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Supporting Caregivers
Alzheimer’s & Dementia 7 (Suppl 1) (2011) CP-03
SUPPORTING CAREGIVERS
Mary Mittelman, DrPH, NYU Center of Excellence on Brain Aging, New York. Background: Family caregivers are essential to the care management of people with dementia. Depending on the severity of dementia, their roles can include decision-making, advocating for the person with dementia in the health care system, providing personal care, homemaking and financial planning and managing formal care services. According to the World Alzheimer Report 2010, prepared by Alzheimer’s Disease International, the worldwide costs of dementia exceeded 1 percent of global GDP in 2010, at $604 billion, US. This estimate included the value of informal care, which was estimated at $251.89 billion US. Caregiving can cause physical, psychological, social and financial burden and increases the risk of depression and physical illness which may lead to termination of informal care and greater societal costs. Thus support for family caregivers is essential, not only to their well-being and that of the person with dementia, but also to reduce the financial burden of relying on formal care systems. Interventions to help caregivers include education, informal support, improving coping strategies, skills training, formal services and enjoyable shared activities with the person with dementia and have various degrees of evidence of efficacy. Interventions can be provided to individuals or groups, and have one or many components. They can involve only the caregiver, the person with dementia and the caregiver, or the caregiver and additional family members. The context of care (i.e., race and ethnicity, socioeconomic status, relationship of caregiver to care receiver and the age, gender and health of the caregiver) can influence the selection of the most appropriate intervention for a specific caregiver. Most interventions are delivered in person, but telephone and internet based interventions are being developed, and may be useful to reach caregivers whose obligations or location make in person counseling less feasible. Some interventions are provided uniformly to all who apply, while others are individualized, based on an assessment of specific need. Caregiver support should be considered an integral part of good comprehensive care for persons with dementia. Physicians play an important role in addressing caregivers’ reluctance to accept help and support for themselves and overcoming other barriers to utilization of these interventions.
S4-03-01
THE CSF LEVELS OF Ab42, BUT NOT TAU, ARE FULLY CHANGED ALREADY 5-10 YEARS BEFORE ONSET OF ALZHEIMER’S DEMENTIA Asa Wallin2, Peder Buchhave1, Oskar Hansson1, Lennart Minthon2, 3 3 1 Henrik Zetterberg , Kaj Blennow , Lund University, Lund, Sweden; 2Lund University, Malm€ o, Sweden; 3University of Gothenburg, M€olndal, Sweden. Background: Early detection of prodromal Alzheimer’s disease (AD) is important as new disease-modifying therapies are most likely to be effective if initiated during early stages of the disease. Methods: 137 patients with mild cognitive impairment (MCI) underwent lumbar puncture at baseline and were followed clinically for a median duration of 9.2 years (range 4.1-11.8). Baseline cerebrospinal fluid (CSF) was analysed for total-tau (T-tau), phosphorylated tau (P-tau) and amyloid-ß1-42 (Aß42). Results: During follow-up 54% of the subjects developed AD and
16% progressed to other forms of dementia. Baseline CSF Aß42 levels were reduced and T-tau and P-tau were elevated in patients who converted to AD during follow-up as compared with non-converters (p <0.0001). CSF Aß42 levels were equally reduced at baseline in patients with MCI who converted to AD within 0-5 years (early converters) compared with those who converted to AD between 5-10 years (late converters). However, CSF T-tau and P-tau were significantly higher in the early converters compared with the late converters. A ratio of baseline Aß42/P-tau predicted the development of AD within 9.2 years with a sensitivity of 88%, specificity of 90%, positive predictive value of 91% and negative predictive value of 86%. Conclusions: Around 90% of MCI patients with pathological CSF biomarkers at baseline will develop AD within 9-10 years. Aß42 levels are already fully decreased at least 5-10 years before conversion to AD dementia, while T-tau and P-tau seem to be later markers. These results provide direct support in humans for the hypothesis that altered Aß metabolism precedes tau-related pathology and neuronal degeneration.
