function after controlling for brain volume. MCBP interacted with educational attainment to predict scores on each of the cognitive outcome measures (ps ≤ 0.02). Post-hoc analysis revealed that the effect of MCBP on cognitive function changed once the level of education reached 16 years. For participants with less than 16 years of education (n = 68), higher MCBP correlated with worse cognitive function, with MCBP accounting for 8-30% of the variance in MMSE and CDR scores (ps ≤ 0.02). For participants with at least 16 years of education (n = 87), MCBP did not correlate with MMSE or CDR scores (R(2)s < 0.02, ps ≥ 0.17). These findings provide support for the cognitive reserve theory in PD and suggest that education may protect PD patients' cognition against cortical β-amyloid pathology.

Correlation between decreased CSF α-synuclein and Aβ1–42 in Parkinson disease

Accumulation of misfolded α-synuclein (α-syn) protein in Lewy bodies and neurites is the cardinal pathologic feature of Parkinson disease (PD), but abnormal deposition of other proteins may also play a role. Cerebrospinal fluid (CSF) levels of proteins known to accumulate in PD may provide insight into disease-associated changes in protein metabolism and their relationship to disease progression. We measured CSF α-syn, amyloid β1–42 (Aβ1–42), and tau from 77 nondemented PD and 30 control participants. CSF α-syn and Aβ1–42 were significantly lower in PD compared with controls. In contrast with increased CSF tau in Alzheimer disease, CSF tau did not significantly differ between PD and controls. CSF protein levels did not significantly correlate with ratings of motor function or performance on neuropsychological testing. As expected, CSF Aβ1–42 inversely correlated with [11C]-Pittsburgh compound B (PiB) mean cortical binding potential, with PiB+ PD participants having lower CSF Aβ1–42 compared with PiB− PD participants. Furthermore, CSF α-syn positively correlated with Aβ1–42 in PD participants but not in controls, suggesting a pathophysiologic connection between the metabolisms of these proteins in PD.

Quantitative Analysis of PiB-PET with FreeSurfer ROIs

In vivo quantification of β-amyloid deposition using positron emission tomography is emerging as an important procedure for the early diagnosis of the Alzheimer's disease and is likely to play an important role in upcoming clinical trials of disease modifying agents. However, many groups use manually defined regions, which are non-standard across imaging centers. Analyses often are limited to a handful of regions because of the labor-intensive nature of manual region drawing. In this study, we developed an automatic image quantification protocol based on FreeSurfer, an automated whole brain segmentation tool, for quantitative analysis of amyloid images. Standard manual tracing and FreeSurfer-based analyses were performed in 77 participants including 67 cognitively normal individuals and 10 individuals with early Alzheimer's disease. The manual and FreeSurfer approaches yielded nearly identical estimates of amyloid burden (intraclass correlation = 0.98) as assessed by the mean cortical binding potential. An MRI test-retest study demonstrated excellent reliability of FreeSurfer based regional amyloid burden measurements. The FreeSurfer-based analysis also revealed that the majority of cerebral cortical regions accumulate amyloid in parallel, with slope of accumulation being the primary difference between regions.

Principal component analysis of PiB distribution in Parkinson and Alzheimer diseases

To use principal component analyses (PCA) of Pittsburgh compound B (PiB) PET imaging to determine whether the pattern of in vivo β-amyloid (Aβ) in Parkinson disease (PD) with cognitive impairment is similar to the pattern found in symptomatic Alzheimer disease (AD). PiB PET scans were obtained from participants with PD with cognitive impairment (n = 53), participants with symptomatic AD (n = 35), and age-matched controls (n = 67). All were assessed using the Clinical Dementia Rating and APOE genotype was determined in 137 participants. PCA was used to (1) determine the PiB binding pattern in AD, (2) determine a possible unique PD pattern, and (3) directly compare the PiB binding patterns in PD and AD groups. The first 2 principal components (PC1 and PC2) significantly separated the AD and control participants (p < 0.001). Participants with PD with cognitive impairment also were significantly different from participants with symptomatic AD on both components (p < 0.001). However, there was no difference between PD and controls on either component. Even those participants with PD with elevated mean cortical binding potentials were significantly different from participants with AD on both components. Using PCA, we demonstrated that participants with PD with cognitive impairment do not exhibit the same PiB binding pattern as participants with AD. These data suggest that Aβ deposition may play a different pathophysiologic role in the cognitive impairment of PD compared to that in AD.

