Alzheimer's - Dementia, Author Interviews / 17.02.2017
Role Identified for Neuronal Protein in Dementia of Frontotemporal Lobar Degeneration
MedicalResearch.com Interview with:
Shinsuke Ishigaki
Department of Neurology
Department of Therapeutics for Intractable Neurological Disorders
Nagoya University Graduate School of Medicine
Nagoya,Japan
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Frontotemporal lobar degeneration (FTLD) is a pathological process that
has been characterized by personality changes, abnormal behaviors,
language impairment, and progressive dementia. The genetic and
pathological similarities in fused in sarcoma (FUS), transactive
response (TAR) DNA-binding protein 43 (TDP-43), and C9orf72 in relation
to FTLD and amyotrophic lateral sclerosis (ALS) have recently lead to
the recognition that the two conditions represent points on a spectrum
of a single disease entity. Additionally, Frontotemporal lobar degeneration has also been classified as a tauopathy, characterized by an accumulation of phosphorylated
microtubule-associated protein tau (tau) in affected neurons.
Our study demonstrated a biological link between FUS/SFPQ and the regulation of
tau isoforms involved in the early phase of Frontotemporal lobar degeneration.
Dr. Pei-Jung Lin[/caption]
Pei-Jung Lin, Ph.D.
Assistant Professor
Center for the Evaluation of Value and Risk in Health
Institute for Clinical Research and Health Policy Studies
Tufts Medical Center
Boston, MA 02111
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Alzheimer’s disease (AD) is a slow, progressive disease. Many people with AD may live for years with the disease left unrecognized or untreated, in part because the early symptoms are mild and often mistaken as part of normal aging. In this study, we found that Alzheimer’s patients may use more health care services and incur higher costs than those without dementia even before they receive a formal diagnosis. For example, total Medicare expenditures were 42% higher among Alzheimer’s patients than matched controls during the year prior to diagnosis ($15,091 vs. $10,622), and 192% higher in the first year immediately following diagnosis ($27,126 vs. $9,274). We also found similar trends among Medicare patients with mild cognitive impairment (MCI)— a prodromal stage of AD and associated with higher dementia risk.
Our study suggests that an Alzheimer’s disease or MCI diagnosis appears to be prompted by other health problems such as cardiovascular and cerebrovascular diseases, pneumonia, renal failure, urinary tract infections, and blood and respiratory infections. This finding likely reflects a failure of ambulatory care related to the impact of cognitive impairment on other chronic conditions.
Dr. Alessandro Biffi[/caption]
Alessandro Biffi, MD
Behavioral Neurology and Neuropsychiatry
Departments of Neurology and Psychiatry
Massachusetts General Hospital / Harvard Medical School
MedicalResearch.com: What is the background for this study?
Dr. Biffi: Intracerebral Hemorrhage (ICH) is the most severe form of stroke. It is a form of hemorrhagic (i.e. bleeding) stroke that accounts for ~ 15% of all acute cerebrovascular conditions, affecting ~ 70,000 Americans every year. However, because of its severity it is responsible for almost half of all stroke-related disability worldwide. Survivors of ICH are at very high risk for cognitive impairment (up to and including dementia) following the acute cerebral bleeding event. However, we possess very limited understanding of the time dynamics and risk factors for post-ICH dementia. In particular, prior to our study it was unclear whether the acute cerebral injury due to ICH would be the only mechanism potentially responsible for subsequent development of dementia.
This question is motivated by prior observations suggesting that Intracerebral Hemorrhage represents the acute manifestation of cerebral small vessel disease, a progressive degenerative disorder of small caliber arteries of the central nervous system.
There exist two major subtypes of small vessel disease:
1) cerebral amyloid angiopathy, caused by the deposition of a toxic protein product, beta-amyloid, in the blood vessels (in a process similar to the formation of beta-amyloid plaques that cause Alzheimer's disease);
2) arteriolosclerosis, caused by long-standing elevated blood pressure. ICH survivors have been previously shown to harbor very severe small vessel disease, which has been linked to dementia in patients without cerebral bleeding.
Our hypothesis was that early-onset dementia (occurring in the first 6 months after ICH) is a manifestation of the acute neurological damage associated with cerebral bleeding, whereas delayed onset dementia (developing beyond 6 months from the acute ICH event) is associated with known markers of small vessel disease, including imaging findings on CT/MRI and genetic markers (such as the APOE gene).
