- Email: [email protected]
4 Optimal treatment for parkinson patients with cognitive disorders
S2
Abstracts / Neurobiology of Aging 33 (2012) S1–S38
Long-term studies in patients with Alzheimer’s disease (AD) treated with oral cholinesterase inhibitors (ChEIs) have shown that benefits associated with ChEI therapy are continued with extended treatment. Importantly, two prospective, three-year, open-label, non-randomized studies found that patients with AD who received higher doses of ChEIs demonstrated better functional and cognitive outcomes than patients who received lower ChEI doses, suggesting that long-term, additional clinical benefit is derived from high-dose cholinesterase inhibition. There are three ChEIs commonly used for symptomatic treatment of AD: donepezil, galantamine and rivastigmine. These ChEIs have important pharmacological differences and specificities; rivastigmine inhibits both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE); donepezil and galantamine inhibit AChE. Emerging evidence, including changes in BuChE activity and expression, points to a role for BuChE in the underlying pathology of AD, and suggests that dual ChEI treatment can provide additional benefits. Interestingly, a 13-week, open-label, randomized trial of patients with AD treated with oral donepezil, galantamine or rivastigmine revealed that donepezil and galantamine are associated with upregulation of AChE in the cerebrospinal fluid (CSF) and potential increases in AChE activity, whereas rivastigmine provided sustained inhibition of CSF AChE and BuChE. These findings were supported by the results of a long-term study which found that ChEIs demonstrate differing effects on AChE and BuChE levels, depending on their mechanism of action. The changes in AChE protein levels associated with ChEI treatment may lead to clinically relevant effects. Maximizing long-term benefit with ChEIs relies on both the selection of ChEI, and on achieving the optimal therapeutic dose. The underlying mechanism of action of ChEIs should be taken into consideration in the long-term management of AD.
3
EVIDENCE IN HUMANS LINKING A SPECIFIC AMYLOID- OLIGOMER TO TAU PATHOBIOLOGY
M. Handoko1, M. Grant1, M. Kuskowski2, A. Wallin3, K. Blennow3, Karen Ashe1, 1University of Minnesota, Minneapolis, MN, USA; 2Minneapolis VA Medical Center, Minneapolis, MN, USA; 3University of Gothenburg, Gothenburg, Sweden. Contact e-mail: [email protected] A major, unanswered question in medical science concerns the molecular agents that initiate AD. A specific A assembly, A*56, impairs memory in AD mouse models independently of neuronal death, suggesting it may trigger synaptic dysfunction in humans before there is neuron loss
severe enough to cause dementia. Here, we present evidence to support this hypothesis, in humans. Soluble globular A oligomers are thought to be the major synaptotoxic A species in AD and to trigger the pathological changes in tau leading to dementia. We previously described a 56-kDa oligomer, A*56, which impairs memory independently of amyloid plaques or neuron loss in several mouse models over-expressing A and may require the cytoskeletal protein tau to disrupt cognition. We hypothesized that A*56 contributes to memory loss and synaptic dysfunction in pre-clinical AD, because of similarities between AD mouse models and pre-clinical AD. To address this hypothesis, we examined non-demented humans with evidence of preclinical AD, as reflected by increases in CSF tau. In unimpaired subjects we found a strong positive relationships between A*56 and p-tau181 (R2 ⫽ 0.58) and total tau (R2 ⫽ 0.52), supporting the idea that A*56 may initiate pathological changes in tau. We found no significant relationship between A1-42 and tau (R2 ⫽ 0.007), indicating that brain amyloidosis and pathological tau are not directly linked. These results are consistent with a model by which A*56 induces abnormalities in tau that cause synaptic dysfunction in pre-clinical AD. This model is consistent with previous results showing that glucose hypometabolism, thought to reflect synaptic dysfunction, correlates robustly with CSF tau and ptau181, but not with CSF A1-42. Our data present a strong candidate for the missing link between A accumulation and tau pathobiology in humans, and are consistent with the hypothesis that A*56 triggers pathological processes leading ultimately to clinical dementia. Further testing of this hypothesis awaits longitudinal evaluations in humans and investigations in animals and cultured cells to elucidate the molecular mechanisms by which A*56 perturbs tau.
