Early Detection of Alzheimer's Disease Beta-amyloid Pathology -Applicability of Positron Emission Tomography with the Amyloid Radioligand 11C-PIB

Early Detection of Alzheimer's Disease Beta-amyloid Pathology -Applicability of Positron Emission Tomography with the Amyloid Radioligand 11C-PIB Accumulation of beta amyloid (Abeta) in the brain is characteristic for Alzheimer’s disease (AD). Carbon-11 labeled 2-(4’-methylaminophenyl)-6-hydroxybenzothiazole (11C-PIB) is a novel positron emission tomography (PET) amyloid imaging agent that appears to be applicable for in vivo Abeta plaque detection and quantitation. The biodistribution and radiation dosimetry of 11C-PIB were investigated in 16 healthy subjects. The reproducibility of a simplified 11C-PIB quantitation method was evaluated with a test-retest study on 6 AD patients and 4 healthy control subjects. Brain 11C-PIB uptake and its possible association with brain atrophy rates were studied over a two-year follow-up in 14 AD patients and 13 healthy controls. Nine monozygotic and 8 dizygotic twin pairs discordant for cognitive impairment and 9 unrelated controls were examined to determine whether brain Abeta accumulation could be detected with 11C-PIB PET in cognitively intact persons who are at increased genetic risk for AD. The highest absorbed radiation dose was received by the gallbladder wall (41.5 mjuGy/MBq). About 20 % of the injected radioactivity was excreted into urine, and the effective whole-body radiation dose was 4.7 mjuSv/MBq. Such a dose allows repeated scans of individual subjects. The reproducibility of the simplified 11C-PIB quantitation was good or excellent both at the regional level (VAR 0.9-5.5 %) and at the voxel level (VAR 4.2-6.4 %). 11C-PIB uptake did not increase during 24 months’ follow-up of subjects with mild or moderate AD, even though brain atrophy and cognitive decline progressed. Baseline neocortical 11C-PIB uptake predicted subsequent volumetric brain changes in healthy control subjects (r = 0.725, p = 0.005). Cognitively intact monozygotic co-twins – but not dizygotic co-twins – of memory-impaired subjects exhibited increased 11C-PIB uptake (117-121 % of control mean) in their temporal and parietal cortices and the posterior cingulate (p11C-PIB PET may be a useful method for patient selection and follow-up for early-phase intervention trials of novel therapeutic agents. AD might be detectable in high-risk individuals in its presymptomatic stage with 11C-PIB PET, which would have important consequences both for future diagnostics and for research on disease-modifying treatments.Alzheimerin taudin beta-amyloidipatologian varhainen toteaminen. 11C-PIB-amyloidimerkkiaineella tehtävän positroniemissiotomografian soveltuvuus Beeta-amyloidin (Abeta) kertyminen aivoihin on tyypillistä Alzheimerin taudille (AT). Hiili-11-isotoopilla leimattu 2-(4’-metyyliaminofenyyli)-6-hydroksibentsotiatsoli (11C-PIB) on uusi positroniemissiotomografiassa (PET) käytettävä merkkiaine, joka vaikuttaa soveltuvan amyloidiplakkien toteamiseen ja niiden määrän arvioimiseen. 11C-PIB:n jakautumista kehossa ja sen aiheuttamaa säderasitusta tutkittiin 16 terveellä henkilöllä. Yksinkertaistettujen 11C-PIB-analyysimenetelmien toistettavuutta selvitettiin toistomittausasetelmalla 6 AT-potilaalla ja 4 terveellä verrokilla. 11C-PIB-kertymän muutosta sekä 11C-PIB-kertymän ja aivojen kutistumisnopeuden välistä suhdetta mitattiin kahden vuoden seurantatutkimuksella, jossa oli 14 AT-potilasta ja 13 tervettä verrokkia. Tutkimalla 9 samanmunaista ja 8 erimunaista muistihäiriön suhteen toisistaan poikkeavaa kaksosparia sekä 9 iäkästä verrokkihenkilöä 11C-PIB PET:lla selvitettiin, voisiko aivoamyloidia olla havaittavissa sellaisilla kognitiivisesti terveillä henkilöillä, joilla on suurentunut riski sairastua AT:iin. Sappirakon seinämä sai elimistä suurimman määrän säteilyä, 41.5 mjuGy/MBq. Noin 20 % annetusta radioaktiivisuusannoksesta erittyi virtsaan. Efektiivinen sädeannos oli 4.7 mjuSv/MBq. Tämä annos mahdollistaa toistetut tutkimukset samoilla henkilöillä. Yksinkertaistettujen 11C-PIB PET –analyysimenetelmien toistettavuus oli hyvää tai erinomaista sekä alueittain (VAR 0.9-5.5%) että kuva-alkioittain (VAR 4.2-6.4%) tarkasteltuna. 11C-PIB-kertymä ei lisääntynyt AT-potilailla seuranta-ajan kuluessa, vaikka aivojen kutistuminen ja kognitiivinen heikentyminen etenivät. Alkutilanteen 11C-PIB-kertymä vaikutti ennustavan terveiden verrokkien aivojen tilavuusmuutoksia seuranta-aikana (r = 0.725, p = 0.005). Kognitiivisesti terveillä muistihäiriöisten samanmunaisilla kaksosilla – mutta ei erimunaisilla kaksosilla - oli suurentuneita 11C-PIB-kertymiä (117-121% verrokkien keskiarvosta) ohimo- ja päälakialueen aivokuorella sekä posteriorisessa cingulumissa (p11C-PIB PET voi olla käypä menetelmä tutkittavien valinnassa ja seurannassa, kun tehdään varhaisen sairausvaiheen tutkimuksia uusilla lääkkeillä. AT saatetaan voida todeta 11C-PIB PET:n avulla täysin oireettomassa vaiheessa sellaisilla henkilöillä, joilla on suurentunut riski sairastua. Tällä voisi olla merkittäviä vaikutuksia taudinmääritykselle ja sellaisten hoitojen tutkimiselle, jotka tähtäävät taudin kulun muuttamiseen.Siirretty Doriast

