Hilary Archer

Amyloid, hypometabolism, and cognition in Alzheimer disease: An [11C]PIB and [18F]FDG PET study

Objective: To investigate the association between brain amyloid load in Alzheimer disease (AD) measured by [11C]PIB-PET, regional cerebral glucose metabolism (rCMRGlc) measured by [18F]FDG-PET, and cognition. Methods: Nineteen subjects with AD and 14 controls had [11C]PIB-PET and underwent a battery of psychometric tests. Twelve of those subjects with AD and eight controls had [18F]FDG-PET. Parametric images of [11C]PIB binding and rCMRGlc were interrogated with a region-of-interest atlas and statistical parametric mapping. [11C]PIB binding and rCMRGlc were correlated with scores on psychometric tests. Results: AD subjects showed twofold increases in mean [11C]PIB binding in cingulate, frontal, temporal, parietal, and occipital cortical areas. Higher cortical amyloid load correlated with lower scores on facial and word recognition tests. Two patients fulfilling the clinical criteria for AD had normal [11C]PIB at baseline. Over 20 months this remained normal in one but increased in the cingulate of the other. Mean levels of temporal and parietal rCMRGlc were reduced by 20% in AD and these correlated with mini mental scores, immediate recall, and recognition memory test for words. Higher [11C]PIB uptake correlated with lower rCMRGlc in temporal and parietal cortices. Conclusion: [11C]PIB-PET detected an increased amyloid plaque load in 89% of patients with clinically probable Alzheimer disease (AD). The high frontal amyloid load detected by [11C]PIB-PET in AD in the face of spared glucose metabolism is of interest and suggests that amyloid plaque formation may not be directly responsible for neuronal dysfunction in this disorder.

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.

Amyloid load and cerebral atrophy in Alzheimer's disease: an 11C-PIB positron emission tomography study.

To determine the relationship between cerebral amyloid plaque load and rates of cerebral atrophy in Alzheimers disease. 11C‐PIB(11C‐6‐OH benzothiazole)PET (positron emission tomography) findings were correlated with volumetric magnetic resonance imaging (MRI) measurements in nine subjects with mild to moderate AD. Analysis revealed a positive correlation between rates of whole brain atrophy and whole brain (p = 0.019) and regional 11C‐PIB uptake. This provides support for the central role of amyloid deposition in the pathogenesis of AD. Ann Neurol 2006;60:145–147

Can target-to-pons ratio be used as a reliable method for the analysis of [ 11C]PIB brain scans?

RATIONALE (11)C]PIB is the most widely used PET imaging marker for amyloid in dementia studies. In the majority of studies the cerebellum has been used as a reference region. However, cerebellar amyloid may be present in genetic Alzheimers (AD), cerebral amyloid angiopathy and prion diseases. Therefore, we investigated whether the pons could be used as an alternative reference region for the analysis of [(11)C]PIB binding in AD. The aims of the study were to: 1) Evaluate the pons as a reference region using arterial plasma input function and Logan graphical analysis of binding. 2) Assess the power of target-to-pons ratios to discriminate controls from AD subjects. 3) Determine the test-retest reliability in AD subjects. 4) Demonstrate the application of target-to-pons ratio in subjects with elevated cerebellar [(11)C]PIB binding. METHODS 12 sporadic AD subjects aged 65 ± 4.5 yrs with a mean MMSE 21.4 ± 4 and 10 age-matched control subjects had [(11)C]PIB PET with arterial blood sampling. Three additional subjects (two subjects with pre-symptomatic presenilin-1 mutation carriers and one probable familial AD) were also studied. Object maps were created by segmenting individual MRIs and spatially transforming the gray matter images into standard stereotaxic MNI space and then superimposing a probabilistic atlas. Cortical [(11)C]PIB binding was assessed with an ROI (region of interest) analysis. Parametric maps of the volume of distribution (V(T)) were generated with Logan analysis. Additionally, parametric maps of the 60-90 min target-to-cerebellar ratio (RATIO(CER)) and the 60-90 min target-to-pons ratio (RATIO(PONS)) were computed. RESULTS All three approaches were able to differentiate AD from controls (p<0.0001, nonparametric Wilcoxon rank sum test) in the target regions with RATIO(CER) and RATIO(PONS) differences higher than V(T) with use of an arterial input function. All methods had a good reproducibility (intraclass correlation coefficient>0.83); RATIO(CER) performed best closely followed by RATIO(PONS). The two subjects with presenilin-1 mutations and the probable familial AD case showed no significant differences in cortical binding using RATIO(CER), but the RATIO(PONS) approach revealed higher [(11)C]PIB binding in cortex and cerebellum. CONCLUSION This study established 60-90 min target-to-pons RATIOs as a reliable method of analysis in [(11)C]PIB PET studies where cerebellum is not an appropriate reference region.