4
OPTIMAL TREATMENT FOR PARKINSON PATIENTS WITH COGNITIVE DISORDERS
Clive Ballard, Wolfson Centre for Age Related Diseases, King’s College London, London, UK. Contact e-mail: [email protected] Patients with Parkinson’s disease developing cognitive disorders and dementia often have complex treatment needs related to the combination of motor symptoms, autonomic dysfunction, cognitive impairment, sleep disorders, fluctuating cognition and prominent neuropsychiatric symptoms and the careful balancing and monitoring of treatment priorities for each individual is essential. In addition the delivery of individualized clinical support and care is essential to enable people to have as good a quality of life as possible. With respect to specific pharmacological interventions targeting cognition and function, a number of care series and well powered randomized placebo controlled trials of rivastigmine capsules have con-
Abstracts / Neurobiology of Aging 33 (2012) S1–S38
ferred significant benefit in patients with Parkinson’s disease dementia (PDD) and Dementia with Lewy bodies (DLB). The rivastigmine transdermal patch is better tolerated and equally efficacious to the capsules in people with Alzheimer’s disease, but there are no published RCT comparisons of the capsules and the transdermal patch in PDD or DLB. Whilst open case series also indicate potential benefit of other cholinesterase inhibitors for the treatment of patients with DLB and PDD, there are no large RCTs of galanthamine in these patient populations, and the only large placebo controlled RCT of donepezil showed modest benefits on some cognitive outcomes, but not on function. Case series data also indicates the potential for benefit from cholinesterase inhibitors in PD patients with less severe cognitive impairment. More recently several placebo controlled RCTs have indicated global clinical benefit with memantine in combined DLB/PDD patient groups, but the specific impact on cognition and function is less clear. A retrospective analysis of one of the studies indicated particular benefit with respect to sleep disturbances, including REM sleep behaviour disorder. The treatment of neuropsychiatric disorders is co0mplicated in these individuals and should always follow the principles of good clinical practice to exclude delirium, other underlying medical problems, contributing sensory impairments and pain. A review and rationalization of other pharmacological therapies which may be contributing, including treatments for motor symptoms is usually helpful. When specific pharmacological treatments are required, the RCTs of rivastigmine in DLB/PDD suggest modest but significant benefits in overall neuropsychiatric symptoms, with greatest benefit seem in individuals with visual hallucinations. The only placebo controlled RCT of an antipsychotic, quetiapine, failed to demonstrate any significant benefit in this patient population, and there is a significant risk of severe neuroleptic sensitivity reactions in DLB and PDD patients and in PD patients with less severe cognitive impairment. To date there has been only modest development of candidate disease modifying therapies, but recent advances in PDD animal models will enable rapid progress in this area over the next few years, with cellular therapies and treatments targeting protein aggregation amongst the emerging candidates.
5
ARE WE READY WITH A NEW TRIAL DESIGN?
Robert E. Becker1, N. Greig2, 1Aristea Translational Medicine Corp., South Freeport ME USA; 2National Institute on Aging, Baltimore, MD, USA. Contact e-mail: [email protected] Recent studies have called into question the degrees of confidence to be afforded to some abandoned drug developments of Alzheimer’s disease (AD) therapy candidates. If the science underlying AD drug developments lacks resources of methods and practices necessary to overcome
S3
threats to invalidation then innovations in design, such as evaluations of drug effects in MCI or other pre-AD conditions may unfortunately fail unnecessarily. Very probably some of the 200 ⫹ AD drug candidates abandoned in development were mistaken as lacking efficacy when in fact the methods and practices used in their development were not able to overcome threats to invalidation. Efficacy, present or absent, was never tested and these candidates abandoned inappropriately. We will present interventions keyed to testing innovative AD trial designs and illustrate and discuss with one or more candidates for pre-AD therapy applications of these interventions supported by our research.
6
HOW SHOULD WE STRUCTURE CARE FOR ALZHEIMER PATIENTS?