PET and MR imaging in Parkinson’s disease patients with cognitive impairment. A study of dopaminergic dysfunction, amyloid deposition, cortical hypometabolism and brain atrophy

Parkinson’s disease (PD) is the second most common neurodegenerative disorder. It is characterized by a severe loss of substantia nigra dopaminergic neurons leading to dopamine depletion in the striatum. PD affects movement, producing motor symptoms such as rigidity, tremor and bradykinesia. Non-motor symptoms include autonomic dysfunction, neurobehavioral problems and cognitive impairment, which may lead to dementia. The pathophysiological basis of cognitive impairment and dementia in PD is unclear. The aim of this thesis was to study the pathophysiological basis of cognitive impairment and dementia in PD. We evaluated the relation between frontostriatal dopaminergic dysfunction and the cognitive symptoms in PD patients with [18F]Fdopa PET. We also combined [C]PIB and [18F]FDG PET and magnetic resonance imaging in PD patients with and without dementia. In addition, we analysed subregional striatal [18F]Fdopa PET data to find out whether a simple ratio approach would reliably separate PD patients from healthy controls. The impaired dopaminergic function of the frontostriatal regions was related to the impairment in cognitive functions, such as memory and cognitive processing in PD patients. PD patients with dementia showed an impaired glucose metabolism but not amyloid deposition in the cortical brain regions, and the hypometabolism was associated with the degree of cognitive impairment. PD patients had atrophy, both in the prefrontal cortex and in the hippocampus, and the hippocampal atrophy was related to impaired memory. A single 15-min scan 75 min after a tracer injection seemed to be sufficient for separating patients with PD from healthy controls in a clinical research environment. In conclusion, the occurrence of cognitive impairment and dementia in PD seems to be multifactorial and relates to changes, such as reduced dopaminergic activity, hypometabolism, brain atrophy and rarely to amyloid accumulation.Siirretty Doriast

