SPEAKER BIOS and ABSTRACTS (M - Z)

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Innate Immune Activation in Neurodegenerative Disease: Differential Effects on Amyloid and Tau Pathology

David G. Morgan

University of South Florida, Tampa, USA

In the 1980s, several teams (McGeer, EIkelenboom, Rogers) noted the significant increase in markers of innate immune system activation (“inflammation”) present within the brains of Alzheimer’s disease victims at autopsy. Since that time a major debate has been the degree to which this activation was itself pathogenic, causing at least some of the neurodegeneration, or increased primarily in response to the ongoing pathology and degeneration. Early attempts to address this question used mouse models of amyloid deposition. These models do develop some innate immune system activation, but lack the severe neuron loss and brain atrophy characteristic of Alzheimer’s dementia. In at least some instances, activation of innate immune representatives in the brain (microglia and astrocytes) led to clearance of the deposited amyloid. One significant method of activating the microglia, with immunotherapy, has proven very efficient at preventing and clearing amyloid deposits. This further leads to functional recovery, even in very old mice.

More recently, mouse models of tau deposition have been developed. These models do exhibit the neuronal loss and brain atrophy characteristic of later stages of dementia. Several approaches to increasing innate immune system activation have found an exacerbation of the tau pathology under these conditions. Moreover, recent work with a protein reducing innate immune system activation in the CNS, fractalkine, has been demonstrated to retard accumulation of pathological forms of tau and protect from neuron loss and brain atrophy. Our present understanding is that amyloid deposition in human brain occurs for 10-20 years prior to onset of symptoms. Furthermore, most mouse models of amyloid deposition lack the neuron loss and atrophy associated with AD and mouse models of tauopathy. It is increasingly recognized that brains of older mice are characterized by increased sensitivity to pro-inflammatory stimuli (referred to as inflammaging or priming). These details lead to a hypothesis that amyloid itself is relatively innocuous, but that conditions of aging lead to excess innate immune system reaction to the amyloid deposits and/or oligomers. This inflammation response then accelerates the development of tau pathology leading to the more severe neurodegeneration and cognitive deterioration associated with mid to late stages of the disease. This hypothesis would predict that some methods of decreasing the innate immune system reaction in the brains of individuals depositing amyloid may delay or prevent later stages of the disease.

Harmonized Clinical Diagnostic Criteria for the Incipient Symptomatic Stages of Alzheimer’s Disease

John C. Morris

Washington University School of Medicine, St. Louis, USA

Two major sets of criteria for the clinical diagnosis of Alzheimer disease (AD) have been published in the last five years. Both sets of criteria recommend supporting the syndrome-based diagnosis of AD with in vivo evidence of AD pathology, as determined by neuroimaging modalities and by assays of AD-related proteins in the cerebrospinal fluid (CSF). Additionally, both sets of criteria recommend that the incipient symptomatic stages of AD, commonly referred to as mild cognitive impairment (MCI) or prodromal AD, receive an etiologic diagnosis. If the clinically determined etiology of AD is validated by in vivo biomarkers or by postmortem neuropathological assessment, then the incipient clinically-expressed disorder can be considered as part of the spectrum of symptomatic AD. Data from the National Alzheimer Coordinating Center (NACC), obtained from participants who were 50 years or older at their last assessment at a federally-funded Alzheimer Disease Center and who died within two years of that assessment and came to autopsy, suggest that the neuropathologic confirmation of AD in individuals with “MCI due to AD” is comparable to that for individuals with a diagnosis of very mild AD dementia. Some level of neuropathologic AD was demonstrated in 76% of MCI participants with an etiologic diagnosis of AD compared to 79% of participants with a diagnosis of very mild (Clinical Dementia Rating 0.5) AD dementia. Hence, an equivalent majority of cases for both clinical classifications represent early-stage symptomatic AD.

