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Biomarkers of Alzheimer’s disease pathology progression in Down syndrome
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S.02. Alzheimer-type dementia in people with Down syndrome
Protein gene (APP) which lies on chromosome 21 and its presence in three copies in DS is thought to largely drive the early onset of AD. It has been noted that the presentation of dementia in individuals with DS differs from sporadic AD, which affects how clinicians diagnose AD in this population. For example, symptoms related to frontal lobe problems are common, but intracerebral haemorrhage (ICH), the main clinical consequence of vascular amyloidosis, is a more poorly defined feature of DS. The clinical differences may be due to several reasons, including the premorbid brain morphology and cognitive phenotype associated with DS. However, there may also be important differences in Amyloid clearance or deposition. I will consider the cognitive phenotype associated with Down syndrome and review the typical clinical symptoms of dementia in this population, before making comparisons with sporadic AD and those with familial Duplication of the APP locus on chromosome 21 (dup-APP) to highlight potentially important mechanisms related to AD in DS. I will consider comparative research into DS and dup-APP that may yield further pathophysiological insight, as well as future clinical trials in this population. Disclosure statement: I have acted as investigator in clinical trials sponsored by Roche Pharmaceuticals
S.02.02 Biomarkers of Alzheimer’s disease pathology progression in Down syndrome P.P. De Deyn1 ° , A.D. Dekker1 1 UMCG, Alzheimer Research Center, Groningen, The Netherlands People with Down syndrome (DS) have a strongly increased risk to develop dementia due to Alzheimer’s disease (AD). From the age of forty, AD-like neuropathology is omnipresent in virtually all DS individuals. However, 30−50% do not develop clinical dementia symptoms in their life. Predicting and monitoring the onset and progression of dementia in DS is thus of utmost importance for adaptive caregiving and early therapeutic interventions [1]. In the general population, AD diagnosis is aided by fairly sensitive CSF biomarkers: low Ab1−42 and elevated tau (t-tau and p-tau). However, such a general CSF biomarker profile is not yet established in DS. Only a few suboptimal CSF studies have been conducted, yielding contradictory results. Instead, efforts focused on Ab1−40 and Ab1−42 in plasma (reduced sampling invasiveness), but results have been controversial [2]. More recently, PET imaging using Pittsburgh compound-B (PIB) revealed that PIB binding was significantly associated with dementia status, though all DS individuals aged 49 years and older showed abnormal binding regardless of the presence of clinical dementia [3]. Given the extensive amyloid pathology in DS from the age of forty, the predictive value of amyloid imaging for dementia diagnostics requires further study. Apart from amyloid and tau, mounting evidence illustrates the great potential of alternative AD biomarkers, such as serum MHPG [4], telomere shortening and Dyrk1a. Despite all efforts, a (combination of) AD biomarker(s) is not yet available in clinic. This presentation summarizes the current situation, and discusses MHPG as a very promising example of non-classical AD biomarker development. References [1] Dekker AD, Strydom A, Coppus AMW, Nizetic D, Vermeiren Y, Naude PJW, et al., 2015. Behavioural and psychological symptoms of
dementia in Down syndrome: Early indicators of clinical Alzheimer’s disease? Cortex 73, 36−61. [2] Coppus AMW, Schuur M, Vergeer J, Janssens ACJW, Oostra BA, Verbeek MM, et al., 2012. Plasma beta amyloid and the risk of Alzheimer’s disease in Down syndrome. Neurobiol Aging 33, 1988−94. [3] Annus T, Wilson LR, Hong YT, Acosta-Cabronero J, Fryer TD, Cardenas-Blanco A, et al., 2015. The pattern of amyloid accumulation in the brains of adults with Down syndrome. Alzheimers Dement, in press. [4] Dekker AD, Coppus AMW, Vermeiren Y, Aerts T, van Duijn CM, Kremer BP, et al., 2015. Serum MHPG strongly predicts conversion to Alzheimer’s disease in behaviorally characterized subjects with Down syndrome. J Alzheimer’s Dis 43, 871−91.
