- Email: [email protected]
CSF analysis detect cerebral β-amyloid accumulation earlier than amyloid PET
Abstracts / Neurobiology of Aging 39 (2016) S1eS13
endemic sheep scrapie and epidemic BSE. While PrP is critically involved in susceptibility to infection and neurodegenerative amyloid pathology, isolated brain particles that lack detectable PrP and PrP amyloid maintain their high infectivity. Thus PrP is not an intrinsic component of the infectious particle. Inclusive biologic and physical data further underscore a causal environmental virus of 20-25nm with a genome that can code for unique agent strains. Deep proteomic analyses of PrP-less infectious particles revealed viral peptide motifs that can protect a TSE agent genome. In addition, other host proteins were unmasked, and these are commonly recruited in several major neurodegenerative diseases such as AD, where the originating cause is unknown. Membrane shuttling pathways to synapses were highlighted, as were proteins critical for synaptic functioning. Synapses are heavily involved in CJD, AD and Parkinson’s disease. Targeting synaptic and disease-linked stress proteins should interfere with infectious as well as noninfectious processes that are central to many types of progressive neurodegeneration. Keywords. Creutzfeldt-Jakob Disease, Innate immunity, Microbiome, Prion protein, Synapse, Virus
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maintenance, nervous system functioning. In the brain, Copper and Zinc are stored in specific synaptic vesicles by glutamatergic neurons and can modulate brain excitability. They play a key role in synaptic plasticity and so in learning. The mechanisms of these metal absorption, distribution, and storage are finely regulated. This reflects the high chemical reactivity of these elements, in line with their double facet. When metals are kept under control, bound to special proteins as co-factors, they yield key-properties, when they spiral out of control, their redox activity makes them dangerous for cell viability, producing oxidative stress in Haber-Weiss and Fenton like chemistry. A huge and consistent evidence demonstrates that this is the case for copper and iron in the sporadic, multifactorial form of Alzheimer’s disease, the most common form of dementia, and for ceruloplasmin, which is the cross-talking protein between copper and iron metabolism. The role of Zinc has been little debated. Aluminum is not an oligo-element, but a toxicant and the most studied environmental agent linked with Alzheimer’s disease, which emerged as a possible suspect during the 1970s. A controversy raised in 1990s, apparently overcome. However, recent meta-analyses suggest that the issue is still open. Keywords. Alzheimer, Alzheimer’s disease, APOE-4
CSF ANALYSIS DETECT CEREBRAL b-AMYLOID ACCUMULATION EARLIER THAN AMYLOID PET 1
2
1 1
Oskar Hansson , Sebastian Palmqvist , Niklas Mattsson . Lund University, Malmö, Sweden; 2 Lund University, Lund, Sweden. E-mail: [email protected] Cerebral accumulation of b-amyloid (Ab) is thought to be the starting mechanism in Alzheimer’s disease (AD). Interventions against pathological Ab metabolism should be initiated early to halt the disease progression. Ab can be detected by analysis of cerebrospinal fluid (CSF) Ab42 or amyloid positron emission tomography (PET), but it is unknown if any of the methods can identify an abnormal Ab load prior to the other. Our aim was to determine whether CSF Ab42 change before amyloid PET during preclinical stages of AD. We included 437 non-demented subjects from the prospective, longitudinal Alzheimer’s Disease Neuroimaging Initiative (ADNI) study. All underwent 18Fflorbetapir PET and CSF Ab42 analysis at baseline and 1 additional PET after a mean follow-up of 2.1 years (range 1.1e4.4 years). Group classifications were based on normal () and abnormal (+) CSF and PET baseline results. Ab accumulation during follow-up was measured in yearly change of standardized uptake value ratio (SUVR) of florbetapir. We found that cases that were isolated CSF Ab positive (CSF+/PET) accumulated Ab with a mean rate of 1.2%/ year (0.0083 SUVR/year), which was similar to the rate in CSF+/PET+ cases (1.2%/year, p ¼ 0.86; 0.011 SUVR/year, p ¼ 0.28). The accumulation rates of CSF+/PET cases were more than three times that of CSF/PET cases (0.35%/ year, p ¼ 0.018; 0.0024 SUVR/year, p ¼ 0.015). CSF+/PET+ cases deteriorated more in memory and hippocampal volume than CSF+/PET subjects (p < 0.001), indicating that the former group is closer to AD dementia. The results were replicated using different CSF and PET cutoffs and after adjustments of different factors. The results were even clearer when classifying PET+/e according to Ab deposition in regions where the amyloid pathology is thought to start. This is the first study to show that individuals who are CSF Ab positive but PET Ab negative (CSF+/PET) have an abnormal cortical Ab accumulating rate similar to CSF+/PET+ individuals and higher than CSF/ PET individuals. The results indicate that CSF Ab42 becomes abnormal in the earliest stages of AD, before amyloid PET and before neurodegeneration starts. Keywords. Alzheimer’s disease, Amyloid, Biomarker, CSF
BIOMARKERS: SELECTING SUBJECTS FOR PREVENTION AND TRIALS Jacques Hugon1, Julien Dumurgier2, Pascal Millet2, Claire Paquet2. 1 Memory Center, Paris, France; 2 N/A, N/A. E-mail: [email protected] The hypothesis that abnormal metabolic events could occur 10 to 20 years before the onset of clinical signs is now admitted in Alzheimer’s disease (AD). The target of secondary prevention trials are cognitively normal people showing risks factor for AD. Prevention trials can be pharmacologic or nonpharmacologic and new research treatments include anti-amyloid active and passive immunotherapies as well as BACE-1 inhibition. The new biomarkers can reflect the pathophysiological process of the disease (low CSF Ab 1-42 levels or positive amyloid PET) or neurodegeneration like increased CSF tau levels, abnormal FDG PET or hippocampal atrophy on MRI. PET tau tracers will come soon as well. Risk factors can be genetic, biological or imaging findings. The presence of ApoE4 alleles can predispose individuals to a more rapid cognitive decline as well as an early onset of AD. Recent GWAS studies have found more than 20 new genetic risks factors but the odds ratio are limited compared to ApoE4. Research groups have proposed that biomarkers could be part of the new criteria of Subjective Cognitive Impairment (SCI) Mild Cognitive Impairment (MCI) or AD. Abnormal biological evidences, including low Ab 1-42 levels, were observed in the CSF of patients affected by familial forms of AD and also in cognitively normal individuals suffering from SCI. They represent a risk for exacerbated cognitive decline. The incorporation of the ratio CSF Ab 42/40 has been proposed to enhance the efficacy of CSF diagnosis. More recently the use of amyloid PET imaging has confirmed these findings showing that in normal individuals or SCI persons with positive PET a more rapid cognitive decline than in the individuals with negative amyloid PET was detected. The major question that remains is how to detect in a normal population, the persons at risk for developing AD. The incorporation of individuals with one or two relatives affected by the disease will certainly be a possibility. The utilization of new cognitive composite scores will afford a better detection of individuals at risk and susceptible to be assessed by a biomarker approach to benefit from secondary prevention trails. Keywords. Biomarkers, Clinical trial, Prevention
METAL DYSFUNCTION AND ALZHEIMER’S DISEASE Rosanna Squitti. Fondazione Fatebenefratelli, AFaR Division, Fatebenefratelli Hospital, Rome, Italy. E-mail: [email protected] Trace metals are essential elements for human biology. Copper and Iron are transition metals that catalyze oxidation-reduction (electron-transfer) reactions, which are essential for life processes. They are co-factors of enzymes which allow the electron transfer in the respiratory chain of mitochondria, and preside many biological functions such as the production of blood cells, transmission of chemical signals by means of cytokines, connective tissue
THE EFFECT OF SOUVENAID ON BRAIN PHOSPHOLIPID METABOLISM IN PATIENTS WITH MILD ALZHEIMER’S DISEASE: RESULTS OF A RANDOMISED CONTROLLED 31P-MAGNETIC RESONANCE SPECTROSCOPY STUDY Anne Rijpma1, Olga Meulenbroek1, Marinette van der Graaf2, Marieke Lansbergen3, John Sijben3, Arend Heerschap4, Marcel Olde Rikkert1. 1 Department of Geriatric Medicine and Radboud Alzheimer Centre, Radboud University Medical Center, Nijmegen, Netherlands; 2 Department of Radiology & Nuclear Medicine, Dept of Paediatrics, Radboud University Medical Center,
