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Article ; Online: Targeting Fyn Kinase in Alzheimer's Disease.

Nygaard, Haakon B

2017 Volume 83, Issue 4, Page(s) 369–376

Abstract: The past decade has brought tremendous progress in unraveling the pathophysiology of Alzheimer's disease (AD). While increasingly sophisticated immunotherapy targeting soluble and aggregated brain amyloid-beta (Aβ) continues to dominate clinical research ...

Abstract	The past decade has brought tremendous progress in unraveling the pathophysiology of Alzheimer's disease (AD). While increasingly sophisticated immunotherapy targeting soluble and aggregated brain amyloid-beta (Aβ) continues to dominate clinical research in AD, a deeper understanding of Aβ physiology has led to the recognition of distinct neuronal signaling pathways linking Aβ to synaptotoxicity and neurodegeneration and to new targets for therapeutic intervention. Identifying specific signaling pathways involving Aβ has allowed for the development of more precise therapeutic interventions targeting the most relevant molecular mechanisms leading to AD. In this review, I highlight the discovery of cellular prion protein as a high-affinity receptor for Aβ oligomers, and the downstream signaling pathway elucidated to date, converging on nonreceptor tyrosine kinase Fyn. I discuss preclinical studies targeting Fyn as a therapeutic intervention in AD and our recent experience with the safety, tolerability, and cerebrospinal fluid penetration of the Src family kinase inhibitor saracatinib in patients with AD. Fyn is an attractive target for AD therapeutics, not only based on its activation by Aβ via cellular prion protein but also due to its known interaction with tau, uniquely linking the two key pathologies in AD. Fyn is also a challenging target, with broad expression throughout the body and significant homology with other members of the Src family kinases, which may lead to unintended off-target effects. A phase 2a proof-of-concept clinical trial in patients with AD is currently under way, providing critical first data on the potential effectiveness of targeting Fyn in AD.
MeSH term(s)	Alzheimer Disease/drug therapy ; Alzheimer Disease/metabolism ; Amyloid beta-Peptides/metabolism ; Animals ; Benzodioxoles/pharmacology ; Enzyme Inhibitors/pharmacology ; Humans ; Prion Proteins/metabolism ; Proto-Oncogene Proteins c-fyn/drug effects ; Proto-Oncogene Proteins c-fyn/metabolism ; Quinazolines/pharmacology
Chemical Substances	Amyloid beta-Peptides ; Benzodioxoles ; Enzyme Inhibitors ; Prion Proteins ; Quinazolines ; saracatinib (9KD24QGH76) ; Proto-Oncogene Proteins c-fyn (EC 2.7.10.2)
Language	English
Publishing date	2017-06-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	209434-4
ISSN	1873-2402 ; 0006-3223
ISSN (online)	1873-2402
ISSN	0006-3223
DOI	10.1016/j.biopsych.2017.06.004
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Article ; Online: Personal value of Alzheimer's disease biomarker testing and result disclosure from the patient and care partner perspective.

Patel, Khushbu J / Yang, David / Feldman, Howard H / Hsiung, Ging-Yuek R / Nygaard, Haakon B / Best, John R / Dwosh, Emily / Robillard, Julie M / DeMarco, Mari L

Alzheimer's & dementia (New York, N. Y.)

2024 Volume 10, Issue 2, Page(s) e12463

Abstract: Introduction: We described patients' and care partners' experiences with Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarker testing and result disclosure in routine care.: Methods: IMPACT-AD BC is an observational study of clinic patients ... ...

Abstract	Introduction: We described patients' and care partners' experiences with Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarker testing and result disclosure in routine care. Methods: IMPACT-AD BC is an observational study of clinic patients who underwent AD CSF biomarker testing as part of their routine medical care ( Results: A majority of patients (90%) rated their decision to undergo testing as "easy." Post-disclosure, the majority (82%) reported overall positive feelings from having greater certainty and the ability to plan ahead, and results spurred them to adopt/continue healthy behaviors such as exercise (84%) and cognitive activities (54%). Care partners expressed relief from having more diagnostic certainty, increased appreciation of future caregiving responsibilities, and a desire to connect with support resources. Discussion: Perspectives of persons with lived experience in dementia provide new insight into the value of biomarker testing and should be included as part of evidence-guided considerations for pre-test counseling and result disclosure. Moreover, study findings identify an interval when patients and care partners are highly receptive to positive lifestyle and medical interventions.
Language	English
Publishing date	2024-04-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	2832891-7
ISSN	2352-8737 ; 2352-8737
ISSN (online)	2352-8737
ISSN	2352-8737
DOI	10.1002/trc2.12463
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Article: A Model Predicting Healthcare Capacity Gaps For Alzheimer's Disease-Modifying Treatment in Canada.

