Nicholas D. Tsopelas

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.

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 β-pleated sheet aggregates of the amyloid-β (Aβ) peptide in vitro. The in vivo retention of PiB in brains of people with Alzheimers disease shows a regional distribution that is very similar to distribution of Aβ 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 Aβ-containing plaques and tau-containing neurofibrillary tangles (NFT), has not been thoroughly investigated. The present study examined 28 clinically diagnosed and autopsy-confirmed Alzheimers disease subjects, including one Alzheimers 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 Aβ plaque load and peptide levels, [3H]PiB binding in vitro, and in vivo PET retention levels. We found that in Alzheimers disease brain tissue sections, the preponderance of 6-CN-PiB binding is in plaques immunoreactive to either Aβ42 or Aβ40, and to vascular Aβ 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 Aβ 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 Alzheimers disease brain tissue homogenates, there was a direct correlation between [3H]PiB binding and insoluble Aβ peptide levels. In the Alzheimers disease subject who underwent PiB-PET prior to death, in vivo PiB retention levels correlated directly with region-matched post-mortem measures of [3H]PiB binding, insoluble Aβ peptide levels, 6-CN-PiB- and Aβ plaque load, but not with measures of NFT. These results demonstrate, in a typical Alzheimers disease brain, that PiB binding is highly selective for insoluble (fibrillar) Aβ deposits, and not for neurofibrillary pathology. The strong direct correlation of in vivo PiB retention with region-matched quantitative analyses of Aβ plaques in the same subject supports the validity of PiB-PET imaging as a method for in vivo evaluation of Aβ 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-β protein is an initiating event in Alzheimers 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.

Diffusion Tensor Imaging Findings in First-Episode and Chronic Schizophrenia Patients

OBJECTIVE Comparisons of diffusion tensor imaging (DTI) data between first-episode and chronic schizophrenia patients assessed in different studies have led to the suggestion that the decreased fractional anisotropy observed in chronic schizophrenia patients is less pronounced in first-episode patients. However, such comparisons of imaging data generated across studies are susceptible to numerous confounders, which may limit the interpretation of any differences. In order to address these issues and determine whether the DTI abnormalities of chronic schizophrenia are present at illness onset, the authors conducted a DTI investigation of the largest cohort of first-episode schizophrenia patients yet reported in conjunction with a group of chronic schizophrenia patients and healthy subjects for comparison. METHOD Fractional anisotropy data generated by diffusion tensor imaging with a 3-T Siemens Allegra head-dedicated MRI system were compared between 40 first-episode schizophrenia patients and 39 age- and gender-matched healthy comparison subjects and between 40 chronic schizophrenia patients and 40 age- and gender-matched healthy comparison subjects. The following regions of interest were assessed: forceps minor (bilaterally), forceps major (bilaterally), inferior longitudinal fasciculus (bilaterally), and the genu and splenium of the corpus callosum. RESULTS In most regions, chronic schizophrenia patients showed significant or trend-level lower fractional anisotropy than healthy comparison subjects, whereas the first-episode schizophrenia patients showed only trend-level lower fractional anisotropy in the inferior longitudinal fasciculus. CONCLUSIONS The cross-sectional data reported here suggest less widespread changes in white matter at illness onset in schizophrenia which progress in more chronic states. More definitive conclusions will require follow-up imaging of first-episode schizophrenia patients.

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 β-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.