Normative database of the serotonergic system in healthy subjects using multi-tracer PET

The highly diverse serotonergic system with at least 16 different receptor subtypes is implicated in the pathophysiology of most neuropsychiatric disorders including affective and anxiety disorders, obsessive compulsive disorder, post-traumatic stress disorder, eating disorders, sleep disturbance, attention deficit/hyperactivity disorder, drug addiction, suicidal behavior, schizophrenia, Alzheimer, etc. Alterations of the interplay between various pre- and postsynaptic receptor subtypes might be involved in the pathogenesis of these disorders. However, there is a lack of comprehensive in vivo values using standardized procedures. In the current PET study we quantified 3 receptor subtypes, including the major inhibitory (5-HT(1A) and 5-HT(1B)) and excitatory (5-HT(2A)) receptors, and the transporter (5-HTT) in the brain of healthy human subjects to provide a database of standard values. PET scans were performed on 95 healthy subjects (age=28.0 ± 6.9 years; 59% males) using the selective radioligands [carbonyl-(11)C]WAY-100635, [(11)C]P943, [(18)F]altanserin and [(11)C]DASB, respectively. A standard template in MNI stereotactic space served for region of interest delineation. This template follows two anatomical parcellation schemes: 1) Brodmann areas including 41 regions and 2) AAL (automated anatomical labeling) including 52 regions. Standard values (mean, SD, and range) for each receptor and region are presented. Mean cortical and subcortical binding potential (BP) values were in good agreement with previously published human in vivo and post-mortem data. By means of linear equations, PET binding potentials were translated to post-mortem binding (provided in pmol/g), yielding 5.89 pmol/g (5-HT(1A)), 23.5 pmol/g (5-HT(1B)), 31.44 pmol/g (5-HT(2A)), and 11.33 pmol/g (5-HTT) being equivalent to the BP of 1, respectively. Furthermore, we computed individual voxel-wise maps with BP values and generated average tracer-specific whole-brain binding maps. This knowledge might improve our interpretation of the alterations taking place in the serotonergic system during neuropsychiatric disorders.

P2‐257: Verbal fluency tests: Sensitivity to disease or drug effects not affected by simplifying scoring

imaging was conducted followingz 12 mCi of [11 C] PIB and 60 min dynamic PET scan in 3D mode (septa retracted). Mean cortical binding potential (MCBP) was determined as previously described. Results: Pearson correlation revealed the following correlations and trends between MCBP (for amyloid) and hippocampal subvolumes: left CA2-3 r 1⁄4 -0.29 (p 1⁄4 0.05); right CA2-3 r1⁄4 -0.25 (p1⁄4 0.09); left CA1 r1⁄4 -0.20 (p1⁄4 0.18); right CA1 r 1⁄4 -0.27 (p 1⁄4 0.07). No other regional volumes were correlated with MCBP. Conclusions: In this young healthy cognitively normal population there were trends towards the same pattern seen recently in an amnestic MCI population, with significantly smaller subfield volumes in CA 2-3 and subiculum compared with controls. In our study group only 8/46 participants had elevated MCBP (> 0.18 BP). We will extend our sample to a larger and older population, which can be expected to have higher numbers of participants with elevated amyloid.

IC‐O1‐03: Amyloid burden and neuropsychological performance in presymptomatic first‐degree relatives at varying APOE‐ɛ4 risk for Alzheimer's disease

has found volume loss at the CA1-CA2 boundary. With the recent development and validation of hippocampus subfield segmentation it is now possible to reliably analyze changes across populations and correlations with other biomarkers. Increased cortical amyloid binding is among the earliest changes in preclinical AD, preceding overall hippocampal atrophy. In this investigation we sought to determine whether hippocampal CA1 and CA2 subfield volume loss correlated with mean amyloid cortical binding potential (MCBP). Methods: Cognitively normal participants (n 1⁄4 46; 34 females (74%) were assessed with the clinical dementia rating (CDR) scale 1⁄4 0 at the Washington University ADRC. Mean and (SD) for age and education were 63.8 (7.6) and 16.1 (2.6) respectively. MRI was perfomed on a 3T Siemens Trio system with 12-channel head coil; voxel size 1⁄4 1x1x1 mm obtained sagitally; Hippocampal subfield segmentation used Freesurfer pipeline (Martinos Center http://surfer.nmr.mgh.harvard.edu/) yielding 7 segments for both left and right hippocampus: CA1, CA2-3, CA4-DG, subiculum, presubiculum, fimbria and hippocampal fissure. Amyloid-b PET imaging was conducted following z 12 mCi of [11C] PIB and 60 min dynamic PET scan in 3D mode (septa retracted). Mean cortical binding potential (MCBP) was determined as previously described. Results: Pearson correlation revealed the following correlations and trends between MCBP (for amyloid) and hippocampal subvolumes: left CA2-3 r 1⁄4 -0.29 (P 1⁄4 0.05); right CA2-3 r1⁄4 -0.25 (P1⁄4 0.09); left CA1 r1⁄4 -0.20 (P1⁄4 0.18); right CA1 r 1⁄4 -0.27 (P 1⁄4 0.07). No other regional volumes were correlated with MCBP. Conclusions: In this young healthy cognitively normal population there were trends towards the same pattern seen recently in an amnestic MCI population, with significantly smaller subfield volumes in CA 2-3 and subiculum compared with controls. In our study group only 8/46 participants had elevated MCBP (> 0.18 BP). We will extend our sample to a larger and older population, which can be expected to have higher numbers of participants with elevated amyloid.