S.02.03 DYRK1A as a biomarker and a therapeutic target for cognitive deficits in Down syndrome and Alzheimer’s disease J.M. Delabar1 ° , N. Janel2 , A. Badel3 , J. Paul4 , A.S. Rebillat5 , P. Coskun6 , J. Busciglio6 , I. Lott6 , M. Schubert7 , M. Sarazin8 , P. Alexopoulos9 1 Institut du Cerveau et de la Moelle, CNRS UMR7225- INSERM U1127, Paris, France; 2 CNRS and Univ Paris Diderot, UMR 8251, Paris, France; 3 Univ Paris Diderot, MTI, Paris, France; 4 AP-HP- Hˆopital Europ´een Georges Pompidou, Biochimie, Paris, France; 5 Institut medical Lejeune, Gerontologie, Paris, France; 6 Univ of California, Univ of Irvine, Irvine, USA; 7 Technische Universit¨at M¨unchen, Imaging, Munich, Germany; 8 Centre Hospitalier Sainte Anne, Neurology of memory and language, Paris, France; 9 Technische Universit¨at M¨unchen, Psychiatry, Munich, Germany Extensive brain amyloidosis, typically associated with dementia, has been noted at autopsy of older individuals who exhibited few or no cognitive complaints prior to death. Biomarkers that may help predict disease before onset or progression of symptoms are critically needed. We have previously shown in mice that hyperhomocysteinemia is associated with a decrease of DYRK1A, a kinase active in brain and tau phosphorylation, in liver and an increase in brain. DYRK1A was detected in plasma and measured in individuals with Alzheimer’s disease (AD). DYRK1A but not DYRK1B levels were significantly lower in plasma and in lymphoblastoid cell lines (LCLs) from AD patients as compared to age-matched controls [1]. A second independent cohort gave similar results. Further, plasma levels of several markers related to AD and to DYRK1A expression in mouse models (BDNF, ApoD, and homocysteine) were found altered in both AD cohorts. ROC curve analysis suggest that plasma DYRK1A might be an efficient risk marker for AD. AD-like dementia is also common in older individuals with Down syndrome (DS) though with a much earlier onset: DYRK1A levels in LCLs from patients with DS and dementia were found decreased when compared to non-demented DS. DYRK1A is also a risk marker for AD in DS. References [1] Janel N, Sarazin M, Corlier F, Corne H, de Souza LC, Hamelin L, Aka A, Lagarde J, Blehaut H, Hindi´e V, Rain JC, Arbones ML, Dubois B, Potier MC, Bottlaender M, Delabar JM. Plasma DYRK1A as a novel risk factor for Alzheimer’s disease. Transl Psychiatry. 2014 Aug 12;4:e425.
S.02. Alzheimer-type dementia in people with Down syndrome
Protein gene (APP) which lies on chromosome 21 and its presence in three copies in DS is thought to largely drive the early onset of AD. It has been noted that the presentation of dementia in individuals with DS differs from sporadic AD, which affects how clinicians diagnose AD in this population. For example, symptoms related to frontal lobe problems are common, but intracerebral haemorrhage (ICH), the main clinical consequence of vascular amyloidosis, is a more poorly defined feature of DS. The clinical differences may be due to several reasons, including the premorbid brain morphology and cognitive phenotype associated with DS. However, there may also be important differences in Amyloid clearance or deposition. I will consider the cognitive phenotype associated with Down syndrome and review the typical clinical symptoms of dementia in this population, before making comparisons with sporadic AD and those with familial Duplication of the APP locus on chromosome 21 (dup-APP) to highlight potentially important mechanisms related to AD in DS. I will consider comparative research into DS and dup-APP that may yield further pathophysiological insight, as well as future clinical trials in this population. Disclosure statement: I have acted as investigator in clinical trials sponsored by Roche Pharmaceuticals
S.02.02 Biomarkers of Alzheimer’s disease pathology progression in Down syndrome P.P. De Deyn1 ° , A.D. Dekker1 1 UMCG, Alzheimer Research Center, Groningen, The Netherlands People with Down syndrome (DS) have a strongly increased risk to develop dementia due to Alzheimer’s disease (AD). From the age of forty, AD-like neuropathology is omnipresent in virtually all DS individuals. However, 30−50% do not develop clinical dementia symptoms in their life. Predicting and monitoring the onset and progression of dementia in DS is thus of utmost importance for adaptive caregiving and early therapeutic interventions [1]. In the general population, AD diagnosis is aided by