Howard Bergman, McGill University/Jewish General Hospital, Montreal, Quebec, Canada. Contact e-mail: [email protected] Alzheimer’s disease’s (AD) already considerable impact on individuals, families and communities as well on resources of the health care system and society is growing dramatically with the aging of the population. It is estimated that nearly one baby boomer in five will develop AD in his or her lifetime. The urgent need to act is recognized internationally. The Quebec AD plan identified the following key requirements for meeting the challenge successfully: 1) increasing knowledge of AD and adopting different attitudes toward people with AD and their families; 2) providing people with AD and families access to co-ordinated, personalized services in a user-friendly system, at all stages of the disease; 3) enhancing quality of life/care for people with AD in alternative living facilities; 4) enhancing quality of life/care at end of life for people with AD; 5) enhancing quality of life/care for informal caregivers; 6) enhancing training and motivation for professionals and support staff; 7) conducting research contributing to high-quality treatment and care. The aim is not to create an “AD healthcare system,” but identify the specific nature of the problem and to propose judicious, coherent changes in the current healthcare system. Central to the plan is the objective to provide access to personalized, co-ordinated assessment and treatment services for people with AD and their family/informal caregivers. The central idea for achieving this objective is to empower and enhance the capacity of primary care to detect, diagnose and treat AD and related disorders according to the chronic-care management model and the collaborative practice model. The first step in doing so will be to establish partnerships between primary care physician-andnurse teams working in Family Medicine Groups on the one
Abstracts / Neurobiology of Aging 33 (2012) S1–S38
Long-term studies in patients with Alzheimer’s disease (AD) treated with oral cholinesterase inhibitors (ChEIs) have shown that benefits associated with ChEI therapy are continued with extended treatment. Importantly, two prospective, three-year, open-label, non-randomized studies found that patients with AD who received higher doses of ChEIs demonstrated better functional and cognitive outcomes than patients who received lower ChEI doses, suggesting that long-term, additional clinical benefit is derived from high-dose cholinesterase inhibition. There are three ChEIs commonly used for symptomatic treatment of AD: donepezil, galantamine and rivastigmine. These ChEIs have important pharmacological differences and specificities; rivastigmine inhibits both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE); donepezil and galantamine inhibit AChE. Emerging evidence, including changes in BuChE activity and expression, points to a role for BuChE in the underlying pathology of AD, and suggests that dual ChEI treatment can provide additional benefits. Interestingly, a 13-week, open-label, randomized trial of patients with AD treated with oral donepezil, galantamine or rivastigmine revealed that donepezil and galantamine are associated with upregulation of AChE in the cerebrospinal fluid (CSF) and potential increases in AChE activity, whereas rivastigmine provided sustained inhibition of CSF AChE and BuChE. These findings were supported by the results of a long-term study which found that ChEIs demonstrate differing effects on AChE and BuChE levels, depending on their mechanism of action. The changes in AChE protein levels associated with ChEI treatment may lead to clinically relevant effects. Maximizing long-term benefit with ChEIs relies on both the selection of ChEI, and on achieving the optimal therapeutic dose. The underlying mechanism of action of ChEIs should be taken into consideration in the long-term management of AD.
3
EVIDENCE IN HUMANS LINKING A SPECIFIC AMYLOID- OLIGOMER TO TAU PATHOBIOLOGY
M. Handoko1, M. Grant1, M. Kuskowski2, A. Wallin3, K. Blennow3, Karen Ashe1, 1University of Minnesota, Minneapolis, MN, USA; 2Minneapolis VA Medical Center, Minneapolis, MN, USA; 3University of Gothenburg, Gothenburg, Sweden. Contact e-mail: [email protected] A major, unanswered question in medical science concerns the molecular agents that initiate AD. A specific A assembly, A*56, impairs memory in AD mouse models independently of neuronal death, suggesting it may trigger synaptic dysfunction in humans before there is neuron loss
severe enough to cause dementia. Here, we present evidence to support this hypothesis, in humans. Soluble globular A oligomers are thought to be the major synaptotoxic A species in AD and to trigger the pathological changes in tau leading to dementia. We previously described a 56-kDa oligomer, A*56, which impairs memory independently of amyloid plaques or neuron loss in several mouse models over-expressing A and may require the cytoskeletal protein tau to disrupt cognition. We hypothesized that A*56 contributes to memory loss and synaptic dysfunction in pre-clinical AD, because of similarities between AD mouse models and pre-clinical AD. To address this hypothesis, we examined non-demented humans with evidence of preclinical AD, as reflected by increases in CSF tau. In unimpaired subjects we found a strong positive relationships between A*56 and p-tau181 (R2 ⫽ 0.58) and total tau (R2 ⫽ 0.52), supporting the idea that A*56 may initiate pathological changes in tau. We found no significant relationship between A1-42 and tau (R2 ⫽ 0.007), indicating that brain amyloidosis and pathological tau are not directly linked. These results are consistent with a model by which A*56 induces abnormalities in tau that cause synaptic dysfunction in pre-clinical AD. This model is consistent with previous results showing that glucose hypometabolism, thought to reflect synaptic dysfunction, correlates robustly with CSF tau and ptau181, but not with CSF A1-42. Our data present a strong candidate for the missing link between A accumulation and tau pathobiology in humans, and are consistent with the hypothesis that A*56 triggers pathological processes leading ultimately to clinical dementia. Further testing of this hypothesis awaits longitudinal evaluations in humans and investigations in animals and cultured cells to elucidate the molecular mechanisms by which A*56 perturbs tau.