Dr. Jennifer Lemon[/caption]
Jennifer Lemon, PhD
Research Associate
Medical Radiation Sciences
McMaster University
MedicalResearch.com: What is the background for this study?
Dr. Lemon: Research with the supplement began in 2000, as part of my doctoral degree; we developed the supplement to try to offset the severe cognitive deterioration and accelerated aging in a mouse model we were working with in the lab. Based on aging research, five mechanisms appeared to be key contributors to the process of aging; those include oxidative stress, inflammation, mitochondrial deterioration, membrane dysfunction and impaired glucose metabolism. The criteria we used for including components in the supplement were as follows: each one of the 30 components had scientific evidence to show they acted on one or more of the above mechanisms were able to be taken orally, and were available to humans over-the-counter. Even then the hope was that if the formulation was successful, this would make it more available to the general public.
Dr. Halima Amjad[/caption]
Halima Amjad, MD, MPH
Post-doctoral Fellow
Johns Hopkins University School of Medicine
Division of Geriatric Medicine and Gerontology
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Amjad: Safety is an important aspect of dementia care. Dementia is underdiagnosed, however, and there is limited understanding of safety issues in people with undiagnosed dementia. We wanted to better understand potentially unsafe activities and living conditions in all older adults with dementia and specifically examine these activities in undiagnosed dementia. We found that in all study participants with probable dementia, the prevalence of driving, cooking, managing finances, managing medications, or going to physician visits alone was over 20%. The prevalence was higher in older adults with probable dementia without a diagnosis, and even after accounting for sociodemographic, medical, and physical impairment factors, the odds of engaging in these activities was over 2.0 in undiagnosed versus diagnosed probable dementia. Potentially unsafe living conditions including unmet needs and performance on cognitive tests were similar between these groups.
Prof. Margitta Elvers[/caption]
Prof. Margitta Elvers, PhD
Institute of Hemostasis, Hemotherapy and Transfusion Medicine
University Clinic of the Heinrich-Heine-University Düsseldorf
Düsseldorf Germany
MedicalResearch.com: What is the background for this study? What are the main findings?
Prof. Elvers: Platelets are the main players in hemostasis and thrombosis, but are also recognized to be involved in the pathology of different neurodegenerative diseases. It is well known that amyloid-beta is able to activate platelets and to induce platelet activation. In Alzheimer’s Disease (AD) patients, platelet activation is enhanced and a correlation between AD and vascular diseases such as stroke and atherosclerosis was shown in different studies However, a direct contribution of platelets to the progression of Alzheimer’s disease (AD) was an open question for many years. In the last years our group in Düsseldorf, Germany, provided strong evidence for platelets to play a relevant role in the progression of AD, because AD transgenic mice showed enhanced platelet signaling that translated into almost unlimited thrombus formation in vitro and accelerated carotid artery occlusion in vivo suggesting that these mice are at high risk of arterial thrombosis leading to cerebrovascular and unexpectedly to cardiovascular complications that might be also relevant in AD patients. In the recent study, we analyzed the contribution of platelets, which accumulate at vascular Abeta deposits, to cerebral amyloid angiopathy (CAA), a vascular dysfunction in most of Alzheimer’s disease patients, characterized by deposits of Abeta in the wall of cerebral vessels. We found that synthetic monomeric Abeta is able to bind to integrin alphaIIbbeta3 via its RHDS (Arg-His-Asp-Ser) sequence thereby stimulating the release of adenosine diphosphate (ADP) and clusterin from platelets. ADP enhanced integrin activation via the ADP receptors P2Y1 and P2Y12 and further increased platelet clusterin release and Abeta fibril formation. Clopidogrel, an antiplatelet drug which irreversible inhibits P2Y12, inhibited Abeta aggregation in human and murine platelet cell cultures. Treatment of AD transgenic mice with clopidogrel for three months reduced clusterin plasma levels and the incidence of CAA.
Dr. Kazem Rahimi[/caption]
Kazem Rahimi, DM, MSc
Oxford Martin School
University of Oxford
United Kingdom
MedicalResearch.com: What is the background for this study?
Dr. Rahimi: Vascular dementia is the second most common cause of dementia and is increasing in prevalence worldwide. Vascular dementia often occurs after stroke and can cause apathy, depression, and a decline in cognitive function, and can eventually result in death. High blood pressure (BP) has been identified as a potential risk factor for the development of vascular dementia. However, previous studies, which have been small in size, have reported conflicting results on the relationship between blood pressure and vascular dementia.