Aren Okello

C-11-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer's disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study

BACKGROUND Carbon-11-labelled Pittsburgh compound B ((11)C-PiB) PET is a marker of cortical fibrillar amyloid-beta load in vivo. We used (11)C-PiB PET to investigate whether bapineuzumab, a humanised anti-amyloid-beta monoclonal antibody, would reduce cortical fibrillar amyloid-beta load in patients with Alzheimers disease. METHODS Patients with mild-to-moderate Alzheimers disease were randomly assigned to receive intravenous bapineuzumab or placebo in a ratio of seven to three in three ascending dose groups (0.5, 1.0, or 2.0 mg/kg). Each dose group was enrolled after safety review of the previous group. Randomisation was by interactive voice response system; masking was achieved with numbered kit allocation. Patients, investigators, study site personnel, sponsor staff, and carers were masked to treatment. Patients received up to six infusions, 13 weeks apart, and had (11)C-PiB PET scans at baseline and at weeks 20, 45, and 78. The primary outcome was the difference between the pooled bapineuzumab group and the pooled placebo group in mean change from screening to week 78 in (11)C-PiB cortical to cerebellar retention ratio averaged across six cortical regions of interest. Analysis was by modified intention to treat. This study is registered with EudraCT, number 2004-004120-12; ISRCTN17517446. FINDINGS 28 patients were assigned to bapineuzumab (n=20) or placebo (n=8). 19 patients in the bapineuzumab group and seven in the placebo group were included in the modified intention-to-treat analysis. Estimated mean (11)C-PiB retention ratio change from baseline to week 78 was -0.09 (95% CI -0.16 to -0.02; p=0.014) in the bapineuzumab group and 0.15 (95% CI 0.02 to 0.28; p=0.022) in the placebo group. Estimated mean difference in (11)C-PiB retention ratio change from baseline to week 78 between the bapineuzumab group and the placebo group was -0.24 (95% CI -0.39 to -0.09; p=0.003). Differences between the bapineuzumab group and the placebo group in the individual regions of interest were similar to the overall mean difference. Adverse events were typically mild to moderate in severity and transient. Two patients in the 2.0 mg/kg bapineuzumab group had transient cerebral vasogenic oedema. INTERPRETATION Treatment with bapineuzumab for 78 weeks reduced cortical (11)C-PiB retention compared with both baseline and placebo. (11)C-PiB PET seems to be useful in assessing the effects of potential Alzheimers disease treatments on cortical fibrillar amyloid-beta load in vivo. FUNDING Elan Pharmaceuticals and Wyeth Research.

Conversion of amyloid positive and negative MCI to AD over 3 years An 11C-PIB PET study

Background: Patients with amnestic mild cognitive impairment (MCI) represent an important clinical group as they are at increased risk of developing Alzheimer disease (AD). 11C-PIB PET is an in vivo marker of brain amyloid load. Objective: To assess the rates of conversion of MCI to AD during a 3-year follow-up period and to compare levels of amyloid deposition between MCI converters and nonconverters. Methods: Thirty-one subjects with MCI with baseline 11C-PIB PET, MRI, and neuropsychometry have been clinically followed up for 1 to 3 years (2.68 ± 0.6 years). Raised cortical 11C-PIB binding in subjects with MCI was detected with region of interest analysis and statistical parametric mapping. Results: Seventeen of 31 (55%) subjects with MCI had increased 11C-PIB retention at baseline and 14 of these 17 (82%) clinically converted to AD during follow-up. Only one of the 14 PIB-negative MCI cases converted to AD. Of the PIB-positive subjects with MCI, half (47%) converted to AD within 1 year of baseline PIB PET, these faster converters having higher tracer-retention values than slower converters in the anterior cingulate (p = 0.027) and frontal cortex (p = 0.031). Seven of 17 (41%) subjects with MCI with known APOE status were ε4 allele carriers, this genotype being associated with faster conversion rates in PIB-positive subjects with MCI (p = 0.035). Conclusions: PIB-positive subjects with mild cognitive impairment (MCI) are significantly more likely to convert to AD than PIB-negative patients, faster converters having higher PIB retention levels at baseline than slower converters. In vivo detection of amyloid deposition in MCI with PIB PET provides useful prognostic information.