Ronald Petersen, MD, PhD

Moderator – MiniSymposium 2 Discussion

Dr. Ronald C. Petersen, MD, PhD, is the Cora Kanow Professorship in Alzheimer’s Disease Research, and a Mayo Clinic Distinguished Investigator at the Mayo Clinic. He is on the National Advisory Council on Aging, and is the chair of the Advisory Council on Research, Care and Services for the National Alzheimer’s Project Act by the Secretary of the Department of Health and Human Services.

Dr. Petersen is a recipient of the 2004 MetLife Award for Medical Research in Alzheimer’s Disease, and the 2005 Potamkin Prize for Research in Pick’s, Alzheimer’s and Related Disorders of the American Academy of Neurology.

Biomarker Patterns in Subtypes of Alzheimer’s Disease – Implications for Pathophysiology and Diagnosis

Gil Rabinovici

University of California, San Francisco, USA

While the most common presentation of Alzheimer’s disease (AD) is episodic memory loss, up to 15% of patients present with primary non-amnestic syndromes. Patients with early-onset AD (age of onset ≤ 65) show greater executive, language and visuospatial impairment and relatively preserved episodic memory compared to those with late-onset AD, and focal cortical syndromes such as posterior cortical atrophy and logopenic-variant primary progressive aphasia are strongly linked to underlying AD pathology. The remarkable heterogeneity of AD poses a clinical challenge, but also an opportunity to inform our understanding of basic principles of disease pathogenesis. In this talk I will summarize work from our lab and others describing biomarker findings across AD phenotypes, including CSF profiles, and patterns found on MRI (structural, functional connectivity and diffusion tensor imaging) and FDG, amyloid and tau PET. Common and distinct patterns will be interpreted in the context of a model in which Aβ aggregates across high-throughput cortical hubs, while tauopathy develops in distinct vulnerable brain regions and spreads through inter-connected posterior brain networks, driving the clinico-anatomic phenotype of the disease.

Marwan Sabbagh

Barrow Neurological Institute, Phoenix, AZ, USA

Subjective complaints have been traditional considered to be an expression of the “worried well” and were often dismissed. New data suggests that that subjective memory complaint (SMC) may predict incident cognitive decline. Recent studies indicate that SMC may predict amyloid positivity but does not correlate well with imaging markers of neurodegeneration. In turn, amyloid positivity has been shown to increase risk of future cognitive decline. In this presentation, the profile of SMC will be reviewed and how biomarkers such as ApoE, amyloid PET, CSF, structural markers of neurodegeneration can influence progression. It is clear that SMC is no longer to be dismissed and could portend future cognitive decline.

Family History, Subjective Memory Complaints and Brain Amyloid Load in the ADNI Study

Andrew Saykin

Indiana University School of Medicine, Indianapolis, USA

Pathophysiological processes associated with Alzheimer’s disease (AD) have been shown to be detectable up to two decades prior to the onset of dementia. Early detection during the long preclinical and prodromal stages of disease is critical to support therapeutic and preventative interventions that likely need to be instituted prior to the neurodegenerative changes that accompany symptomatic stages of disease. The presence of self-perceived cognitive changes (variously described as subjective complaints, concerns, decline or impairment) and similar observations by knowledgeable informants may represent the earliest prodromal stage. However, there is heterogeneity in symptom expression and considerable variability in how these changes are defined and assessed. Recently, an international working group arrived at a consensus framework to describe this condition as subjective cognitive decline (SCD) and efforts are underway to develop fully operationalized research criteria for classifying SCD.

Early studies by our group and others showed that older adults with cognitive complaints had changes on MRI similar to those seen in amnestic mild cognitive impairment (MCI) and increasing data is now becoming available on changes in other AD biomarkers including PET and CSF in individuals with SCD. Given the substantial heritability of AD, estimated to be as high as 60-80%, cognitive concerns are often given more weight by clinicians where there is a positive family history of dementia and genetic risk and protective factors are being investigated.