Amyloid‐beta plaque growth in cognitively normal adults: Longitudinal [11C]Pittsburgh compound B data

Amyloid-beta (Aβ) accumulation was evaluated with 2 [(11)C]Pittsburgh compound B (PiB) positron emission tomography scans about 2.5 years apart in 146 cognitively normal adults. Seventeen of 21 participants with initially elevated Aβ deposition demonstrated subsequent Aβ plaque growth (approximately 8.0% per year), and none reverted to a state of no Aβ deposits. Ten individuals converted from negative to positive PiB status, based on a threshold of the mean cortical binding potential, representing a conversion rate of 3.1% per year. Individuals with an ε4 allele of apolipoprotein E demonstrated increased incidence of conversion (7.0% per year). Our findings suggest that the major growth in Aβ burden occurs during a preclinical stage of Alzheimer disease (AD), prior to the onset of AD-related symptoms.

Potential effects of the APOE ε2 allele and of family history of Alzheimer's disease on brain amyloid-β in normal elderly

Cirrito et al. (1) provided compelling data from investigations in PS1/APP double-transgenic mice that acute and chronic pharmacological manipulations of serotonin signaling were associated with significant reductions in brain interstitial fluid amyloid-β (Aβ) levels and plaque load, respectively. More importantly, they also reported that cognitively intact elderly individuals with a retrospectively obtained history of antidepressant treatment with serotonin reuptake inhibitor (SSRI) drugs, within the past 5 y, showed less brain amyloid load as quantified by PET-Pittsburgh Compound B (PIB) than controls without such a history. In addition, longer duration of SSRI treatment was associated with lower Aβ levels. The authors controlled for a number of factors that are known to influence brain amyloid independently of SSRIs, including the APOE e4 allele. However, they did not comment on potential group differences either in the frequency of the APOE e2 allele, for which this group previously provided some evidence that it might be protective against age-related increases in mean cortical binding potential for PIB (2), or in family history of Alzheimer's disease, which has been reported (3) to associate with increased brain amyloid deposits, as measured by PIB in cognitively normal individuals.

Role of Family History for Alzheimer Biomarker Abnormalities in the Adult Children Study

To assess whether family history (FH) of Alzheimer disease (AD) alone influences AD biomarker abnormalities. Adult Children Study. Washington University's Charles F. and Joanne Knight Alzheimer's Disease Research Center. A total of 269 cognitively normal middle- to older-aged individuals with and without an FH for AD. Clinical and cognitive measures, magnetic resonance imaging-based brain volumes, diffusion tensor imaging-based white matter microstructure, cerebrospinal fluid biomarkers, and molecular imaging of cerebral fibrillar amyloid with positron emission tomography using the [(11)C] benzothiazole tracer, Pittsburgh compound B. A positive FH for AD was associated with an age-related decrease of cerebrospinal fluid Aβ42; the ε4 allele of apolipoprotein E (APOE4) did not alter this effect. Age-adjusted cerebrospinal fluid Aβ42 was decreased for individuals with APOE4 compared with the level for those without, and the decrease was larger for individuals with a positive FH compared with the decrease for those without. The variation of cerebrospinal fluid tau and Pittsburgh compound B mean cortical binding potential increased by age. For individuals younger than 55, an age-related increase in mean cortical binding potential was associated with APOE4 but not FH. For individuals older than 55, a positive FH and a positive APOE4 implied the fastest age-related increase in mean cortical binding potential. A positive FH was associated with decreased fractional anisotropy from diffusion tensor imaging in the genu and splenium of the corpus callosum. Independent of APOE4, FH is associated with age-related change of several cerebrospinal fluid, Pittsburgh compound B, and diffusion tensor imaging biomarkers in cognitively normal middle- to older-aged individuals, suggesting that non- APOE susceptibility genes for AD influence AD biomarkers.

