Keith A. Josephs - US grants

DESCRIPTION (provided by applicant): Speech and language based dementias (SLDs) (often referred to as primary progressive aphasias) are neurodegenerative diseases in which speech and language impairments are the most salient features of the disease and explain deficits in activities of daily living. These dementias may or may not be associated with the deposition of the protein beta-amyloid in the brain, which until recently could only be determined at postmortem. Since new treatments will likely target underlying abnormal proteins, accurate prediction of the pathology underlying the SLDs is critical. The recent development of amyloid imaging compounds now allows the in vivo detection of beta-amyloid in the brain. Unfortunately, amyloid imaging compounds are expensive and are not accessible to most medical centers throughout the United States. The objectives of the studies outlined in this proposal are to identify clinical, neuropsychological or non-amyloid imaging biomarkers that are readily available, relatively inexpensive, and non-invasive, that will allow the prediction of beta-amyloid in the brain in patients with SLDs. To accomplish this goal we will be using the amyloid imaging compound 11C Pittsburgh Compound B (PiB) as the gold standard for the detection of beta-amyloid. The methods will include detailed neurological, speech and language and neuropsychological assessments, magnetic resonance imaging, and [18-F]-fluoro-deoxy-glucose (FDG) and PiB PET scanning. Associations between PiB positive scanning and these techniques will be sought. One of the most salient features of the speech and language assessments will be the determination of the presence and severity of apraxia of speech and its association with beta-amyloid deposition. This study will be carried out at the Mayo Clinic in Rochester, MN, which evaluates a large number of patients with SLDs annually. The study also intends to recruit minorities with SLDs which are currently understudied. The methods will be performed by a team of world renowned scientists including dementia, movement disorders and speech pathology specialists, radiology researchers, a nuclear medicine scientist, neuropsychologists, and biostatisticians. The long term goal of our research is to develop a cost effective algorithmic approach to the evaluation and diagnosis of patients with SLDs. PUBLIC HEALTH RELEVANCE: This study will identify ways to determine whether Alzheimer's disease is the underlying cause of a patient's progressive speech and language problem. In addition, the study aims to identify the most cost effective way to do this so that more patients, including minorities, can be given an accurate diagnosis. Results from this grant will ultimately lead to better targeted future treatments for patients with problems with speech and language.

? DESCRIPTION (provided by applicant): Progressive supranuclear palsy (PSP) is a devastating neurodegenerative disorder characterized by postural instability with falls, axial rigidity and vertical supranuclear gaze palsy. It affects approximately 20,000 Americans and is untreatable. It typically results in patients being confined to a wheel-chair and with dysphagia that can result in death after 7-8 years. At autopsy, patients with PSP show deposition of the protein tau in the brain. Unfortunately, studies of tau in PSP during life have not been possible due to the absence of a tau biomarker. Understanding the role of tau to the disease is critical as it is a major target for future treatments of PSP. A positron emission tomography (PET) ligand, [F18] AV-1451 (formerly [F18]-T807), has recently been developed which specifically binds to tau and provides us with the opportunity, for the first time, to assess the regional distribution o tau in the brains of living patients with PSP. The goal of this grant is to characterize the cross-sectional and longitudinal patterns of tau deposition in patients with PSP using this PET imaging ligand, and to determine whether tau deposition correlates to neurological outcomes and imaging measures of atrophy and white matter tract degeneration. To accomplish these aims we will recruit a total of 84 subjects diagnosed with possible or probable PSP. Each subject will undergo two serial assessments one year apart. For each assessment, subjects will undergo a neurological and swallowing evaluation, a 3T magnetic resonance imaging (MRI) that includes structural MRI and diffusion tensor imaging (DTI), and tau-PET using the AV-1451 ligand. Eighty four matched healthy controls from the Mayo Clinic Study of Aging that have already undergone a neurological evaluation and serial MRI and tau-PET scanning will be utilized for analyses. The regional distribution of tau-PET uptake across the brain in PSP compared to controls will be assessed using voxel-level analyses. Global and regional tau-PET burden measures will be generated for the baseline and follow-up brain scans. Statistical analyses will be performed to identify regions of the brain in which tau-PET burden correlates with specific neurological features, including gait, ocular motor, and executive dysfunction, and dysphagia. We will also determine the relationship between global and regional tau-PET burden and anatomical changes on MRI, including grey matter atrophy and white matter tract degeneration. The analyses will focus specifically on regions typically involved in PSP, including midbrain, superior cerebellar peduncle, thalamus, basal ganglia, cerebellum and superior frontal cortex. Lastly, we will determine whether tau-PET can help predict future decline in neurological and MRI outcomes. This mechanistic approach will increase our understanding of disease progression and the relationship between pathological processes and the neurological and anatomical features of PSP; knowledge that will be critical for the future development of effective therapies for PSP and to determine whether tau-PET measures could be useful to aid prognosis in individual subjects.