endemic sheep scrapie and epidemic BSE. While PrP is critically involved in susceptibility to infection and neurodegenerative amyloid pathology, isolated brain particles that lack detectable PrP and PrP amyloid maintain their high infectivity. Thus PrP is not an intrinsic component of the infectious particle. Inclusive biologic and physical data further underscore a causal environmental virus of 20-25nm with a genome that can code for unique agent strains. Deep proteomic analyses of PrP-less infectious particles revealed viral peptide motifs that can protect a TSE agent genome. In addition, other host proteins were unmasked, and these are commonly recruited in several major neurodegenerative diseases such as AD, where the originating cause is unknown. Membrane shuttling pathways to synapses were highlighted, as were proteins critical for synaptic functioning. Synapses are heavily involved in CJD, AD and Parkinson’s disease. Targeting synaptic and disease-linked stress proteins should interfere with infectious as well as noninfectious processes that are central to many types of progressive neurodegeneration. Keywords. Creutzfeldt-Jakob Disease, Innate immunity, Microbiome, Prion protein, Synapse, Virus
S7
maintenance, nervous system functioning. In the brain, Copper and Zinc are stored in specific synaptic vesicles by glutamatergic neurons and can modulate brain excitability. They play a key role in synaptic plasticity and so in learning. The mechanisms of these metal absorption, distribution, and storage are finely regulated. This reflects the high chemical reactivity of these elements, in line with their double facet. When metals are kept under control, bound to special proteins as co-factors, they yield key-properties, when they spiral out of control, their redox activity makes them dangerous for cell viability, producing oxidative stress in Haber-Weiss and Fenton like chemistry. A huge and consistent evidence demonstrates that this is the case for copper and iron in the sporadic, multifactorial form of Alzheimer’s disease, the most common form of dementia, and for ceruloplasmin, which is the cross-talking protein between copper and iron metabolism. The role of Zinc has been little debated. Aluminum is not an oligo-element, but a toxicant and the most studied environmental agent linked with Alzheimer’s disease, which emerged as a possible suspect during the 1970s. A controversy raised in 1990s, apparently overcome. However, recent meta-analyses suggest that the issue is still open. Keywords. Alzheimer, Alzheimer’s disease, APOE-4
CSF ANALYSIS DETECT CEREBRAL b-AMYLOID ACCUMULATION EARLIER THAN AMYLOID PET 1
2
1 1
Oskar Hansson , Sebastian Palmqvist , Niklas Mattsson . Lund University, Malmö, Sweden; 2 Lund University, Lund, Sweden. E-mail: [email protected] Cerebral accumulation of b-amyloid (Ab) is thought to be the starting mechanism in Alzheimer’s disease (AD). Interventions against pathological Ab metabolism should be initiated early to halt the disease progression. Ab can be detected by analysis of cerebrospinal fluid (CSF) Ab42 or amyloid positron emission tomography (PET), but it is unknown if any of the methods can identify an abnormal Ab load prior to the other. Our aim was to determine whether CSF Ab42 change before amyloid PET during preclinical stages of AD. We included 437 non-demented subjects from the prospective, longitudinal Alzheimer’s Disease Neuroimaging Initiative (ADNI) study. All underwent 18Fflorbetapir PET and CSF Ab42 analysis at baseline and 1 additional PET after a mean follow-up of 2.1 years (range 1.1e4.4 years). Group classifications were based on normal () and abnormal (+) CSF and PET baseline results. Ab accumulation during follow-up was measured in yearly change of standardized uptake value ratio (SUVR) of florbetapir. We found that cases that were isolated CSF Ab positive (CSF+/PET) accumulated Ab with a mean rate of 1.2%/ year (0.0083 SUVR/year), which was similar to the rate in CSF+/PET+ cases (1.2%/year, p ¼ 0.86; 0.011 SUVR/year, p ¼ 0.28). The accumulation rates of CSF+/PET cases were more than three times that of CSF/PET cases (0.35%/ year, p ¼ 0.018; 0.0024 SUVR/year, p ¼ 0.015). CSF+/PET+ cases deteriorated more in memory and