S4-03-02
DISCOVERY OF NOVEL [18F]-PET AGENTS FOR IMAGING NEUROFIBRILLARY TANGLES (NFTS)
Hartmuth Kolb, Siemens, Culver City, California, United States. Background: There are two main neuropathologic hallmarks in AD, senile neuritic plaques (SP) around an amyloid beta core and neurofibrillar protein aggregates containing tau protein. In AD patients tau is abnormally phosphorylated and loses its normal function. Unlike ß-amyloid plaque deposition, human post-mortem studies indicate that neurofibrillary tangle density correlates with neurodegeneration and cognitive impairment. Furthermore, abundant neurofibrillary tangles are not observed in cognitively unimpaired individuals, in contrast to ß-amyloid plaques that can be present also in cognitively normal people. Therefore, a tau PET tracer might be a good diagnostic tool for Alzheimer’s disease that can be correlated with the progression of clinical symptoms. Methods: In order to screen many compounds as potential tau binders, we developed a competitive autoradiography screening method utilizing human AD brain sections. Brain sections from over 40 human AD brains were immunostained for tau and Aß and quantified by area measurements. Selectivity of tau binding compounds was determined by competition experiments in tau rich or Aß rich brain sections. Grey and white matter binding was measured for each candidate. Double staining of fluorescent analogs confirms binding of these compounds to tau tangles in AD brains. Brain uptake of [F18]-labeled tracers was measured in rodents and monkeys. Metabolism and pharmacokinetic studies were performed in mice. Results: We have discovered several novel, small molecule tau binding compounds that show high selectivity for native tau aggregates in human AD brain sections over ß-amyloid. Several of these candidates were further optimized to show a high brain uptake/fast clearance in mice, rats, and monkeys. White matter distribution in monkeys is very low. Metabolism studies of our lead candidates show very good stability in plasma and no metabolite presence in mouse brains. Conclusions: We have identified several novel small heterocyclic tau binders. Our in vitro and in vivo studies confirm that our lead candidate [F18]-T808 binds to tau selectively over ß-amyloid, shows good PK and metabolic properties, and exhibits excellent brain uptake/washout kinetics in rodent and monkey brains.
SUPPORTING CAREGIVERS
Mary Mittelman, DrPH, NYU Center of Excellence on Brain Aging, New York. Background: Family caregivers are essential to the care management of people with dementia. Depending on the severity of dementia, their roles can include decision-making, advocating for the person with dementia in the health care system, providing personal care, homemaking and financial planning and managing formal care services. According to the World Alzheimer Report 2010, prepared by Alzheimer’s Disease International, the worldwide costs of dementia exceeded 1 percent of global GDP in 2010, at $604 billion, US. This estimate included the value of informal care, which was estimated at $251.89 billion US. Caregiving can cause physical, psychological, social and financial burden and increases the risk of depression and physical illness which may lead to termination of informal care and greater societal costs. Thus support for family caregivers is essential, not only to their well-being and that of the person with dementia, but also to reduce the financial burden of relying on formal care systems. Interventions to help caregivers include education, informal support, improving coping strategies, skills training, formal services and enjoyable shared activities with the person with dementia and have various degrees of evidence of efficacy. Interventions can be provided to individuals or groups, and have one or many components. They can involve only the caregiver, the person with dementia and the caregiver, or the caregiver and additional family members. The context of care (i.e., race and ethnicity, socioeconomic status, relationship of caregiver to care receiver and the age, gender and health of the caregiver) can influence the selection of the most appropriate intervention for a specific caregiver. Most interventions are delivered in person, but telephone and internet based interventions are being developed, and may be useful to reach caregivers whose obligations or location make in person counseling less feasible. Some interventions are provided uniformly to all who apply, while others are individualized, based on an assessment of specific need. Caregiver support should be considered an integral part of good comprehensive care for persons with dementia. Physicians play an important role in addressing caregivers’ reluctance to accept help and support for themselves and overcoming other barriers to utilization of these interventions.
