Amyloid Deposits In Persons Without Dementia May Be First Sign of Alzheimer’s Disease 

MedicalResearch.com Interview with:

Willemijn Jansen, PhD  Postdoctoral researcher Department of Psychiatry & Neuropsychology Maastricht University Medical Center School for Mental Health and Neuroscience Alzheimer Center Limburg 

Dr. Jansen

Willemijn Jansen, PhD
Postdoctoral researcher
Department of Psychiatry & Neuropsychology
Maastricht University Medical Center
School for Mental Health and Neuroscience
Alzheimer Center Limburg 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Cerebral amyloid-β aggregation is an early pathological event in Alzheimer’s disease (AD), starting decades prior to dementia onset. About 25% of cognitively normal elderly and 50% of patients with mild cognitive impairment (MCI) have biomarker evidence of amyloid pathology. These persons are at increased risk for developing AD-type dementia, but the extent to which amyloid-β aggregation affects cognitive function in persons without dementia is unclear. This is important to know for a better understanding of the course of Alzheimer’s disease and for the design of AD prevention trials.

We here investigate the association between amyloid plaques and memory scores, using data from 53 international studies included in the Amyloid Biomarker study. Cognitively healthy elderly people with plaques have a low memory score twice as often as these persons without plaques. MCI patients with plaques had 20% more often low memory and low global cognition scores than MCI patients without plaques.

We further observed 10- to 15-year intervals between the onset of amyloid positivity and emergence of low memory scores in cognitively healthy persons.

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Sleep Apnea Increases Amyloid Load In Brain, A Hallmark of Alzheimer’s Disease

MedicalResearch.com Interview with:

Ricardo S Osorio MD Center for Brain Health Department of Psychiatry Center of Excellence on Brain Aging NYU Langone Medical Center New York, NY 10016, USA

Dr. Osorio

Ricardo S Osorio MD
Center for Brain Health
Department of Psychiatry
Center of Excellence on Brain Aging
NYU Langone Medical Center
New York, NY 10016, USA 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: This was a study that was performed in a group of healthy normal elderly from the community that volunteered for studies on memory and aging.

The main findings were that sleep apnea was very common, in almost all cases undiagnosed, and that it was associated with a longitudinal increase in amyloid burden which is considered one of the hallmark lesions of Alzheimer’s disease

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Hip and Knee Replacements More Common In Patients With Transthryretin Cardiac Amyloidosis

MedicalResearch.com Interview with:

Dr. Mathew Maurer, Medical Director The Hypertrophic Cardiomyopathy Center NewYork-Presbyterian/Columbia University Medical Center.

Dr. Maurer

Dr. Mathew Maurer, Medical Director
The Hypertrophic Cardiomyopathy Center
NewYork-Presbyterian/Columbia University Medical Center.

MedicalResearch.com: What is the background for this study?

Response: Transthryretin cardiac amyloidosis (TTR-CA) is an underdiagnosed type of cardiomyopathy in which TTR (transthyretin, also known as prealbumin), a protein that forms amyloid fibrils, deposits in the heart. The deposits cause thickening of the ventricular wall and diastolic as well as systolic dysfunction. It is usually discovered around age 75 and presents more commonly in men than in women. With advances in non-invasive diagnostic modalities and growing awareness, TTR-CA is being diagnosed increasingly more frequently. Additionally, there are several emerging treatments that are under active investigation. Most of these therapies prevent disease progression and don’t address the amyloid already deposited in the heart. Accordingly, it is imperative that we diagnose TTR-CA before patients develop significant amyloid heart disease. However, this presents a great challenge since there are few known clinical predictors that might alert even the most astute physician that a patient is at such risk. With identification of predictors that may appropriately raise the index of clinical suspicion, clinicians may begin to pick up more subtle (and perhaps not yet clinically significant) forms of TTR-CA and initiate treatment before significant damage occurs.

The few known clinical predictors of TTR-CA include bilateral carpal tunnel syndrome and lumbar spinal stenosis, and numerous studies found TTR on biopsies and autopsies of other musculoskeletal sites, particularly in hip and knee joints. (Just last week, and also discussed here on MedicalResearch.com, biceps tendon rupture was also shown to occur more frequently in TTR-CA!) We suspected that patients who ultimately develop TTR-CA may first develop clinically significant hip and knee disease, enough to even warrant a hip (THA) or knee (TKA) replacement.