hippocampal volume than CSF+/PET subjects (p < 0.001), indicating that the former group is closer to AD dementia. The results were replicated using different CSF and PET cutoffs and after adjustments of different factors. The results were even clearer when classifying PET+/e according to Ab deposition in regions where the amyloid pathology is thought to start. This is the first study to show that individuals who are CSF Ab positive but PET Ab negative (CSF+/PET) have an abnormal cortical Ab accumulating rate similar to CSF+/PET+ individuals and higher than CSF/ PET individuals. The results indicate that CSF Ab42 becomes abnormal in the earliest stages of AD, before amyloid PET and before neurodegeneration starts. Keywords. Alzheimer’s disease, Amyloid, Biomarker, CSF
BIOMARKERS: SELECTING SUBJECTS FOR PREVENTION AND TRIALS Jacques Hugon1, Julien Dumurgier2, Pascal Millet2, Claire Paquet2. 1 Memory Center, Paris, France; 2 N/A, N/A. E-mail: [email protected] The hypothesis that abnormal metabolic events could occur 10 to 20 years before the onset of clinical signs is now admitted in Alzheimer’s disease (AD). The target of secondary prevention trials are cognitively normal people showing risks factor for AD. Prevention trials can be pharmacologic or nonpharmacologic and new research treatments include anti-amyloid active and passive immunotherapies as well as BACE-1 inhibition. The new biomarkers can reflect the pathophysiological process of the disease (low CSF Ab 1-42 levels or positive amyloid PET) or neurodegeneration like increased CSF tau levels, abnormal FDG PET or hippocampal atrophy on MRI. PET tau tracers will come soon as well. Risk factors can be genetic, biological or imaging findings. The presence of ApoE4 alleles can predispose individuals to a more rapid cognitive decline as well as an early onset of AD. Recent GWAS studies have found more than 20 new genetic risks factors but the odds ratio are limited compared to ApoE4. Research groups have proposed that biomarkers could be part of the new criteria of Subjective Cognitive Impairment (SCI) Mild Cognitive Impairment (MCI) or AD. Abnormal biological evidences, including low Ab 1-42 levels, were observed in the CSF of patients affected by familial forms of AD and also in cognitively normal individuals suffering from SCI. They represent a risk for exacerbated cognitive decline. The incorporation of the ratio CSF Ab 42/40 has been proposed to enhance the efficacy of CSF diagnosis. More recently the use of amyloid PET imaging has confirmed these findings showing that in normal individuals or SCI persons with positive PET a more rapid cognitive decline than in the individuals with negative amyloid PET was detected. The major question that remains is how to detect in a normal population, the persons at risk for developing AD. The incorporation of individuals with one or two relatives affected by the disease will certainly be a possibility. The utilization of new cognitive composite scores will afford a better detection of individuals at risk and susceptible to be assessed by a biomarker approach to benefit from secondary prevention trails. Keywords. Biomarkers, Clinical trial, Prevention
METAL DYSFUNCTION AND ALZHEIMER’S DISEASE Rosanna Squitti. Fondazione Fatebenefratelli, AFaR Division, Fatebenefratelli Hospital, Rome, Italy. E-mail: [email protected] Trace metals are essential elements for human biology. Copper and Iron are transition metals that catalyze oxidation-reduction (electron-transfer) reactions, which are essential for life processes. They are co-factors of enzymes which allow the electron transfer in the respiratory chain of mitochondria, and preside many biological functions such as the production of blood cells, transmission of chemical signals by means of cytokines, connective tissue
THE EFFECT OF SOUVENAID ON BRAIN PHOSPHOLIPID METABOLISM IN PATIENTS WITH MILD ALZHEIMER’S DISEASE: RESULTS OF A RANDOMISED CONTROLLED 31P-MAGNETIC RESONANCE SPECTROSCOPY STUDY Anne Rijpma1, Olga Meulenbroek1, Marinette van der Graaf2, Marieke Lansbergen3, John Sijben3, Arend Heerschap4, Marcel Olde Rikkert1. 1 Department of Geriatric Medicine and Radboud Alzheimer Centre, Radboud University Medical Center, Nijmegen, Netherlands; 2 Department of Radiology & Nuclear Medicine, Dept of Paediatrics, Radboud University Medical Center,