Black, Sandra E / Budd, Nathalie / Nygaard, Haakon B / Verret, Louis / Virdi, Shikha / Tamblyn Watts, Laura / Wilson, Melanie

The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques

2023 , Page(s) 1–8

Abstract: Background: Alzheimer's disease (AD) is experienced by > 600,000 Canadians. Disease-modifying therapies (DMTs) for earlier stages of disease are in development. Existing health system capacity constraints and the need for biomarker-driven diagnostics to ...

Abstract	Background: Alzheimer's disease (AD) is experienced by > 600,000 Canadians. Disease-modifying therapies (DMTs) for earlier stages of disease are in development. Existing health system capacity constraints and the need for biomarker-driven diagnostics to confirm DMT eligibility are concerning. This study aimed to characterize the capacity gap related to early AD (eAD) treatment with DMTs in Canada. Methods: A capacity model was developed to simulate the flow of a patient from screening to treatment for eAD to quantify the gap between available and required healthcare resources and qualify the bottlenecks restricting the patient journey at a provincial and national level. The model inputs (epidemiological, human resource, and clinical) were evidence-based, healthcare professional-, and patient advocate-informed. Results: The model estimated that nationally < 2% of patients would have access to the required healthcare resources for treatment with a DMT. Eligibility assessment represented the step with the largest capacity gap across all provinces, with a wait list of about 382,000 Canadians one year following DMT introduction. The top three resource gaps included AD specialist time and positron emission tomography and magnetic resonance imaging exam slots. Sensitivity analysis showed that full reliance on cerebrospinal fluid for eligibility testing increased capacity for assessment by about 47,000 patients. Conclusion: This model highlights that the Canadian health system is critically under-resourced to diagnose, assess, and treat patients with eAD with DMT. It underscores an urgent need for national policy and provincial resource allocation to close the gap.
Language	English
Publishing date	2023-08-18
Publishing country	England
Document type	Journal Article
ZDB-ID	197622-9
ISSN	0317-1671
ISSN	0317-1671
DOI	10.1017/cjn.2023.270
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Zs.A 1203: Show issues

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Article ; Online: The Use of Patient-Derived Induced Pluripotent Stem Cells for Alzheimer's Disease Modeling.

Lee, Christopher / Willerth, Stephanie M / Nygaard, Haakon B

Progress in neurobiology

2020 Volume 192, Page(s) 101804

Abstract: Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by a progressive deterioration in multiple facets of cognitive function. As the average age of the population rises, AD poses a massive current and future healthcare threat. ... ...

Abstract	Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by a progressive deterioration in multiple facets of cognitive function. As the average age of the population rises, AD poses a massive current and future healthcare threat. Today, there is no cure for AD nor well-established interventions to slow progression, and treatment is largely symptomatic. The failure rate for new drugs in clinical trials has remained high, pointing out a critical need for better disease modeling that can enhance our understanding of basic disease pathophysiology, leading to better drug discovery and preclinical validation. The advent of induced pluripotent stem cells (iPSCs) has allowed researchers access to an unlimited supply of patient cells that can be differentiated into a neural fate, allowing for modeling of neurological disorders such as AD. This development has propelled AD research and presents opportunities to produce more accurate AD models to facilitate research into pathophysiology as well as drug screening and development. In this review, we conduct an in-depth assessment of the literature to identify the majority of work to date on patient-derived iPSCs. We outline research into both the familial and sporadic forms of the disease, as well as modern methods of modeling the disease three-dimensionally. Finally, we identify challenges to be addressed and areas of further research for iPSC modeling of AD.
MeSH term(s)	Alzheimer Disease ; Bioprinting ; Humans ; Induced Pluripotent Stem Cells ; Models, Biological
Language	English
Publishing date	2020-05-25
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	185535-9
ISSN	1873-5118 ; 0301-0082
ISSN (online)	1873-5118
ISSN	0301-0082
DOI	10.1016/j.pneurobio.2020.101804
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Article ; Online: Sleep and its regulation: An emerging pathogenic and treatment frontier in Alzheimer's disease.