Microglial activation and amyloid deposition in mild cognitive impairment: a PET study.

Background: Activated microglia may play a role in the pathogenesis of Alzheimer disease (AD) as they cluster around beta-amyloid (Aβ) plaques. They are, therefore, a potential therapeutic target in both AD and its prodrome amnestic mild cognitive impairment (MCI). Objective: To characterize in vivo with 11C-(R)-PK11195 and 11C-PIB PET the distribution of microglial activation and amyloid deposition in patients with amnestic MCI. Methods: Fourteen subjects with MCI had 11C-(R)-PK11195 and 11C-PIB PET with psychometric tests. Results: Seven out of 14 (50%) patients with MCI had increased cortical 11C-PIB retention (p < 0.001) while 5 out of 13 (38%) subjects with MCI showed increased 11C-(R)-PK11195 uptake. The MCI subgroup with increased 11C-PIB retention also showed increased cortical 11C-(R)-PK11195 binding (p < 0.036) though this increase only remained significant in frontal cortex after a correction for multiple comparisons. There was no correlation between regional levels of 11C-(R)-PK11195 and 11C-PIB binding in individual patients with MCI: only three of the five MCI cases with increased 11C-(R)-PK11195 binding had increased levels of 11C-PIB retention. Conclusions: Our findings indicate that, while amyloid deposition and microglial activation can be detected in vivo in around 50% of patients with mild cognitive impairment (MCI), these pathologies can occur independently. The detection of microglial activation in patients with MCI suggests that anti-inflammatory therapies may be relevant to the prevention of AD.

Carbon-11-Pittsburgh compound B positron emission tomography imaging of amyloid deposition in presenilin 1 mutation carriers

(11)Carbon-Pittsburgh compound B positron emission tomography studies have suggested early and prominent amyloid deposition in the striatum in presenilin 1 mutation carriers. This cross-sectional study examines the (11)Carbon-Pittsburgh compound B positron emission tomography imaging profiles of presymptomatic and mildly affected (mini-mental state examination ≥ 20) carriers of seven presenilin 1 mutations, comparing them with groups of controls and symptomatic sporadic Alzheimers disease cases. Parametric ratio images representing (11)Carbon-Pittsburgh compound B retention from 60 to 90 min were created using the pons as a reference region and nine regions of interest were studied. We confirmed that increased amyloid load may be detected in presymptomatic presenilin 1 mutation carriers with (11)Carbon-Pittsburgh compound B positron emission tomography and that the pattern of retention is heterogeneous. Comparison of presenilin 1 and sporadic Alzheimers disease groups revealed significantly greater thalamic retention in the presenilin 1 group and significantly greater frontotemporal retention in the sporadic Alzheimers disease group. A few individuals with presenilin 1 mutations showed increased cerebellar (11)Carbon-Pittsburgh compound B retention suggesting that this region may not be as suitable a reference region in familial Alzheimers disease.

An early and late peak in microglial activation in Alzheimer's disease trajectory