? DESCRIPTION (provided by applicant): The primary goal of this R21 is to generate data on the behavior of a new type of PET scan, tau-PET, in subjects diagnosed with primary progressive aphasia (PPA) and the three well recognized variants of PPA: agrammatic, semantic and logopenic PPA. Pathological studies have identified an abnormal protein, tau, as being an important player in the neurodegenerative process. Tau is thought to be one of the leading causes of neurodegenerative diseases. It was not possible however, until recently, to determine whether tau deposition was present in the brain during life. An imaging ligand AV-1451 (formerly 18F-T807) was recently developed, which specifically binds to tau in human brains. No studies have investigated tau binding in PPA using neuroimaging. Over the 2 years of the R21 we will recruit subjects with all three PPA variants and compare AV-1451 binding in PPA and PPA variants, to AV-1451 binding in normal control subjects to get an estimate of what proportion of PPA subjects and PPA variants do test positive for tau with AV-1451. We will also assess whether there is any evidence that binding patterns for tau differs across the three PPA variants. In our final aim we will use the unbiased technique of cluster analysis to determine whether there is any support for clinico-anatomically defined PPA variants based on binding patterns of tau with AV-1451, independent of the clinically defined PPA variants. These are important steps that are necessary to move the field forward given that tau-PET is a new technique with little existing data to draw upon for hypothesis testing. Therefore, this R21 will b important to generate hypotheses for a future R01.The proposal is novel and feasible. To accomplish our aims, we will perform detailed neurological, speech and language, and neuropsychological testing, as well as the new AV-1451 PET scan and volumetric head MRI scanning. The Principal Investigator of this grant, Dr. Keith Josephs is a world renowned neurodegenerative specialist who has assembled a team of world renowned experts in speech and language (Dr. Joseph Duffy), neuroimaging (Drs. Clifford Jack, Val Lowe, Jennifer Whitwell) and neuropsychology (Dr. Mary Machulda) to collectively work to address the aims. The team will have state of the art facilities and equipment in order to do so.