Visualizing the emergence of posterior cortical atrophy

Posterior cortical atrophy (PCA) is a neurodegenerative condition characterized by a progressive loss of visual processing skills and other posterior functions. Diagnosis is often delayed in PCA as symptoms can be difficult for the patient to articulate and for the clinician to detect. Diagnosis is particularly challenging in the earliest stages of the disease since visual symptoms are often mistaken as being related to ocular rather than cortical dysfunction. This report describes a 61-year-old man who volunteered as a healthy control participant in a longitudinal research study and was followed up for 5 years. During that time he showed a gradual decline in posterior cortical functions including visuoperceptual, visuospatial, and literacy impairments in the context of intact verbal episodic memory. Structural image analysis revealed atrophy which was initially most marked in inferior temporal and posterior parietal cortices before spreading to occipital cortices and subsequently to more anterior regions. Based on the clinical, neuropsychological and neuroimaging features, a diagnosis of PCA was made. The present case represents a unique opportunity to study and visualize the evolution of PCA from the very earliest symptomatic stages.

Strategies for the generation of parametric images of [11C]PIB with plasma input functions considering discriminations and reproducibility

Pittsburgh compound B or [11C]PIB is an amyloid imaging agent which shows a clear differentiation between subjects with Alzheimers disease (AD) and controls. However the observed signal difference in other forms of dementia such as dementia with Lewy bodies (DLB) is smaller, and mild cognitively impaired (MCI) subjects and some healthy elderly normals may show intermediate levels of [11C]PIB binding. The cerebellum, a commonly used reference region for non-specific tracer uptake in [11C]PIB studies in AD may not be valid in Prion disorders or monogenic forms of AD. The aim of this work was to: 1-compare methods for generating parametric maps of [11C]PIB retention in tissue using a plasma input function in respect of their ability to discriminate between AD subjects and controls and 2-estimate the test-retest reproducibility in AD subjects. 12 AD subjects (5 of which underwent a repeat scan within 6 weeks) and 10 control subjects had 90 minute [11C]PIB dynamic PET scans, and arterial plasma input functions were measured. Parametric maps were generated with graphical analysis of reversible binding (Logan plot), irreversible binding (Patlak plot), and spectral analysis. Between group differentiation was calculated using Students t-test and comparisons between different methods were made using p values. Reproducibility was assessed by intraclass correlation coefficients (ICC). We found that the 75 min value of the impulse response function showed the best group differentiation and had a higher ICC than volume of distribution maps generated from Logan and spectral analysis. Patlak analysis of [11C]PIB binding was the least reproducible.

A decade of pre-diagnostic assessment in a case of familial Alzheimer’s disease: tracking progression from asymptomatic to MCI and dementia

Detailed study of the very earliest phases of Alzheimer’s disease (AD) is seldom possible, especially those changes preceding the development of mild cognitive impairment (MCI), which may occur years before diagnosis. Knowledge of imaging and neuropsychological features of these early stages would add insight into this poorly understood phase of the disease. We present data from a subject who entered a longitudinal study of individuals at risk of familial Alzheimer’s disease (FAD), as a healthy volunteer with no memory complaints, undergoing 12 assessments between 1992 and 2003. Longitudinal MRI, neuropsychological and clinical data are presented over the decade preceding this man’s diagnosis, through the asymptomatic and prodromal preludes to his presentation with MCI and on to eventual conversion to AD. We thank TOP and his wife for participating in this study, and the assistants of the neuropsychology department of the National Hospital of Neurology and Neurosurgery who performed the neuropsychology assessments and assisted in data collation, including Ms Susanna Cole. Mutation analysis was performed by Professor John Collinge and Mr John Beck of the MRC Prion Unit, Institute of Neurology. Funding was provided by an MRC programme grant, number G9626876. NCF holds an MRC senior clinical scientist fellowship.

Memory complaints and increased rates of brain atrophy: risk factors for mild cognitive impairment and Alzheimer's disease

To determine rates of cerebral atrophy in individuals with symptoms of memory loss but no objective cognitive impairment (SNCI) and their association with future cognitive decline.

Symptoms of memory loss as predictors of cognitive impairment? : The use and reliability of memory ratings in a clinic population

BackgroundSymptoms of memory loss are very common with estimated prevalence between 22% and 50% in those older than 65 years of age. Those with symptoms of memory loss and impaired performance on memory tests are at high risk of progression to Alzheimer disease. The relative importance of different aspects of the clinical history in predicting cognitive impairment is uncertain. MethodsFifty-six patients with symptoms of memory loss were recruited from the National Hospital for Neurology and Neurosurgery. A clinician recorded type and duration of memory symptoms as perceived by the patient and their informant, and use of memory aids. All patients subsequently underwent magnetic resonance imaging (MRI) and neuropsychologic testing. Findings(i) Informant, but not patient, ratings of memory were associated with performance on tests of memory function and with hippocampal size on MRI. (ii) Decreased use of memory aids and shorter duration of memory symptoms were more common in those with memory impairment. InterpretationIn a clinical setting, information gathered from the history was associated with cognitive impairment on memory testing and brain appearances on MRI. The history from a close informant is particularly important being more strongly predictive of cognitive impairment (P=0.0002) than subjective symptoms, use of memory aids or duration of symptoms.