Amyloid-β deposition, neuroinflammation and tau tangle formation all play a significant role in Alzheimers disease. We hypothesized that there is microglial activation early on in Alzheimers disease trajectory, where in the initial phase, microglia may be trying to repair the damage, while later on in the disease these microglia could be ineffective and produce proinflammatory cytokines leading to progressive neuronal damage. In this longitudinal study, we have evaluated the temporal profile of microglial activation and its relationship between fibrillar amyloid load at baseline and follow-up in subjects with mild cognitive impairment, and this was compared with subjects with Alzheimers disease. Thirty subjects (eight mild cognitive impairment, eight Alzheimers disease and 14 controls) aged between 54 and 77 years underwent 11C-(R)PK11195, 11C-PIB positron emission tomography and magnetic resonance imaging scans. Patients were followed-up after 14 ± 4 months. Region of interest and Statistical Parametric Mapping analysis were used to determine longitudinal alterations. Single subject analysis was performed to evaluate the individualized pathological changes over time. Correlations between levels of microglial activation and amyloid deposition at a voxel level were assessed using Biological Parametric Mapping. We demonstrated that both baseline and follow-up microglial activation in the mild cognitive impairment cohort compared to controls were increased by 41% and 21%, respectively. There was a longitudinal reduction of 18% in microglial activation in mild cognitive impairment cohort over 14 months, which was associated with a mild elevation in fibrillar amyloid load. Cortical clusters of microglial activation and amyloid deposition spatially overlapped in the subjects with mild cognitive impairment. Baseline microglial activation was increased by 36% in Alzheimers disease subjects compared with controls. Longitudinally, Alzheimers disease subjects showed an increase in microglial activation. In conclusion, this is one of the first longitudinal positron emission tomography studies evaluating longitudinal changes in microglial activation in mild cognitive impairment and Alzheimers disease subjects. We found there is an initial longitudinal reduction in microglial activation in subjects with mild cognitive impairment, while subjects with Alzheimers disease showed an increase in microglial activation. This could reflect that activated microglia in mild cognitive impairment initially may adopt a protective activation phenotype, which later change to a cidal pro-inflammatory phenotype as disease progresses and amyloid clearance fails. Thus, we speculate that there might be two peaks of microglial activation in the Alzheimers disease trajectory; an early protective peak and a later pro-inflammatory peak. If so, anti-microglial agents targeting the pro-inflammatory phenotype would be most beneficial in the later stages of the disease.

Longitudinal influence of microglial activation and amyloid on neuronal function in Alzheimer’s disease

Amyloid deposition, tangle formation, neuroinflammation and neuronal dysfunction are pathological processes involved in Alzheimers disease. However, the relative role of these processes in driving disease progression is still unclear. The aim of this positron emission tomography study was to: (i) investigate longitudinal changes of microglial activation, amyloid and glucose metabolism; and (ii) assess the temporospatial relationship between these three processes in Alzheimers disease. A group of eight patients with a diagnosis of Alzheimers disease (66 ± 4.8 years) and 14 healthy controls (65 ± 5.5 years) underwent T1 and T2 magnetic resonance imaging, along with (11)C-(R)-PK11195, (11)C-Pittsburgh compound B and (18)F-fluorodeoxyglucose positron emission tomography scans for microglial activation, amyloid deposition and glucose metabolism. All patients were followed-up with repeated magnetic resonance imaging and three positron emission tomography scans after 16 months. Parametric maps were interrogated using region of interest analysis, Statistical Parametric Mapping, and between-group correlation analysis at voxel-level using Biological Parametric Mapping. At baseline, patients with Alzheimers disease showed significantly increased microglial activation compared to the control subjects. During follow-up, for the first time, we found that while there is a progressive reduction of glucose metabolism, there was a longitudinal increase of microglial activation in the majority of the patients with Alzheimers disease. Voxel-wise correlation analysis revealed that microglial activation in patients with Alzheimers disease was positively correlated with amyloid deposition and inversely correlated with regional cerebral metabolic rate at voxel level over time. Even though one of the limitations of this study is the lack of longitudinal follow-up of healthy control subjects, this study demonstrates that there is persistent neuroinflammation throughout the Alzheimers disease process with associated synaptic dysfunction and reduced glucose metabolism. Voxel-wise correlation analysis suggests that neuroinflammation is associated with localized amyloid deposition and glucose metabolism over time, however, the level of inflammation could also occur independently of amyloid pathology, especially in the later stages of Alzheimers disease.

11C-PIB PET in subjective cognitive impairment

People with Subjective Cognitive Impairment (SCI) may be at increased risk of dementia. In this study we examined amyloid load in 5 SCI subjects and 14 controls using PIB PET scanning. One SCI subject had significantly increased PIB retention in the cortical areas of interest. Larger, longitudinal studies are indicated.