Kent, Brianne A / Feldman, Howard H / Nygaard, Haakon B

Progress in neurobiology

2020 Volume 197, Page(s) 101902

Abstract: A majority of patients with Alzheimer's disease (AD) experience some form of sleep disruption, including nocturnal sleep fragmentation, increased daytime napping, decreased slow-wave sleep (SWS, stage N3), and decreased rapid-eye-movement sleep (REM). ... ...

Abstract	A majority of patients with Alzheimer's disease (AD) experience some form of sleep disruption, including nocturnal sleep fragmentation, increased daytime napping, decreased slow-wave sleep (SWS, stage N3), and decreased rapid-eye-movement sleep (REM). Clinical studies are investigating whether such sleep disturbances are a consequence of the underlying disease, and whether they also contribute to the clinical and pathological manifestations of AD. Emerging research has provided a direct link between several of these sleep disruptions and AD pathophysiology, suggesting that treating sleep disorders in this population may target basic mechanisms of the disease. Here, we provide a comprehensive review of sleep disturbances associated with the spectrum of AD, ranging from the preclinical stages through dementia. We discuss how sleep interacts with AD pathophysiology and, critically, whether sleep impairments can be targeted to modify the disease course in a subgroup of affected AD patients. Ultimately, larger studies that fully utilize new diagnostic and experimental tools will be required to better define the most relevant sleep disturbance to target in AD, the interventions that best modulate this target symptom, and whether successful early intervention can modify AD risk and prevent dementia.
MeSH term(s)	Alzheimer Disease/therapy ; Humans ; Sleep ; Sleep Wake Disorders/therapy
Language	English
Publishing date	2020-08-30
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	185535-9
ISSN	1873-5118 ; 0301-0082
ISSN (online)	1873-5118
ISSN	0301-0082
DOI	10.1016/j.pneurobio.2020.101902
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Article ; Online: Current and emerging therapies for Alzheimer's disease.

Nygaard, Haakon B

Clinical therapeutics

2013 Volume 35, Issue 10, Page(s) 1480–1489

Abstract: Alzheimer's disease (AD) is a devastating neurodegenerative disorder, with a rapidly increasing worldwide prevalence. Although no cure for AD has yet been found, substantial progress has been made in our understanding of AD pathogenesis. This progress ... ...

Abstract	Alzheimer's disease (AD) is a devastating neurodegenerative disorder, with a rapidly increasing worldwide prevalence. Although no cure for AD has yet been found, substantial progress has been made in our understanding of AD pathogenesis. This progress has led to the development of numerous promising compounds in various stages of clinical testing. In this review, the current pharmacologic treatments for AD are discussed in detail, followed by an overview of the main experimental strategies that will shape AD therapeutics over the next decade.
MeSH term(s)	Alzheimer Disease/drug therapy ; Alzheimer Disease/therapy ; Amyloid beta-Peptides/metabolism ; Cholinesterase Inhibitors/pharmacology ; Cholinesterase Inhibitors/therapeutic use ; Clinical Trials as Topic ; Humans ; Immunization, Passive ; Immunotherapy, Active ; Molecular Targeted Therapy
Chemical Substances	Amyloid beta-Peptides ; Cholinesterase Inhibitors
Language	English
Publishing date	2013-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	603113-4
ISSN	1879-114X ; 0149-2918
ISSN (online)	1879-114X
ISSN	0149-2918
DOI	10.1016/j.clinthera.2013.09.009
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Zs.A 1435: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Clinical value of Alzheimer's disease biomarker testing.

Patel, Khushbu J / Yang, David / Best, John R / Chambers, Colleen / Lee, Philip E / Henri-Bhargava, Alexandre / Funnell, Clark R / Foti, Dean J / Pettersen, Jacqueline A / Feldman, Howard H / Nygaard, Haakon B / Hsiung, Ging-Yuek R / DeMarco, Mari L

Alzheimer's & dementia (New York, N. Y.)