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Ruptured Biceps Tendon and Wild-type Transthyretin Amyloidosis

MedicalResearch.com Interview with:

Avinainder Singh, M.B.B.S. Research Fellow Cardiovascular Medicine Brigham & Women's Hospital Harvard Medical School Boston, MA

Dr. Singh

Avinainder Singh, M.B.B.S.
Research Fellow
Cardiovascular Medicine
Brigham & Women’s Hospital
Harvard Medical School
Boston, MA

MedicalResearch.com: What is the background for this study?

Response: Amyloidosis due to aberrant folding of proteins. These misfolded proteins can deposit in various parts of the body and lead to organ dysfunction. The two most common types of amyloidosis affecting the heart include transthyretin and light chain amyloidosis. Transthyretin is a protein produced by the liver which supports the transport of thyroxine and retinol.

Wild-type transthyretin amyloidosis (ATTRwt, previously known as senile amyloidosis) occurs due to deposition of misfolded fibrils derived from transthyretin and primarily affects elderly men. Once considered a rare disease, it is now reported to be responsible for nearly 13% of heart failure with preserved ejected fraction and increased wall thickness.

Rupture of the biceps tendon is a rare occurrence in the general population (<1 per 1000). We noticed a ruptured biceps tendon in several patients with wild-type transthyretin amyloidosis and performed this study to further evaluate this finding in a group of patients with wild-type transthyretin amyloidosis and in a control group of age-matched patients with non-amyloid heart failure.

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Patients and Providers Feel Amyloid PET Scanning Diagnosis of Alzheimer’s Disease Beneficial

MedicalResearch.com Interview with:

Liana Apostolova, MD, MSc, FAAN Barbara and Peer Baekgaard Professor  in Alzheimer's Disease Research Professor in Neurology, Radiology. Medical and Molecular Genetics Indiana University School of Medicine Indiana Alzheimer's Disease Center Indianapolis, IN 46202

Dr. Apostolova

Liana Apostolova, MD, MSc, FAAN
Barbara and Peer Baekgaard Professor  in Alzheimer’s Disease Research
Professor in Neurology, Radiology. Medical and Molecular Genetics
Indiana University School of Medicine
Indiana Alzheimer’s Disease Center
Indianapolis, IN 46202

MedicalResearch.com: What is the background for this study?

Response: While many studies have evaluated the diagnostic or prognostic implications associated with amyloid PET, few have explored its effects on the patient or caregiver. Amyloid imaging does not only help clinicians with their diagnosis and management. It also affects patient and caregiver decisions related to lifestyle, financial and long-term care planning, and at times also employment. Few studies to date have explored patient and caregiver views on the clinical use of amyloid PET and the potential benefits they could derive from having more precise diagnosis.

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Gene Linked To Decreased Plasma Amyloid and Lower Alzheimer’s Disease Risk

MedicalResearch.com Interview with:

Mikko Hiltunen, PhD Professor of Tissue and Cell Biology University of Eastern Finland School of Medicine, Institute of Biomedicine Kuopio,  Finland

Dr. Hiltunen

Mikko Hiltunen, PhD
Professor of Tissue and Cell Biology
University of Eastern Finland
School of Medicine, Institute of Biomedicine
Kuopio,  Finland 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response:  We wanted to assess among the population-based METSIM (METabolic Syndrome In Men) cohort whether protective variant in APP gene (APP A673T) affects the beta-amyloid levels in plasma. The rationale behind this was that previous genetic studies have discovered that the APP A673T variant decreases the risk of having Alzheimer’s disease (AD).

However, the protective functional outcome measures related to this variant were lacking and thus we anticipated that the elucidation of plasma samples in terms of beta-amyloid levels would provide the much needed link between APP A673T variant and potential protective functions.

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Technetium Cardiac Imaging Predicts Prognosis of Cardiac Amyloidosis

MedicalResearch.com Interview with:

Adam Castano, M.D., M.S. Division of Cardiology Columbia University Medical Center New York Presbyterian Hospital

Dr. Adam Castano

Adam Castano, M.D., M.S.
Division of Cardiology
Columbia University Medical Center
New York Presbyterian Hospital

MedicalResearch.com: What is the background for this study?