2014 Update of the Alzheimer's Disease Neuroimaging Initiative: A review of papers published since its inception

The Alzheimer's Disease Neuroimaging Initiative (ADNI) is an ongoing, longitudinal, multicenter study designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of Alzheimer's disease (AD). The initial study, ADNI-1, enrolled 400 subjects with early mild cognitive impairment (MCI), 200 with early AD, and 200 cognitively normal elderly controls. ADNI-1 was extended by a 2-year Grand Opportunities grant in 2009 and by a competitive renewal, ADNI-2, which enrolled an additional 550 participants and will run until 2015. This article reviews all papers published since the inception of the initiative and summarizes the results to the end of 2013. The major accomplishments of ADNI have been as follows: (1) the development of standardized methods for clinical tests, magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebrospinal fluid (CSF) biomarkers in a multicenter setting; (2) elucidation of the patterns and rates of change of imaging and CSF biomarker measurements in control subjects, MCI patients, and AD patients. CSF biomarkers are largely consistent with disease trajectories predicted by β-amyloid cascade (Hardy, J Alzheimer's Dis 2006;9(Suppl 3):151-3) and tau-mediated neurodegeneration hypotheses for AD, whereas brain atrophy and hypometabolism levels show predicted patterns but exhibit differing rates of change depending on region and disease severity; (3) the assessment of alternative methods of diagnostic categorization. Currently, the best classifiers select and combine optimum features from multiple modalities, including MRI, [(18)F]-fluorodeoxyglucose-PET, amyloid PET, CSF biomarkers, and clinical tests; (4) the development of blood biomarkers for AD as potentially noninvasive and low-cost alternatives to CSF biomarkers for AD diagnosis and the assessment of α-syn as an additional biomarker; (5) the development of methods for the early detection of AD. CSF biomarkers, β-amyloid 42 and tau, as well as amyloid PET may reflect the earliest steps in AD pathology in mildly symptomatic or even nonsymptomatic subjects and are leading candidates for the detection of AD in its preclinical stages; (6) the improvement of clinical trial efficiency through the identification of subjects most likely to undergo imminent future clinical decline and the use of more sensitive outcome measures to reduce sample sizes. Multimodal methods incorporating APOE status and longitudinal MRI proved most highly predictive of future decline. Refinements of clinical tests used as outcome measures such as clinical dementia rating-sum of boxes further reduced sample sizes; (7) the pioneering of genome-wide association studies that leverage quantitative imaging and biomarker phenotypes, including longitudinal data, to confirm recently identified loci, CR1, CLU, and PICALM and to identify novel AD risk loci; (8) worldwide impact through the establishment of ADNI-like programs in Japan, Australia, Argentina, Taiwan, China, Korea, Europe, and Italy; (9) understanding the biology and pathobiology of normal aging, MCI, and AD through integration of ADNI biomarker and clinical data to stimulate research that will resolve controversies about competing hypotheses on the etiopathogenesis of AD, thereby advancing efforts to find disease-modifying drugs for AD; and (10) the establishment of infrastructure to allow sharing of all raw and processed data without embargo to interested scientific investigators throughout the world

Unconventional markers of Alzheimer Disease

Although typically conceptualized as a cortical disease, recent neuropathological and neuroimaging investigations on Alzheimer Disease suggest that other brain structures play an important role in the pathogenesis and progression of this devastating condition. In this thesis, we explored novel markers of Alzheimer Disease beyond the classical cortical pathology measures of amyloid, tau, and neurodegeneration. We focused on the role of white matter abnormalities, assessed with magnetic resonance imaging but also with amyloid positron emission tomography, in predicting early pathologic changes and disease progression, as well as on the added value of cognition to amyloid, tau, and neurodegeneration biomarkers. Overall, we found that these unconventional markers provide useful information to detect the earliest pathological changes of the disease, providing a better understanding of the mechanisms that lead to amyloid deposition and cognitive decline

Genetically Determined Hypometabolism in Alzheimer’s Disease and Midlife Risk Factors for Cognitive Impairment