Longitudinal changes in fibrillar amyloid-beta deposition across the cognitive spectrum: Effect of the APOE4 allele

Background: The concept of preclinical Alzheimer’s disease (AD) implies that beta-amyloid (As) deposits may accumulate in the brain for a decade or more prior to the clinical manifestations of AD. The highest initial As deposition is observed in the precuneus. APOE e4 genotype is the major genetic susceptibility factor for AD associated with increased As deposition. In this longitudinal [C] PIB PET study, we compared regional rates of As accumulation in a large cohort of cognitively normal APOE e4 carriers (e4+) and non-carriers (e4-). Methods: One hundred forty six cognitively normal individuals (96 e4and 50 e4+ individuals; mean age 66 6 10 yo) underwent two [C] PIB scans, separated by 2.6 6 1.1 years. Regional binding potential (BP) values were estimated in manually derived MRI-based regions including precuneus, prefrontal, temporal, gyrus rectus, anterior cingulate, and occipital cortex and caudate nucleus. Mean cortical BP (MCBP) was calculated from the first four regions and used as a globalmeasure of brain As deposition (with 0.18 as a threshold level for abnormality). The rate of As accumulation was estimated from the annual change in BP.Results: In 115 of 146 individuals (85 e4and 30 e4+), As accumulation was low on both [C] PIB scans (Low-PIB), while 31 individuals (11 e4and 20 e4+) had elevated As accumulation on the second or both [C] PIB scans (High-PIB). The rate of As accumulation in the precuneus was significantly higher in the group of 50 e4+ individuals compared to 96 e4individuals (0.024 + 0.040 BP/year for e4+ and 0.011 + 0.036 BP/ year for e4-, p 1⁄4 0.044, two-tailed unpaired t-test). It also was higher in High-PIB (0.054 + 0.039 BP/year for e4+ and 0.016 + 0.028 BP/year for e4-, p 1⁄4 0.008, two-tailed unpaired t-test), but not in Low-PIB individuals. The other brain regions evaluated did not demonstrate significant changes in the rate of As accumulation between e4+ and e4individuals.Conclusions: In cognitively normal APOE e4 carriers the rate of As accumulation is significantly increased in the precuneus, indicating greater vulnerability of this cortical region at the early stage of AD pathology.

Amyloid imaging of Lewy body‐associated disorders

Clinicopathologic studies of Parkinson disease dementia (PDD) and dementia with Lewy bodies (DLB) commonly reveal abnormal β-amyloid deposition in addition to diffuse Lewy bodies (α-synuclein aggregates), but the relationship among these neuropathologic features and the development of dementia in these disorders remains uncertain. The purpose of this study was to determine whether amyloid-β deposition detected by PET imaging with Pittsburgh Compound B (PIB) distinguishes clinical subtypes of Lewy body-associated disorders. Nine healthy controls, 8 PD with no cognitive impairment, 9 PD with mild cognitive impairment, 6 DLB, and 15 PDD patients underwent [(11)C]-PIB positron emission tomography imaging, clinical examination, and cognitive testing. The binding potential (BP) of PIB for predefined regions and the mean cortical BP (MCBP) were calculated for each participant. Annual longitudinal follow-up and postmortem examinations were performed on a subset of participants. Regional PIB BPs and the proportion of individuals with abnormally elevated MCBP were not significantly different across participant groups. Elevated PIB binding was associated with worse global cognitive impairment in participants with Lewy body disorders but was not associated with any other clinical or neuropsychological features, including earlier onset or faster rate of progression of cognitive impairment. These results suggest that the presence of fibrillar amyloid-β does not distinguish between clinical subtypes of Lewy body-associated disorders, although larger numbers are needed to more definitively rule out this association. Amyloid-β may modify the severity of global cognitive impairment in individuals with Lewy body-associated dementia.