The Alzheimer’s Disease Neuroimaging Initiative (ADNI) has focused on multimodal longitudinal biomarker studies of early and late stage MCI and clinical AD, as well as cognitively normal controls. A new group with significant memory concerns (SMC), essentially equivalent to SCD, was added during ADNI-2. Efforts to standardize SCD/SMC within ADNI included a psychometrically-defined score on episodic memory items (n=12) from the 20 item Cognitive Change Index (CCI). Genetic factors play a significant role in SMC, particularly the strong influence of APOE ε4 carrier status on measures of amyloid burden (Risacher et al 2015). When contrasting the SMC group to controls and those with early MCI across key AD biomarkers available in ADNI it is clear that genetics plays a selective role depending on the specific biomarker modality.

Important future directions include longer-term follow-up of SMC/SCD samples, advances in assessment and operationalization of SCD, and analyses of other genes and biological pathways as larger samples become available. The epidemiology of SCD in older adults and the degree to which SCD can meaningfully enrich clinical trials warrant further investigation. Screening for SCD in primary care settings is feasible enabling individuals to be referred to memory centers for more detailed assessment and treatment or participation in intervention trials, as appropriate.

The Prevalence of Amyloid Positivity by Age, APOE Genotype and Cognitive Status – Implications for the Diagnosis of Alzheimer’s Disease

Philip Scheltens

VU University Medical Center, Amsterdam, Netherlands

Recently, we showed in two meta-analyses published in JAMA (1,2) that amyloid positivity as shown by either PET or CSF occurs in normal individuals from the age of 40 (panel A below). As such it precedes the occurrence of dementia by 20-30 years at least. There is a strong relationship with APOE4, indicating higher amyloid load in carriers of the epsilon 4 alle(s) (panel B below).

It also happens in other dementias, although a certain percentage of misdiagnosis needs to be accounted for here (panel A below). In AD it goes down with increasing age and amyloid burden (panel A) is lower in APOE4 non-carriers (panel B). There is a high concordance between amyloid PET and amyloid at pathology.

The following consequences for the diagnosis of AD will be discussed:

1. A diagnosis of AD rests on the presence of both amyloid and tau pathology

2. Interpreting biomarkers indicating the presence of amyloid only should be done with care, since amyloid may be present in normal aging and is influenced by APOE status, meaning that it denotes a risk state and not a diagnosis per se in clinically unaffected individuals.

3. biomarkers should never be used out of the clinical context and age should be taken into account when interpreting the results

References 1: Ossenkoppele R, Jansen WJ, Rabinovici GD, Knol DL, van der Flier WM, van Berckel BN, Scheltens P, Visser PJ et al. Prevalence of amyloid PET positivity in dementia syndromes: a meta-analysis. JAMA. 2015 May 19;313(19):1939-49. 10.1001/jama.2015.4669. PubMed PMID: 25988463; PubMed Central PMCID: PMC4517678. 2: Jansen WJ, Ossenkoppele R, Knol DL, Tijms BM, Scheltens P, Verhey FR, Visser PJ, et al. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA. 2015 May 19;313(19):1924-38. 10.1001/jama.2015.4668. PubMed PMID: 25988462; PubMed Central PMCID: PMC4486209.

Subjective Memory Complaint in Aging: Neuropathological Associations (Symposium)

Frederick Schmitt

University of Kentucky, Lexington, USA

Insight into cognitive functioning has been shown to change with advancing age.  More recently the concept of ‘subjective memory complaint’ (SMC) has gained momentum as a possible marker for dementia risk.  In this presentation, the concept of metacognition will be briefly reviewed. Findings from a prevention trial and longitudinal cohort studies that link autopsy-based brain pathologies and awareness of memory change or SMC will be highlighted.  SMC as a risk for brain pathologies will be described in terms of cognitive trajectories prior to autopsy as well as the multiple brain pathologies (AD and non-AD) that underlie SMC progression to dementia.