2024 Volume 10, Issue 2, Page(s) e12464

Abstract: Introduction: In the Investigating the Impact of Alzheimer's Disease Diagnostics in British Columbia (IMPACT-AD BC) study, we aimed to understand how Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarker testing-used in medical care-impacted ... ...

Abstract	Introduction: In the Investigating the Impact of Alzheimer's Disease Diagnostics in British Columbia (IMPACT-AD BC) study, we aimed to understand how Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarker testing-used in medical care-impacted medical decision-making (medical utility), personal decision-making (personal utility), and health system economics. Methods: The study was designed as an observational, longitudinal cohort study. A total of 149 patients were enrolled between February 2019 and July 2021. Patients referred to memory clinics were approached to participate if their dementia specialist ordered AD CSF biomarker testing as part of their routine medical care, and the clinical scenario met the appropriate use criteria for lumbar puncture and AD CSF biomarker testing. For the medical utility pillar, detailed clinical management plans were collected via physician questionnaires pre- and post-biomarker disclosure. Results: Patients with completed management questionnaires ( Discussion: AD biomarker testing was associated with significant and positive changes in clinical management, including decreased health care resource use, therapy optimization, and increased patient and family member counseling. While certain changes in management were linked to the AD biomarker profile (e.g., referral to clinical trials), the majority of changes were independent of baseline clinical presentation and level of cognitive impairment, demonstrating a broad value for AD biomarker testing in individuals meeting the appropriate use criteria for testing.
Language	English
Publishing date	2024-04-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	2832891-7
ISSN	2352-8737 ; 2352-8737
ISSN (online)	2352-8737
ISSN	2352-8737
DOI	10.1002/trc2.12464
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Article ; Online: Community participation in activities and places among older adults with and without dementia.

Chaudhury, Habib / Mahal, Tanveer / Seetharaman, Kishore / Nygaard, Haakon B

Dementia (London, England)

2020 Volume 20, Issue 4, Page(s) 1213–1233

Abstract: Availability of community-based destinations and amenities can facilitate healthy aging by supporting older adults' functional abilities and enabling their participation in society, especially for those experiencing declining cognitive abilities. This ... ...

Abstract	Availability of community-based destinations and amenities can facilitate healthy aging by supporting older adults' functional abilities and enabling their participation in society, especially for those experiencing declining cognitive abilities. This study used a survey tool called participation in ACTivities and places OUTside the Home for older adults, specifically designed to examine the out-of-home participation of older adults living with or without dementia, to collect data on specific places and activities that individuals participate in over time. Thirty cognitively intact participants and 29 participants living with dementia were recruited. The past/present net participation figures indicate that all destinations are likely to be abandoned by persons with dementia over time. The findings indicate that both groups of participants were most likely to abandon recreation and physical activity places, although a higher number of persons with dementia reported that they would likely abandon these places in the future than the cognitively intact participants. Participants with dementia indicated multiple en route and at destination challenges, as well as their coping strategies. This study adds to our understanding of the out-of-home places visited by persons living with and without dementia and the patterns of changes in those visits over time. The findings are useful for health and social care professionals, including occupational therapists, social workers, as well as family caregivers, in recognizing the relative importance of certain out-of-home places and activities over others and the challenges faced by persons with dementia in getting to those places. This knowledge can inform programme and service providers to develop targeted interventions to support continued engagement by older adults with dementia and cognitively intact older adults.
MeSH term(s)	Aged ; Caregivers ; Community Participation ; Dementia ; Humans ; Social Support ; Surveys and Questionnaires
Language	English
Publishing date	2020-05-29
Publishing country	England
Document type	Journal Article
ZDB-ID	2084045-7
ISSN	1741-2684 ; 1471-3012
ISSN (online)	1741-2684
ISSN	1471-3012
DOI	10.1177/1471301220927230
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Article ; Online: Recommendations for Preclinical Testing of Treatments Against Alzheimer's Disease-Related Epileptiform Spikes in Transgenic Rodent Models.