Alzheimer disease identification using amyloid imaging and reserve variables

Several factors may influence the relationship between Alzheimer disease (AD) lesions and the expression of dementia, including those related to brain and cognitive reserve. Other factors may confound the association between AD pathology and dementia. We tested whether factors thought to influence the association of AD pathology and dementia help to accurately identify dementia of the Alzheimer type (DAT) when considered together with amyloid imaging. Participants with normal cognition (n = 180) and with DAT (n = 25), aged 50 years or older, took part in clinical, neurologic, and psychometric assessments. PET with the Pittsburgh compound B (PiB) tracer was used to measure brain amyloid, yielding a mean cortical binding potential (MCBP) reflecting PiB uptake. Logistic regression was used to generate receiver operating characteristic curves, and the areas under those curves (AUC), to compare the predictive accuracy of using MCBP alone vs MCBP together with other variables selected using a stepwise selection procedure to identify participants with DAT vs normal cognition. The AUC resulting from MCBP alone was 0.84 (95% confidence interval [CI] = 0.73-0.94; cross-validated AUC = 0.80, 95% CI = 0.68-0.92). The AUC for the predictive equation generated by a stepwise model including education, normalized whole brain volume, physical health rating, gender, and use of medications that may interfere with cognition was 0.94 (95% CI = 0.90-0.98; cross-validated AUC = 0.91, 95% CI = 0.85-0.96), an improvement (p = 0.025) over that yielded using MCBP alone. Results suggest that factors reported to influence associations between AD pathology and dementia can improve the predictive accuracy of amyloid imaging for the identification of symptomatic AD.

Cognitively unimpaired HIV-positive subjects do not have increased 11 C-PiB

Diagnostic challenges exist for differentiating HIV dementia from Alzheimer disease (AD) in older HIV-infected (HIV+) individuals. Similar abnormalities in brain amyloid-beta42 (Alphabeta42) metabolism may be involved in HIV-associated neuropathology and AD. We evaluated the amyloid-binding agent (11)C-Pittsburgh compound B ((11)C-PiB), a biomarker for Alphabeta42 deposition, in cognitively unimpaired HIV+ (n = 10) participants and matched community controls without dementia (n = 20). In this case-control study, all participants had an (11)C-PiB scan within 2 years of concomitant CSF studies and neuropsychometric testing. Statistical differences between HIV+ and community controls for demographic and clinical values were assessed by chi(2) tests. Participants were further divided into either low (<500 pg/mL) or normal (>or=500 pg/mL) CSF Alphabeta42 groups with Student t tests performed to determine if regional differences in fibrillar amyloid plaque deposition varied with CSF Alphabeta42. Regardless of CSF Alphabeta42 level, none of the HIV+ participants had fibrillar amyloid plaques as assessed by increased (11)C-PiB mean cortical binding potential (MCBP) or binding potential within 4 cortical regions. In contrast, some community controls with low CSF Alphabeta42 (<500 pg/mL) had high (11)C-PiB MCBP with elevated binding potentials (>0.18 arbitrary units) within cortical regions. Cognitively unimpaired HIV+ participants, even with low CSF Alphabeta42 (<500 pg/mL), do not have (11)C-PiB parameters suggesting brain fibrillar amyloid deposition. The dissimilarity between unimpaired HIV+ and preclinical AD may reflect differences in Abeta42 production and/or formation of diffuse plaques. Future longitudinal studies of HIV+ participants with low CSF Abeta42 and normal (11)C-PiB are required.

APOE predicts amyloid‐beta but not tau Alzheimer pathology in cognitively normal aging

To examine interactions of apolipoprotein E (APOE) genotype with age and with in vivo measures of preclinical Alzheimer disease (AD) in cognitively normal aging. Two hundred forty-one cognitively normal individuals, aged 45-88 years, had cerebral amyloid imaging studies with Pittsburgh Compound-B (PIB). Of the 241 individuals, 168 (70%) also had cerebrospinal fluid (CSF) assays of amyloid-beta(42) (Abeta(42)), tau, and phosphorylated tau (ptau(181)). All individuals were genotyped for APOE. The frequency of individuals with elevated mean cortical binding potential (MCBP) for PIB rose in an age-dependent manner from 0% at ages 45-49 years to 30.3% at 80-88 years. Reduced levels of CSF Abeta(42) appeared to begin earlier (18.2% of those aged 45-49 years) and increase with age in higher frequencies (50% at age 80-88 years) than elevations of MCBP. There was a gene dose effect for the APOE4 genotype, with greater MCBP increases and greater reductions in CSF Abeta(42) with increased numbers of APOE4 alleles. Individuals with an APOE2 allele had no increase in MCBP with age and had higher CSF Abeta(42) levels than individuals without an APOE2 allele. There was no APOE4 or APOE2 effect on CSF tau or ptau(181). Increasing cerebral Abeta deposition with age is the pathobiological phenotype of APOE4. The biomarker sequence that detects Abeta deposition may first be lowered CSF Abeta(42), followed by elevated MCBP for PIB. A substantial proportion of cognitively normal individuals have presumptive preclinical AD.