Response: Transthyretin cardiac amyloidosis (ATTR-CA) is an increasingly recognized cause of heart failure with preserved ejection fraction (HFpEF). Traditionally, the gold standard for diagnosis has required an endomyocardial biopsy coupled with either immunohistochemistry or mass spectroscopy. These specialized tests are only performed at centers with experienced satff, do not yield prognostically useful information, may be inadvisable for frail older adults, and often present logistical challenges that lead to delayed care.

Fortunately, single center studies have demonstrated excellent diagnostic accuracy using technetium 99m pyrophosphate (Tc99mPYP) cardiac imaging for noninvasively detecting ATTR-CA and differentiating it from another major type of cardiac amyloidosis called light chain (AL). But the diagnostic accuracy of this technique in a multicenter study and the association of Tc99mPYP myocardial uptake with survival were not known prior to this study.

Therefore, we assessed in a multicenter study Tc99mPYP cardiac imaging as a diagnostic tool and its association with survival. We conducted a retrospective cohort study of 229 patients evaluated at 3 academic specialty centers for cardiac amyloidosis and also underwent Tc99mPYP cardiac imaging. We measured retention of Tc99mPYP in the heart using a semiquantitative visual score (range 0-3) and a more quantitative heart-to-contralateral (H/CL) ratio calculated as total counts in a region of interest over the heart divided by background counts in an identical size region of interest over the contralateral chest. The outcome measured was time to death after Tc99mPYP imaging.

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PET Scan Can Detect Amyloid In Alzheimer’s and Other Dementias

Rik Ossenkoppele PhD. Postdoctoral researcher UCSF Memory and Aging CenterMedicalResearch.com Interview with:
Rik Ossenkoppele PhD.
Postdoctoral researcher
UCSF Memory and Aging Center

MedicalResearch: What is the background for this study?

Dr. Ossenkoppele: Since 2004, several PET tracers have been developed that measure fibrillar amyloid-β plaques, a neuropathological hallmark of Alzheimer’s disease (AD). Through visual assessment by a nuclear medicine physician or quantitative cut-points, the presence or absence of amyloid-β pathology can be determined in the living human brain. The FDA, in support of the clinical application of amyloid imaging, has recently approved three of these PET tracers. A proportion of patients with other types of dementia then Alzheimer’s disease that harbor cerebral amyloid-β pathology, however, potentially limits the clinical utility of amyloid imaging. When ordering clinical amyloid PET scans and correctly interpreting the significance of amyloid PET results, clinicians need to understand the prevalence of amyloid-positivity across different types of dementia. It is also important to be aware of the relationships of amyloid-positivity prevalence and demographic (e.g. age and sex), cognitive and genetic (e.g. presence of the AD-risk allele apolipoprotein E [APOE] ε4) factors. Most amyloid PET studies to date come from single centers with modest sample sizes. We therefore conducted a meta-analysis with individual participant data from 29 cohorts worldwide, including 1359 patients with clinically diagnosed Alzheimer’s disease and 538 patients with non-AD dementia. We also included 1849 healthy controls with amyloid PET data, and an independent sample of 1369 AD patients with autopsy data from the NACC database.

MedicalResearch: What are the main findings?

Dr. Ossenkoppele: In patients clinically diagnosed with Alzheimer’s disease, the prevalence of amyloid-positivity decreased from 93% at age 50 to 79% at age 90. The drop in amyloid-positivity was most prominent in older Alzheimer’s disease patients who did not carry an APOE ε4 allele (~1/3 of these patients had a negative amyloid PET scan). This most likely reflects a mix of
1) clinical misdiagnoses (i.e. non-AD pathology causing an AD phenotype),
2) false negative PET scans (i.e. abundance of cerebral amyloid pathology that is not detected by PET), and
3) possibly elder patients need less amyloid pathology (sub-threshold levels for PET) to reach the stage of dementia due to age-related reductions in cognitive resilience (“cognitive reserve theory”) or simultaneous presence of multiple pathologies (“double-hit theory”).
The relatively high rate of amyloid-negative Alzheimer’s disease patients highlights the necessity of biomarker-informed patient selection for Alzheimer’s disease clinical trials.