Why is an Early Diagnosis of Alzheimer’s Important and How Do We Achieve It? (Forum)

Frederick Schmitt

University of Kentucky, Lexington, USA

This presentation will review: (1) the potential risks of early dementia screening and (2) how screening for dementia may benefit individuals and their families.  In addition, guidelines for effective dementia diagnosis in primary care and the Medicare Annual Wellness Visit are highlighted.  Finally, new findings regarding awareness of memory change and their eventual associated brain pathologies will be discussed.

Diagnostic Complexities in Current Clinical and Morphological Criteria for Alzheimer’s Disease

Julie Schneider

Rush University Medical Center, Chicago, USA

Alzheimer’s disease (AD) is the most common clinical and pathologic diagnosis in persons with age-related dementia; however, both diagnoses are fraught with complexities. These complexities are demonstrated using data from 2 large longitudinal community-based clinical-pathologic studies of aging and dementia. While community-dwelling older persons with the clinical diagnosis of probable AD at death are confirmed to have a pathologic diagnosis AD, almost 90% of the time; over half are shown to have additional common pathologies. These pathologies include vascular pathologies: specifically – macroscopic infarcts, microinfarcts, arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy; and other neurodegenerative pathologies including Lewy body disease, hippocampal sclerosis and TDP-43 pathology.

Often older persons harbor multiple additional pathologies, including both vascular and neurodegenerative pathologies. These pathologies lower threshold for dementia, add to cognitive impairment, and most affect episodic memory the clinical hallmark of AD, making clinical distinction of AD vs. mixed AD pathologies difficult. Patterns of mixed pathology may differ in special populations, especially racially diverse cohorts, clinic cohorts, and the oldest old. Another complexity is the common presence of AD pathology in normal older persons.

Indeed, both pathologic and radiographic studies have also shown that about 1/3 of older persons without cognitive impairment have sufficient AD pathology to render a pathologic diagnosis of AD. This has led to the concept of preclinical Alzheimer’s disease, where the pathologic hallmarks of AD are present but clinical symptoms are minimal or absent. While non-AD neurodegenerative pathologies and vascular pathologies lower brain reserve, other factors may increase cognitive or neural reserve. These factors include genetics, lifestyle, diet, and personality factors. Further study of these factors that increase and lower neural reserve may provide clues to prevention and treatment.

Genetic Pathways linking Neuroinflammation, Vascular Disease and Neurodegeneration

Sudha Seshadri

Boston University, Boston, USA

Over the past two decades evidence has accrued linking circulating biomarkers of inflammation, and clinical and imaging markers of brain vascular injury to risk of dementia, including dementia of the Alzheimer’s type. On the  other hand, this evidence is not consistent across studies and intervention trials targeting inflammation and vascular risk factors have been largely disappointing. It remains unclear if these mechanisms are independent and incidental or play a causal role in neurodegeneration. Since genetic changes are present from conception, studying genetic links between these 3 processes may help us better understand temporality (which comes first), and may identify novel causal pathways underlying Alzheimer and other neurodegenerative disorders.

Recently genome-wide association studies have identified novel loci and genes determining the risk of stroke, subclinical vascular brain injury and many of these genes appear to impact immune/inflammatory pathways; some additionally affect cognition and risk of dementia. As an example, the stroke associated gene HDAC9 alters PPAR-gamma and RANKL expression, brain inflammation and beta-amyloid removal. Other recently identified stroke genes alter pericyte function and blood-brain barrier integrity. Conversely, many of the recently identified AD genes, such as TREM2 are expressed in the blood vessels of the brain and/or alter microglial activation, a measure of local inflammation, in the brain. Pathway analyses of sub threshold genetic associations with AD identify greatest enrichment of genes in the immune response pathway. Further there is a 50-fold enrichment of genetic variants determining C-reactive protein levels among genes determining AD risk. Whereas all these data are intriguing, they are, as yet, insufficient data to clearly craft a single robust, verifiable hypothesis causally linking inflammation and vascular brain injury to neurodegeneration. However, since inflammation and vascular injury are complex, inter-related and above all, modifiable, this is an area of growing interest.