The role of genetic factors in the pathogenesis of Alzheimer’s disease (AD) is not completely understood. In order to improve this understanding, the cerebral glucose metabolism of seven monozygotic and nine dizygotic twin pairs discordant for AD was compared to that of 13 unrelated controls using positron emission tomography (PET). Traditional region of interest analysis revealed no differences between the non-demented dizygotic co-twins and controls. In contrast, in voxel-level and automated region of interest analyses, the non-demented monozygotic co-twins displayed a lower metabolic rate in temporal and parietal cortices as well as in subcortical grey matter structures when compared to controls. Again, no reductions were seen in the non-demented dizygotic co-twins. The reductions seen in the non-demented monozygotic co-twins may indicate a higher genetically mediated risk of AD or genetically mediated hypometabolism possibly rendering them more vulnerable to AD pathogenesis. With no disease modifying treatment available for AD, prevention of dementia is of the utmost importance. A total of 2 165 at least 65 years old twins of the Finnish Twin Cohort with questionnaire data from 1981 participated in a validated telephone interview assessing cognitive function between 1999 and 2007. Those subjects reporting heavy alcohol drinking in 1981 had an elevated cognitive impairment risk over 20 years later compared to light drinkers. In addition, binge drinking was associated with an increased risk even when total alcohol consumption was controlled for, suggesting that binge drinking is an independent risk factor for cognitive impairment. When compared to light drinkers, also non-drinkers had an increased risk of cognitive impairment. Midlife hypertension, obesity and low leisure time physical activity but not hypercholesterolemia were significant risk factors for cognitive impairment. The accumulation of risk factors increased cognitive impairment risk in an additive manner. A previously postulated dementia risk score based on midlife demographic and cardiovascular factors was validated. The risk score was found to well predict cognitive impairment risk, and cognitive impairment risk increased significantly as the score became higher. However, the risk score is not accurate enough for use in the clinic without further testing.Siirretty Doriast

Tau pathology, microglia activation, and network dysfunction in Alzheimer’s disease

Tau pathology and neuroinflammation are key etio-pathogenetic mediators of Alzheimer’s disease (AD). Network dysfunction has also been reported in AD and linked to cognitive impairment. However, it is unclear how tau pathology and neuroinflammation contribute to network dysfunction and cognitive deficit in AD. I study these issues by combining: 1) positron emission tomography imaging using the [18F-AV]-1451 tracer (measuring in vivo tau pathology) or [11C]PK11195 ligand (indexing in vivo neuroinflammation), with 2) connectivity measures of resting-state functional magnetic resonance imaging. I found increased [18F-AV]-1451 binding (reflecting tau pathology) in AD patients, relative to controls, in the medial/lateral temporal and parietal cortices. In terms of functional connectivity, more strongly connected brain regions accrued more tau pathology. Increasing tau burden was also linked to progressive weakening of the connectivity across the same regions. I also found increased [11C]PK11195 binding (reflecting neuroinflammation) in the medial/lateral temporal and parietal cortices in AD patients, relative to controls. [11C]PK11195 binding in the cuneus/precuneus correlated with episodic memory deficits in AD patients. This pattern of neuroinflammation was linked to large-scale network’ dysfunction and cognitive deficit. AD patients with enhanced neuroinflammation showed more abnormal connectivity across the whole-brain. The expression of a stronger association between altered functional connectivity and high levels of neuroinflammation related to cognitive deficit in AD. My studies have wide-ranging implications that include: 1) the validation of animal models of tau propagation in living patients with AD; 2) improvements in our understanding of the relationship between in vivo tau pathology and brain functioning; 3) evidence for a primary role of neuroinflammation in mediating network dysfunction in AD; 4) support to the notion that immune-therapeutic strategies targeting tau pathology and neuroinflammation may be useful in AD.MRC and NIHR funde

Differentiation of Alzheimer's disease dementia, mild cognitive impairment and normal condition using PET-FDG and AV-45 imaging : a machine-learning approach