Brain metabolite abnormalities in the white matter of elderly schizophrenic subjects: implication for glial dysfunction

BACKGROUND Abnormalities in the white matter of the brain may occur in individuals with schizophrenia as well as with normal aging. Therefore, elderly schizophrenic patients may suffer further cognitive decline as they age. This study determined whether elderly schizophrenia participants, especially those with declined cognitive function (Clinical Dementia Rating score > 1), show white matter metabolite abnormalities on proton magnetic resonance spectroscopy and whether there are group differences in age-dependent changes in these brain metabolites. METHOD Twenty-three elderly schizophrenia and twenty-two comparison participants fulfilling study criteria were enrolled. Localized, short echo-time (1)H MRS at 4 Tesla was used to assess neurometabolite concentrations in several white matter regions. RESULTS Compared with healthy subjects, schizophrenia participants had lower N-acetyl compounds (-12.6%, p = .0008), lower myo-inositol (-16.4%, p = .026), and higher glutamate + glutamine (+28.7%, p = .0016) concentrations across brain regions. Schizophrenia participants with Clinical Dementia Rating >/= 1 showed the lowest NA in the frontal and temporal regions compared with control subjects. Interactions between age and schizophrenia status on total creatine and choline-containing compounds were observed; only schizophrenia participants showed age-related decreases of these metabolites in the right frontal region. CONCLUSIONS Decreased NA in these white matter brain regions likely reflects reduced neuronal content associated with decreased synapses and neuronal cell volumes. The elevated glutamate + glutamine, if reflecting elevated glutamate, could result from excess neuronal glutamate release or glial dysfunction in glutamate reuptake. The decreased myo-inositol in participants with schizophrenia suggests decreased glial content or dysfunctional glia, which might result from glutamate-mediated toxicity.

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 Alzheimers 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].

Pimozide Augmentation of Clozapine Inpatients with Schizophrenia and Schizoaffective Disorder Unresponsive to Clozapine Monotherapy

Despite its superior efficacy, clozapine is helpful in only a subset of patients with schizophrenia unresponsive to other antipsychotics. This lack of complete success has prompted the frequent use of various clozapine combination strategies despite a paucity of evidence from randomized controlled trials supporting their efficacy. Pimozide, a diphenylbutylpiperidine, possesses pharmacological and clinical properties distinct from other typical antipsychotics. An open-label trial of pimozide adjunctive treatment to clozapine provided promising pilot data in support of a larger controlled trial. Therefore, we conducted a double-blind, placebo-controlled, parallel-designed 12-week trial of pimozide adjunctive treatment added to ongoing optimal clozapine treatment in 53 patients with schizophrenia and schizoaffective disorder partially or completely unresponsive to clozapine monotherapy. An average dose of 6.48 mg/day of pimozide was found to be no better than placebo in combination with clozapine at reducing Positive and Negative Syndrome Scale total, positive, negative, and general psychopathology scores. There is no suggestion from this rigorously conducted trial to suggest that pimozide is an effective augmenting agent if an optimal clozapine trial is ineffective. However, given the lack of evidence to guide clinicians and patients when clozapine does not work well, more controlled trials of innovative strategies are warranted.

O3-06-08

quantified by distribution volume ratio (DVR). Results: Neocortical A deposition was present in 100% of AD subjects, 89% of DLB subjects, 43% of MCI subjects, 18% of elderly controls and no FTD subjects. PIB distribution was similar in AD and DLB, being greatest in medial frontal, precuneus, parietal and lateral temporal cortex, and caudate nuclei. Occipital, sensori-motor and mesial temporal cortex were less affected. Neocortical DVR measured 2.0 0.3 in AD, 1.6 0.3 in DLB, 1.5 0.4 in MCI, 1.2 0.2 in control and 1.1 0.1 in FTD subjects (p 0.01 for all differences). Five of the NC had cortical binding predominantly in frontal cortex with one progressing to MCI at 12-month follow-up. DVR correlated with MMSE and memory impairment across all subjects (r 0.7, p 0.0001) but not within groups (in AD group p 0.16), and with a shorter interval from onset of cognitive impairment to diagnosis in DLB (r 0.9, p 0.002). Conclusions: PIB PET will permit earlier diagnosis of AD and improve differential diagnosis of dementia. Longitudinal follow-up is required to determine the significance of the PIB binding in the normal elderly controls and MCI subjects. Our findings suggest that PIB PET will detect AD before demonstrable cognitive decline and therefore be a useful tool for early intervention trials.

P2-366: 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 Alzheimers 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.