What are Subjective Memory Complaints and What is their Significance (Forum)

Ingmar Skoog, Silke Kern, Boo Johansson, Johan Skoog and Simona Sacuiu

University of Gothenburg, Gothenburg, Sweden

Subjective complaints of memory and other cognitive problems brings the patient to the doctor, and is a main component in criteria for mild cognitive impairment. However, the relevance of subjective complaints is debated, especially at the population level, and methods for measurement vary widely between studies. There is currently no consensus regarding criteria for subjective memory complaints. Nevertheless, it has been related to preclinical Alzheimer’s disease, depression, anxiety, somatic disorders, personality, and also to biological markers of Alzheimer’s disease in individuals without dementia.

Longitudinal studies on representative populations of older persons from different birth cohorts have been conducted in Gothenburg since the 1970s with comprehensive examinations, including psychiatric, cognitive, and somatic examinations, as well as brain imaging and laboratory tests. In these studies, objective cognitive function increased continuously between subsequent birth cohorts, while the prevalence of subjective memory complaints did not change. It further did not change with age. Subjective memory complaints were related to an increased risk for dementia at follow-up, but the associations were weak, and positive predictive value and sensitivity was low. Cross-sectionally, associations were stronger with depressive symptoms than with cognitive function. Self-reported executive function was related to frontal and occipital atrophy on CT, while self-reported memory complaints were related to white matter lesions. The presence of subjective memory complaints increased the risk for dementia substantially in individuals with white matter lesions. In conclusion, subjective memory complaints alone are only weakly associated with the development of dementia, and seems more related to depressive symptoms. However, it is still an important clinical observation in the context of other more objective tests of cognitive function, and in the context of other brain pathology.

The Epidemiological Relevance of Subjective Cognitive Decline (Symposium)

Ingmar Skoog, Silke Kern, Boo Johansson, Johan Skoog and Simona Sacuiu

University of Gothenburg, Gothenburg, Sweden

Background: Subjective complaints of memory and other cognitive problems is what brings the patient to the doctor, and is a main component in criteria for mild cognitive impairment. However, the relevance of subjective complaints is debated, especially at the population level.

Methods: Longitudinal studies on representative populations of elderly persons from different birth cohorts have been conducted in Gothenburg since the 1970s with comprehensive examinations, including psychiatric, cognitive, and somatic examinations, as well as brain imaging and laboratory tests.

Results: Objective cognitive function increased continuously between subsequent birth cohorts, while the prevalence of subjective memory complaints did not change. Subjective memory complaints were related to an increased risk for dementia at follow-up, but the associations were weak, and positive predictive value, sensitivity and specificity was low. Cross-sectionally, associations were stronger with depressive symptoms than with cognitive function. Self-reported executive function was related to frontal and occipital atrophy on CT, while self-reported memory complaints were not.

Conclusion: Subjective memory complaints alone were only weakly associated with the development of dementia in our Swedish populations, and was more related to depressive symptoms. However, it is still an important clinical observation in the context of other more objective tests of cognitive function.

The Importance of Participation in Clinical Trials in Alzheimer’s Disease

Amanda Smith

University of South Florida, Tampa, USA

Participating in a clinical trial or study helps medical researchers find new ways to treat and prevent Alzheimer’s and other diseases, and could help future generations lead healthier lives. Today, at least 70,000 volunteers are urgently needed to participate in more than 150 active clinical trials and studies in the United States that are testing ways to understand, treat, prevent, or cure Alzheimer’s disease. All kinds of people, including healthy volunteers, are needed. Women and minorities are especially needed. You or a loved one may have heard of clinical trials and research studies but are not sure what they are or if you want to join one. Or, you may be a health professional who isn’t sure what to say when patients and families ask about clinical trials. This public educational forum session provides information on types of clinical research in Alzheimer’s disease, answers frequently asked questions about research, and highlights the ways that clinical trial participation can bring us closer to a cure.