PROJECT SUMMARY The first two cycles of our R01 entitled, ?Understanding the role of TDP-43 in Alzheimer's disease and FTLD? were very successful with over 50 peer-reviewed publications and many novel discoveries. In the 2nd cycle we focused mainly on how TDP-43, tau and beta-amyloid contributed to neurodegeneration in those with Alzheimer's disease neuropathologic changes (ADNC). Our studies were conducted on a cohort of 756 ADNC cases. We discovered that TDP-43 deposition in ADNC was heterogeneous and for the first time showed that there are two distinct types of TDP-43 deposition in ADNC that we termed TDP type-? and type-?. What is most interesting about this discovery is that TDP type-? have strikingly similar features to one pathological type of FTLD-TDP (FTLD-TDP type A) while TDP type-? is strongly associated with the presence of neurofibrillary tangles, and hence tau. A second discovery was that different inclusions associated with the different pathological types of FTLD-TDP (type A, type B and type C) had different molecular compositions of TDP-43 specie. For example, while most inclusions consisted of C-terminal fragments of TDP-43, pre-inclusions and perivascular inclusions consisted of a greater burden of full-length TDP-43 than C-terminal fragments. Therefore, one of the main goals of the 3rd cycle is to further assess how ADNC TDP types (type-? and type-?) are related to FTLD-TDP types (type-A, type-B, type-C) by investigating associations with the different molecular specie of TDP-43 including C-terminal fragments, full-length and phosphorylated TDP-43. A second goal of the R01 is to further our findings from the 2nd cycle in order to better understand how TDP types (type-? and type-?) modifies the associations between TDP-43 and neurodegeneration. We will investigate, specifically, how TDP, including TDP types, tau and beta-amyloid and other pathological and genetic factors are associated with trajectories of volume loss of hippocampus and neocortex over time. Our cohort will consist of cases with multiple head MRI scans (range: 2-13 yearly MRI scans; total scans=2316) prior to death. Last, but not least, we will address one of the biggest knowledge gaps in the field, the lack of a biomarker that can help predict the presence of TDP-43 in ADNC during life. We will use [18F]fluorodeoxyglucose PET, which we have shown is superior to MRI, to predict TDP-43. We will first develop the biomarker and then test it in an independent cohort. In order to accomplish all the aims of the 3rd cycle we will upgrade our cohort size to 1303 pathologically confirmed cases of ADNC and FTLD. Findings from this 3rd cycle will significantly improve understanding of TDP-43, and TDP-43 types, and help to address the nagging issue of where the boundary lies between TDP-43 in ADNC and FTLD-TDP. Given that TDP-43 is a potential therapeutic target for the treatment of FTLD and now Alzheimer's disease, the 3rd cycle will likely also have a significant impact on the field.

PROJECT SUMMARY Progressive supranuclear palsy (PSP) is a devastating neurodegenerative disorder that is characterized by deposition of the protein 4-repeat (4R) tau in the brain. Patients typically present with postural instability with falls, axial rigidity and vertical supranuclear gaze palsy, although other atypical clinical syndromes occur in which patients present with parkinsonism, freezing of gait, behavioral abnormalities, limb apraxia or speech and language difficulties. In the 1st cycle of the R01 we characterized the cross-sectional and longitudinal behavior of the tau-PET ligand [18F]AV-1451 in PSP and showed that it is related to other neuroimaging measures of neurodegeneration. The 1st cycle focused on the typical clinical presentation of PSP. Since the 1st cycle, a panel of leading experts published new criteria with a standard to diagnose the atypical clinical syndromes. We currently lack understanding of the neurobiology of the atypical PSP syndromes. The primary goal of the 2nd cycle is, therefore, to characterize the clinical, neuroimaging and neuropathological features across typical and atypical PSP syndromes. Specifically, we aim to characterize the cross- sectional and longitudinal multi-modal neuroimaging signatures of the PSP syndromes, determine the relationship between neuroimaging and clinical evolution, and evaluate the autopsy characteristics of the PSP syndromes. We will have data from 160 PSP patients to allow us to address our aims (84 recruited into the 1st cycle and 76 which will be recruited in the 2nd cycle). Each newly recruited patient will undergo the identical examinations as the 84 patients from the 1st cycle, including a neurological and dysphagia evaluation, a 3T magnetic resonance imaging (MRI) that includes structural MRI and diffusion tensor imaging (DTI), and tau- PET using the [18F]AV-1451 ligand. All patients will undergo two serial assessments one year apart. We will assess differences and commonalities in all three neuroimaging modalities across PSP syndromes primarily using a focused region-of-interest approach which will target key brainstem, subcortical and cortical regions that are involved in PSP. We will then ascertain whether the PSP syndromes exhibit unique multi-modal signatures using a classification model. Voxel-level analyses will also be performed to assess patterns across the whole brain. The relationship between clinical evolution, including the evolution of dysphagia, and the PSP syndromes and neuroimaging measures will be assessed. Autopsy examinations will be performed on all patients from both cycles that die and 4R tau burden will be compared across PSP syndromes. We will also determine the degree to which neuroimaging differences across syndromes are related to tau burden and investigate how additional pathologies are associated with the different syndromes. The results of this grant will increase our knowledge of the neural underpinnings of the clinical and anatomical heterogeneity in PSP and will also be essential for the development of optimum biomarkers for PSP that will aid diagnosis, track disease progression and allow patients with all PSP syndromes to be included in future treatment trials.