Jin, Nanxiang / Babiloni, Claudio / Drinkenburg, Wilhelmus H / Hajós, Mihály / Nygaard, Haakon B / Tanila, Heikki

Journal of Alzheimer's disease : JAD

2021 Volume 88, Issue 3, Page(s) 849–865

Abstract: Recent evidence suggests that about 30%of patients with mild to moderate Alzheimer's disease (AD) without a known diagnosis of epilepsy may display epileptiform spikes during electroencephalographic (EEG) recordings. These abnormal discharges occur ... ...

Abstract	Recent evidence suggests that about 30%of patients with mild to moderate Alzheimer's disease (AD) without a known diagnosis of epilepsy may display epileptiform spikes during electroencephalographic (EEG) recordings. These abnormal discharges occur predominantly during sleep and may be associated with accelerated disease progression. Subclinical spikes may represent a relevant target for clinical drug interventions, and there is a clear unmet need for preclinical testing of novel disease modifying agents in suitable animal models. Transgenic rodent models of AD pathology exhibit various forms of epileptiform EEG activity related to the abnormal levels of amyloid species in the brain. Among them, large-amplitude cortical and hippocampal EEG spikes in mouse and rat AD models may be reminiscent of the subclinical epileptiform EEG spikes recorded in some AD patients. This article reports the recommendations of a multidisciplinary panel of experts on optimal EEG markers and experimental designs to measure and report epileptiform activities and their response to symptomatic and disease-modifying drugs in transgenic AD model rodents. These recommendations may harmonize future preclinical EEG studies in the drug discovery research and may increase the comparability of experimental outcomes and their translational clinical value.
MeSH term(s)	Alzheimer Disease/drug therapy ; Alzheimer Disease/genetics ; Alzheimer Disease/pathology ; Animals ; Brain/pathology ; Electroencephalography ; Epilepsy/genetics ; Mice ; Rats ; Rodentia
Language	English
Publishing date	2021-05-04
Publishing country	Netherlands
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-210209
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Article ; Online: hiPSC-derived GRN-deficient astrocytes delay spiking activity of developing neurons.

Lee, Christopher / Frew, Jonathan / Weilinger, Nicholas L / Wendt, Stefan / Cai, Wenji / Sorrentino, Stefano / Wu, Xiujuan / MacVicar, Brian A / Willerth, Stephanie M / Nygaard, Haakon B

Neurobiology of disease

2023 Volume 181, Page(s) 106124

Abstract: Frontotemporal dementia (FTD) refers to a group of neurodegenerative disorders that are characterized by pathology predominantly localized to the frontal and temporal lobes. Approximately 40% of FTD cases are familial, and up to 20% of these are caused ... ...

Abstract	Frontotemporal dementia (FTD) refers to a group of neurodegenerative disorders that are characterized by pathology predominantly localized to the frontal and temporal lobes. Approximately 40% of FTD cases are familial, and up to 20% of these are caused by heterozygous loss of function mutations in the gene encoding for progranulin (PGRN), GRN. The mechanisms by which loss of PGRN leads to FTD remain incompletely understood. While astrocytes and microglia have long been linked to the neuropathology of FTD due to mutations in GRN (FTD-GRN), a primary mechanistic role of these supporting cells have not been thoroughly addressed. In contrast, mutations in MAPT, another leading cause of familial FTD, greatly alters astrocyte gene expression leading to subsequent non-cell autonomous effects on neurons, suggesting similar mechanisms may be present in FTD-GRN. Here, we utilized human induced pluripotent stem cell (hiPSC)-derived neural tissue carrying a homozygous GRN R493X
MeSH term(s)	Humans ; Frontotemporal Dementia/pathology ; Intercellular Signaling Peptides and Proteins/genetics ; Intercellular Signaling Peptides and Proteins/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Astrocytes/metabolism ; Progranulins/genetics ; Neurons/metabolism ; Mutation ; Pick Disease of the Brain/metabolism
Chemical Substances	Intercellular Signaling Peptides and Proteins ; Progranulins ; GRN protein, human
Language	English
Publishing date	2023-04-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1211786-9
ISSN	1095-953X ; 0969-9961
ISSN (online)	1095-953X
ISSN	0969-9961
DOI	10.1016/j.nbd.2023.106124
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