Nous avons utilisé l'imagerie TEP avec les traceurs F18-FDG et AV45 en conjonction avec les méthodes de classification du domaine du "Machine Learning". Les images ont été acquises en mode dynamique, une image toutes les 5 minutes. Les données ont été transformées par Analyse en Composantes Principales et Analyse en Composantes Indépendantes. Les images proviennent de trois sources différentes: la base de données ADNI (Alzheimer's Disease Neuroimaging Initiative) et deux protocoles réalisés au sein du centre TEP de l'hôpital Purpan. Pour évaluer la performance de la classification nous avons eu recours à la méthode de validation croisée LOOCV (Leave One Out Cross Validation). Nous donnons une comparaison entre les deux méthodes de classification les plus utilisées, SVM (Support Vector Machine) et les réseaux de neurones artificiels (ANN). La combinaison donnant le meilleur taux de classification semble être SVM et le traceur AV45. Cependant les confusions les plus importantes sont entre les patients MCI et les sujets normaux. Les patients Alzheimer se distinguent relativement mieux puisqu'ils sont retrouvés souvent à plus de 90%. Nous avons évalué la généralisation de telles méthodes de classification en réalisant l'apprentissage sur un ensemble de données et la classification sur un autre ensemble. Nous avons pu atteindre une spécificité de 100% et une sensibilité supérieure à 81%. La méthode SVM semble avoir une meilleure sensibilité que les réseaux de neurones. L'intérêt d'un tel travail est de pouvoir aider à terme au diagnostic de la maladie d'Alzheimer.We used PET imaging with tracers F18-FDG and AV45 in conjunction with the classification methods in the field of "Machine Learning". PET images were acquired in dynamic mode, an image every 5 minutes.The images used come from three different sources: the database ADNI (Alzheimer's Disease Neuro-Imaging Initiative, University of California Los Angeles) and two protocols performed in the PET center of the Purpan Hospital. The classification was applied after processing dynamic images by Principal Component Analysis and Independent Component Analysis. The data were separated into training set and test set. To evaluate the performance of the classification we used the method of cross-validation LOOCV (Leave One Out Cross Validation). We give a comparison between the two most widely used classification methods, SVM (Support Vector Machine) and artificial neural networks (ANN) for both tracers. The combination giving the best classification rate seems to be SVM and AV45 tracer. However the most important confusion is found between MCI patients and normal subjects. Alzheimer's patients differ somewhat better since they are often found in more than 90%. We evaluated the generalization of our methods by making learning from set of data and classification on another set . We reached the specifity score of 100% and sensitivity score of more than 81%. SVM method showed a bettrer sensitivity than Artificial Neural Network method. The value of such work is to help the clinicians in diagnosing Alzheimer's disease

The Cortical Signature of Alzheimer's Disease: Regionally Specific Cortical Thinning Relates to Symptom Severity in Very Mild to Mild AD Dementia and is Detectable in Asymptomatic Amyloid-Positive Individuals

Alzheimer's disease (AD) is associated with neurodegeneration in vulnerable limbic and heteromodal regions of the cerebral cortex, detectable in vivo using magnetic resonance imaging. It is not clear whether abnormalities of cortical anatomy in AD can be reliably measured across different subject samples, how closely they track symptoms, and whether they are detectable prior to symptoms. An exploratory map of cortical thinning in mild AD was used to define regions of interest that were applied in a hypothesis-driven fashion to other subject samples. Results demonstrate a reliably quantifiable in vivo signature of abnormal cortical anatomy in AD, which parallels known regional vulnerability to AD neuropathology. Thinning in vulnerable cortical regions relates to symptom severity even in the earliest stages of clinical symptoms. Furthermore, subtle thinning is present in asymptomatic older controls with brain amyloid binding as detected with amyloid imaging. The reliability and clinical validity of AD-related cortical thinning suggests potential utility as an imaging biomarker. This “disease signature” approach to cortical morphometry, in which disease effects are mapped across the cortical mantle and then used to define ROIs for hypothesis-driven analyses, may provide a powerful methodological framework for studies of neuropsychiatric diseases