In most patients clinically diagnosed with non-AD, the prevalence of amyloid-positivity increased with aging and was ~18% higher in APOE ε4 carriers. Presence of amyloid pathology in non-AD dementia may reflect
1) clinical misdiagnosis (i.e. AD pathology is the causative pathology), or
2) comorbid pathologies, where amyloid may be secondary to other pathologies that are actually driving the clinical presentation. Interestingly, patients with a clinical diagnosis of non-AD dementia who harbored cerebral amyloid pathology showed lower Mini-Mental State Examination scores (measure of global cognition), suggesting that amyloid-β is not just an innocent bystander.

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Diabetes Associated with Brain Pathology, but Not Amyloid Accumulation

Rosebud O Roberts, M.B., Ch.B. Professor of Epidemiology Professor of Neurology Mayo ClinicMedicalResearch.com Interview with:
Rosebud O Roberts, M.B., Ch.B.
Professor of Epidemiology
Professor of Neurology
Mayo Clinic


MedicalResearch.com: What are the main findings of the study?

Dr. Roberts: We found that among persons 70 years and older, people with type 2 diabetes had a reduced glucose uptake (hypometabolism) in  brain cells.  We also found a similar association for people without type 2 diabetes but who had elevated hemoglobin A1c levels levels at the time of enrollment (HBA1c is a measure of glucose control, and represents the average blood glucose levels over a 3 month period). However, we did not find an association of diabetes with increased brain amyloid accumulation.  Our findings were based on an investigation of the association of type 2 diabetes with markers of brain pathology: brain hypometabolism was assessed by 18F-fluorodeoxyglucose positron emission tomography [PET] and amyloid accumulation was assessed by 11-C Pittsburgh Compound B PET imaging.
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Brain Amyloid Deposition Strongly Related to Arterial Stiffness

MedicalResearch.com Interview Invitation with:
Timothy Hughes, PhD, MPH Roena B. Kulynych Center for Memory & Cognition Research Department of Internal Medicine Division of Gerontology and Geriatric Medicine Wake Forest School of Medicine Medical Center Boulevard, Winston-Salem, NC  27157-1207Timothy Hughes, PhD, MPH
Roena B. Kulynych Center for Memory & Cognition Research
Department of Internal Medicine
Division of Gerontology and Geriatric Medicine
Wake Forest School of Medicine
Medical Center Boulevard, Winston-Salem, NC  27157-1207

MedicalResearch.com: What are the main findings of the study?

Dr. Hughes: This study is a follow-up to our recent paper that showed a novel relationship between arterial stiffness (commonly measured by pulse wave velocity) and the presence and extent of amyloid deposition in the brain, a hallmark of Alzheimer’s disease. For this study, we repeated brain amyloid imaging (using the Pittsburgh Compound B during PET imaging) in order to look for predictors of change in amyloid over two years in n=81 elderly adults aged 80+ and free from dementia. We observed that measures of systemic arterial stiffness (e.g. brachial ankle pulse wave velocity) was strongly associated with the extent of amyloid deposition in the brain at both baseline and follow-up. The change in brain amyloid accumulation over two years resulted in an increase in in the number of participants with Alzheimer’s-like (amyloid-positive) from 45% at baseline to a surprising 75% after just two years. This change in brain amyloid accumulation over two years was strongly related to having greater central stiffness (as measured by carotid femoral pulse wave velocity). These relationships between arterial stiffness and brain amyloid deposition were independent of the effects of age, gender, body mass index, antihypertensive medication use and even current blood pressure.

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High LDL, Low HDL Levels and Elevated Brain Amyloid

MedicalResearch.com Interview with:
Dr. Bruce Reed PhD Professor of Neurology, Associate Director UC Davis Alzheimer's Disease Center Davis, CA 95616
Dr. Bruce Reed PhD

Professor of Neurology,
Associate Director UC Davis Alzheimer’s Disease Center
Davis, CA 95616

MedicalResearch.com: What are the main findings of the study?

Dr. Reed: We found that high LDL cholesterol and low HDL cholesterol in blood  were both associated with higher amyloid deposition in the brain.  This is potentially very important because the deposition of amyloid seems to be a critical step that kicks off a whole chain of events that eventually lead to Alzheimer’s disease.  It is widely believed (although not proven) that if this deposition of amyloid could be blocked that we could greatly decrease the incidence of Alzheimer’s.  The connection to cholesterol is exciting because we know a fair amount about how to change cholesterol levels.  A great deal more research needs to be done, but this does suggest a potential new path toward trying to prevent AD.

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