PET Amyloid imaging and cognition in patients with Alzheimer's disease, Mild Cognitive Impairment (MCI) and healthy controls: a European multicenter study

were further classified according to the presence or absence of an ApoE4 allele and by their subjective memory complaints (MC). All participants underwent a comprehensive neuropsychological examination, a MRI and a PiB-PET scan. Correlational analyses were performed between the different study outcomes. Results: Cortical PIB binding was markedly elevated in all AD patients except one. MCI subjects presented either an ‘‘AD-like’’ (63%) or normal pattern. Cortical PiB retention was abnormal in 34% of HC and its prevalence increased with age. HC with subjective memory complaints carrying an ApoE4 allele had significantly higher Ab burdens than non ApoE4 carriers. Conclusions: Phase I of the AIBL study has established the foundations for the longitudinal assessment of Ab burden in HC, MCI and AD. This will assist the development of techniques for early detection of AD while providing a cohort suitable for targeted early intervention studies.

Early subcortical amyloid deposition in familial Alzheimer's disease is accompanied by changes in tissue volume and diffusivity

Introduction The primary progressive aphasias (PPA) are a group of neurodegenerative language-led dementias. Three major subtypes are recognised: progressive nonfluent aphasia (PNFA) characterised by speech apraxia and agrammatism; semantic dementia (SemD), characterised by loss of vocabulary due to primary semantic memory impairment; and logopenic aphasia (LPA), characterised by word-finding pauses, anomia, and impaired phonological memory. Other subtypes have been proposed including aphasia associated with progranulin mutations (GAA). Whereas considerable progress has been made in defining profiles of cortical atrophy in PPA, information about white matter tracts connecting cortical areas remains limited. Here we addressed this issue using diffusion tensor tractography in a cohort of patients with PPA. Methods 20 consecutive patients with a clinical diagnosis of PPA (7 SemD, 6 PNFA, 5 LPA, 2 GAA) and 12 age-matched healthy controls underwent volumetric brain MRI with diffusion tensor imaging (DTI). White matter tract changes in each group and intergroup differences were assessed using Tract Based Spatial Statistics (http://www.fmrib.ox.ac.uk/fsl/tbss). Results PPA syndromic groups showed well-defined fractional anisotropy, axial and radial diffusivity changes tracking white matter pathways implicated in language processing. Compared with healthy individuals, all PPA groups showed changes in the anterior superior longitudinal fasciculus (SLF), and additional tracts were involved in particular subgroups (in SemD, inferior longitudinal fasciculus (ILF), uncinate fasciculus (UF), and commissural pathways; in PNFA, more posterior SLF; in LPA and GAA, ILF). Intergroup comparisons showed significantly greater involvement of ILF and UF in SD than in PNFA or GAA; and greater involvement of left ILF in GAA than PNFA. Tract alterations were restricted to the left hemisphere in GAA but bi-hemispheric in other syndromes. Discussion PPA syndromes are associated with distinctive profiles of altered white matter tract integrity and these tract changes provide substrates for the dysfunction of specific language networks in PPA.

S25-05 Subjective cognitive impairment: Functional MRI during divided attention and measurement of amyloid load using 11C-PIB PET

Background Evidence suggests that healthy older adults with subjective memory complaints are at increased risk of dementia. Subjective Cognitive Impairment (SCI) may precede Mild Cognitive Impairment (MCI) in the clinical continuum of Alzheimers disease (AD). Attentional deficits may be present early in AD, and associated functional changes have been reported in both MCI and AD. In the present study, activation during divided attention in SCI subjects was investigated using functional magnetic resonance imaging (fMRI). Additionally, amyloid uptake was investigated using 11 C-PIB with positron emission tomography (PET). Methods Brain activation in 11 SCI subjects and 10 controls was compared during a divided attention task using fMRI. Additionally, five SCI subjects and 14 cognitively normal healthy controls underwent 11 C-PIB PET scanning. Criteria for diagnosis of SCI were: 1. self-reported memory complaints, 2. objectively normal cognition on detailed neurocognitive testing, 3. absence of psychiatric or causative physical illness, 4. normal activities of daily living and 5. absence of MCI or dementia. Results There were no differences in performance between SCI and control groups in terms of cognitive or behavioural measures. However, SCIs had increased activation in left medial temporal lobe, and bilateral thalamus, posterior cingulate and caudate. One SCI subject and one control subject had a pattern of 11 C-PIB uptake similar to that seen in AD. Conclusions The activation changes identified in SCI may relate to compensatory increased activation in the face of early AD pathology. Larger, longitudinal studies are needed to determine the extent and significance of PIB uptake in SCI.