S4-03-01
THE CSF LEVELS OF Ab42, BUT NOT TAU, ARE FULLY CHANGED ALREADY 5-10 YEARS BEFORE ONSET OF ALZHEIMER’S DEMENTIA Asa Wallin2, Peder Buchhave1, Oskar Hansson1, Lennart Minthon2, 3 3 1 Henrik Zetterberg , Kaj Blennow , Lund University, Lund, Sweden; 2Lund University, Malm€ o, Sweden; 3University of Gothenburg, M€olndal, Sweden. Background: Early detection of prodromal Alzheimer’s disease (AD) is important as new disease-modifying therapies are most likely to be effective if initiated during early stages of the disease. Methods: 137 patients with mild cognitive impairment (MCI) underwent lumbar puncture at baseline and were followed clinically for a median duration of 9.2 years (range 4.1-11.8). Baseline cerebrospinal fluid (CSF) was analysed for total-tau (T-tau), phosphorylated tau (P-tau) and amyloid-ß1-42 (Aß42). Results: During follow-up 54% of the subjects developed AD and
16% progressed to other forms of dementia. Baseline CSF Aß42 levels were reduced and T-tau and P-tau were elevated in patients who converted to AD during follow-up as compared with non-converters (p <0.0001). CSF Aß42 levels were equally reduced at baseline in patients with MCI who converted to AD within 0-5 years (early converters) compared with those who converted to AD between 5-10 years (late converters). However, CSF T-tau and P-tau were significantly higher in the early converters compared with the late converters. A ratio of baseline Aß42/P-tau predicted the development of AD within 9.2 years with a sensitivity of 88%, specificity of 90%, positive predictive value of 91% and negative predictive value of 86%. Conclusions: Around 90% of MCI patients with pathological CSF biomarkers at baseline will develop AD within 9-10 years. Aß42 levels are already fully decreased at least 5-10 years before conversion to AD dementia, while T-tau and P-tau seem to be later markers. These results provide direct support in humans for the hypothesis that altered Aß metabolism precedes tau-related pathology and neuronal degeneration.
S4-03-02
DISCOVERY OF NOVEL [18F]-PET AGENTS FOR IMAGING NEUROFIBRILLARY TANGLES (NFTS)
Hartmuth Kolb, Siemens, Culver City, California, United States. Background: There are two main neuropathologic hallmarks in AD, senile neuritic plaques (SP) around an amyloid beta core and neurofibrillar protein aggregates containing tau protein. In AD patients tau is abnormally phosphorylated and loses its normal function. Unlike ß-amyloid plaque deposition, human post-mortem studies indicate that neurofibrillary tangle density correlates with neurodegeneration and cognitive impairment. Furthermore, abundant neurofibrillary tangles are not observed in cognitively unimpaired individuals, in contrast to ß-amyloid plaques that can be present also in cognitively normal people. Therefore, a tau PET tracer might be a good diagnostic tool for Alzheimer’s disease that can be correlated with the progression of clinical symptoms. Methods: In order to screen many compounds as potential tau binders, we developed a competitive autoradiography screening method utilizing human AD brain sections. Brain sections from over 40 human AD brains were immunostained for tau and Aß and quantified by area measurements. Selectivity of tau binding compounds was determined by competition experiments in tau rich or Aß rich brain sections. Grey and white matter binding was measured for each candidate. Double staining of fluorescent analogs confirms binding of these compounds to tau tangles in AD brains. Brain uptake of [F18]-labeled tracers was measured in rodents and monkeys. Metabolism and pharmacokinetic studies were performed in mice. Results: We have discovered several novel, small molecule tau binding compounds that show high selectivity for native tau aggregates in human AD brain sections over ß-amyloid. Several of these candidates were further optimized to show a high brain uptake/fast clearance in mice, rats, and monkeys. White matter distribution in monkeys is very low. Metabolism studies of our lead candidates show very good stability in plasma and no metabolite presence in mouse brains. Conclusions: We have identified several novel small heterocyclic tau binders. Our in vitro and in vivo studies confirm that our lead candidate [F18]-T808 binds to tau selectively over ß-amyloid, shows good PK and metabolic properties, and exhibits excellent brain uptake/washout kinetics in rodent and monkey brains.