4
OPTIMAL TREATMENT FOR PARKINSON PATIENTS WITH COGNITIVE DISORDERS
Clive Ballard, Wolfson Centre for Age Related Diseases, King’s College London, London, UK. Contact e-mail: [email protected] Patients with Parkinson’s disease developing cognitive disorders and dementia often have complex treatment needs related to the combination of motor symptoms, autonomic dysfunction, cognitive impairment, sleep disorders, fluctuating cognition and prominent neuropsychiatric symptoms and the careful balancing and monitoring of treatment priorities for each individual is essential. In addition the delivery of individualized clinical support and care is essential to enable people to have as good a quality of life as possible. With respect to specific pharmacological interventions targeting cognition and function, a number of care series and well powered randomized placebo controlled trials of rivastigmine capsules have con-
Abstracts / Neurobiology of Aging 33 (2012) S1–S38
ferred significant benefit in patients with Parkinson’s disease dementia (PDD) and Dementia with Lewy bodies (DLB). The rivastigmine transdermal patch is better tolerated and equally efficacious to the capsules in people with Alzheimer’s disease, but there are no published RCT comparisons of the capsules and the transdermal patch in PDD or DLB. Whilst open case series also indicate potential benefit of other cholinesterase inhibitors for the treatment of patients with DLB and PDD, there are no large RCTs of galanthamine in these patient populations, and the only large placebo controlled RCT of donepezil showed modest benefits on some cognitive outcomes, but not on function. Case series data also indicates the potential for benefit from cholinesterase inhibitors in PD patients with less severe cognitive impairment. More recently several placebo controlled RCTs have indicated global clinical benefit with memantine in combined DLB/PDD patient groups, but the specific impact on cognition and function is less clear. A retrospective analysis of one of the studies indicated particular benefit with respect to sleep disturbances, including REM sleep behaviour disorder. The treatment of neuropsychiatric disorders is co0mplicated in these individuals and should always follow the principles of good clinical practice to exclude delirium, other underlying medical problems, contributing sensory impairments and pain. A review and rationalization of other pharmacological therapies which may be contributing, including treatments for motor symptoms is usually helpful. When specific pharmacological treatments are required, the RCTs of rivastigmine in DLB/PDD suggest modest but significant benefits in overall neuropsychiatric symptoms, with greatest benefit seem in individuals with visual hallucinations. The only placebo controlled RCT of an antipsychotic, quetiapine, failed to demonstrate any significant benefit in this patient population, and there is a significant risk of severe neuroleptic sensitivity reactions in DLB and PDD patients and in PD patients with less severe cognitive impairment. To date there has been only modest development of candidate disease modifying therapies, but recent advances in PDD animal models will enable rapid progress in this area over the next few years, with cellular therapies and treatments targeting protein aggregation amongst the emerging candidates.
5
ARE WE READY WITH A NEW TRIAL DESIGN?
Robert E. Becker1, N. Greig2, 1Aristea Translational Medicine Corp., South Freeport ME USA; 2National Institute on Aging, Baltimore, MD, USA. Contact e-mail: [email protected] Recent studies have called into question the degrees of confidence to be afforded to some abandoned drug developments of Alzheimer’s disease (AD) therapy candidates. If the science underlying AD drug developments lacks resources of methods and practices necessary to overcome
S3
threats to invalidation then innovations in design, such as evaluations of drug effects in MCI or other pre-AD conditions may unfortunately fail unnecessarily. Very probably some of the 200 ⫹ AD drug candidates abandoned in development were mistaken as lacking efficacy when in fact the methods and practices used in their development were not able to overcome threats to invalidation. Efficacy, present or absent, was never tested and these candidates abandoned inappropriately. We will present interventions keyed to testing innovative AD trial designs and illustrate and discuss with one or more candidates for pre-AD therapy applications of these interventions supported by our research.
6
HOW SHOULD WE STRUCTURE CARE FOR ALZHEIMER PATIENTS?
Howard Bergman, McGill University/Jewish General Hospital, Montreal, Quebec, Canada. Contact e-mail: [email protected] Alzheimer’s disease’s (AD) already considerable impact on individuals, families and communities as well on resources of the health care system and society is growing dramatically with the aging of the population. It is estimated that nearly one baby boomer in five will develop AD in his or her lifetime. The urgent need to act is recognized internationally. The Quebec AD plan identified the following key requirements for meeting the challenge successfully: 1) increasing knowledge of AD and adopting different attitudes toward people with AD and their families; 2) providing people with AD and families access to co-ordinated, personalized services in a user-friendly system, at all stages of the disease; 3) enhancing quality of life/care for people with AD in alternative living facilities; 4) enhancing quality of life/care at end of life for people with AD; 5) enhancing quality of life/care for informal caregivers; 6) enhancing training and motivation for professionals and support staff; 7) conducting research contributing to high-quality treatment and care. The aim is not to create an “AD healthcare system,” but identify the specific nature of the problem and to propose judicious, coherent changes in the current healthcare system. Central to the plan is the objective to provide access to personalized, co-ordinated assessment and treatment services for people with AD and their family/informal caregivers. The central idea for achieving this objective is to empower and enhance the capacity of primary care to detect, diagnose and treat AD and related disorders according to the chronic-care management model and the collaborative practice model. The first step in doing so will be to establish partnerships between primary care physician-andnurse teams working in Family Medicine Groups on the one