Subjective Cognitive Impairment, Neuroticism and Brain Amyloid Load

Beth Snitz

University of Pittsburgh, Pittsburgh, USA

Subjective cognitive complaints in otherwise normal aging are very common. It is well established that memory complaints are associated with psychosocial variables, such as personality, mood symptoms, gender, and beliefs about aging. Subjective memory complaints may also be associated with preclinical Alzheimer Disease and clinical progression/cognitive decline. Little is known, however, about when complaints may be valid indicators of underlying brain pathology, when they are not, and whether psychological variables may be useful making the distinction.

In a recent study, we explored personality factors as potential moderators of associations between subjective complaints and brain amyloid-β in cognitively normal older adults. N=92 healthy research volunteers were screened for normal cognition with comprehensive neuropsychological evaluation. Amyloid-β deposition was assessed with Pittsburgh compound B (PiB)-PET imaging.

Results indicated one of three cognitive complaint measures, the Memory Functioning Questionnaire, was associated with global PiB retention. Neuroticism modified this association such that only high neuroticism individuals showed the predicted pattern of poorer self-perceived cognition associated with higher PiB retention. Cognitive complaints and neuroticism may reflect a common susceptibility toward psychological distress and negative affect, which are in turn risk factors for cognitive decline in aging and incident Alzheimer Disease.

Expression and endorsement of subjective cognitive complaints, and their correlates, are also highly dependent on study setting. Subjective memory findings will be briefly compared among three ongoing studies: 1) a large, representative population study in small-town southwest Pennsylvania (MYHAT Project); 2) an ADRC / specialty memory clinic; and 3) a community research volunteer sample.

Detection of Preclinical Alzheimer’s Disease: Implications for Prevention Trials

Reisa Sperling

Massachusetts General Hospital/Harvard Medical School, Boston, USA

Converging data from PET amyloid imaging, cerebrospinal fluid studies and large autopsy series suggest that one-third of clinically normal older individuals harbor a substantial burden of cerebral amyloid-beta (Aß). It remains unknown whether these individuals are indeed in the preclinical stages of Alzheimer’s disease (AD) and what proportion will progress to dementia over time. Accumulating evidence from these “Aß-positive normals” show aberrant network, cortical thinning, increased neocortical tau on Tau PET imaging, and other “AD-like” abnormalities on multi-modality imaging. Clinical studies have reported an association between Aß burden and memory performance, increased subjective cognitive concerns, and a significantly increased risk of cognitive decline, particularly among older individuals with markers of both accumulation Aß and neurodegeneration.

One of the continued dilemmas in the field is how best to identify individuals who are clearly on the AD trajectory but at an earlier enough stage of pathology to be maximally responsive to therapeutic intervention. Several secondary prevention trials in both genetic at-risk (Dominantly Inherited Alzheimer Network and the Alzheimer Prevention Initiative) and age at-risk individuals are now ongoing, testing anti-amyloid mechanisms. The Anti-Amyloid Treatment in Asymptomatic AD (A4) Study will enroll over 1000 older individuals with evidence of amyloid accumulation on screening PET scans to determine if treatment with an anti-amyloid antibody, initiated prior to cognitive impairment, will slow neurodegeneration and the progression of memory decline towards AD dementia. The A4 Study is a 3-year Phase 3 registration trial with a primary cognitive endpoint as well as multiple biomarker outcomes, including Tau PET imaging. The A4 Study currently being conducted at 65 sites in US, Canada, and Australia. The EARLY (A5) Study will utilize a similar trial design with a BACE inhibitor in an asymptomatic population at risk for developing cognitive decline due to AD has already begun in Europe and will begin in the US in mid-2016.