fairly sensitive CSF biomarkers: low Ab1−42 and elevated tau (t-tau and p-tau). However, such a general CSF biomarker profile is not yet established in DS. Only a few suboptimal CSF studies have been conducted, yielding contradictory results. Instead, efforts focused on Ab1−40 and Ab1−42 in plasma (reduced sampling invasiveness), but results have been controversial [2]. More recently, PET imaging using Pittsburgh compound-B (PIB) revealed that PIB binding was significantly associated with dementia status, though all DS individuals aged 49 years and older showed abnormal binding regardless of the presence of clinical dementia [3]. Given the extensive amyloid pathology in DS from the age of forty, the predictive value of amyloid imaging for dementia diagnostics requires further study. Apart from amyloid and tau, mounting evidence illustrates the great potential of alternative AD biomarkers, such as serum MHPG [4], telomere shortening and Dyrk1a. Despite all efforts, a (combination of) AD biomarker(s) is not yet available in clinic. This presentation summarizes the current situation, and discusses MHPG as a very promising example of non-classical AD biomarker development. References [1] Dekker AD, Strydom A, Coppus AMW, Nizetic D, Vermeiren Y, Naude PJW, et al., 2015. Behavioural and psychological symptoms of
dementia in Down syndrome: Early indicators of clinical Alzheimer’s disease? Cortex 73, 36−61. [2] Coppus AMW, Schuur M, Vergeer J, Janssens ACJW, Oostra BA, Verbeek MM, et al., 2012. Plasma beta amyloid and the risk of Alzheimer’s disease in Down syndrome. Neurobiol Aging 33, 1988−94. [3] Annus T, Wilson LR, Hong YT, Acosta-Cabronero J, Fryer TD, Cardenas-Blanco A, et al., 2015. The pattern of amyloid accumulation in the brains of adults with Down syndrome. Alzheimers Dement, in press. [4] Dekker AD, Coppus AMW, Vermeiren Y, Aerts T, van Duijn CM, Kremer BP, et al., 2015. Serum MHPG strongly predicts conversion to Alzheimer’s disease in behaviorally characterized subjects with Down syndrome. J Alzheimer’s Dis 43, 871−91.
S.02.03 DYRK1A as a biomarker and a therapeutic target for cognitive deficits in Down syndrome and Alzheimer’s disease J.M. Delabar1 ° , N. Janel2 , A. Badel3 , J. Paul4 , A.S. Rebillat5 , P. Coskun6 , J. Busciglio6 , I. Lott6 , M. Schubert7 , M. Sarazin8 , P. Alexopoulos9 1 Institut du Cerveau et de la Moelle, CNRS UMR7225- INSERM U1127, Paris, France; 2 CNRS and Univ Paris Diderot, UMR 8251, Paris, France; 3 Univ Paris Diderot, MTI, Paris, France; 4 AP-HP- Hˆopital Europ´een Georges Pompidou, Biochimie, Paris, France; 5 Institut medical Lejeune, Gerontologie, Paris, France; 6 Univ of California, Univ of Irvine, Irvine, USA; 7 Technische Universit¨at M¨unchen, Imaging, Munich, Germany; 8 Centre Hospitalier Sainte Anne, Neurology of memory and language, Paris, France; 9 Technische Universit¨at M¨unchen, Psychiatry, Munich, Germany Extensive brain amyloidosis, typically associated with dementia, has been noted at autopsy of older individuals who exhibited few or no cognitive complaints prior to death. Biomarkers that may help predict disease before onset or progression of symptoms are critically needed. We have previously shown in mice that hyperhomocysteinemia is associated with a decrease of DYRK1A, a kinase active in brain and tau phosphorylation, in liver and an increase in brain. DYRK1A was detected in plasma and measured in individuals with Alzheimer’s disease (AD). DYRK1A but not DYRK1B levels were significantly lower in plasma and in lymphoblastoid cell lines (LCLs) from AD patients as compared to age-matched controls [1]. A second independent cohort gave similar results. Further, plasma levels of several markers related to AD and to DYRK1A expression in mouse models (BDNF, ApoD, and homocysteine) were found altered in both AD cohorts. ROC curve analysis suggest that plasma DYRK1A might be an efficient risk marker for AD. AD-like dementia is also common in older individuals with Down syndrome (DS) though with a much earlier onset: DYRK1A levels in LCLs from patients with DS and dementia were found decreased when compared to non-demented DS. DYRK1A is also a risk marker for AD in DS. References [1] Janel N, Sarazin M, Corlier F, Corne H, de Souza LC, Hamelin L, Aka A, Lagarde J, Blehaut H, Hindi´e V, Rain JC, Arbones ML, Dubois B, Potier MC, Bottlaender M, Delabar JM. Plasma DYRK1A as a novel risk factor for Alzheimer’s disease. Transl Psychiatry. 2014 Aug 12;4:e425.