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Lewy Body Dementia Biomarkers (U01)

PI Name: KIRK FREY
Institute: University of Michigan

 

 

Project Summary:

We will evaluate the ability of recently-developed research brain imaging methods to identify different types of symptoms or symptom progression in individual patients.

 

 

Project Summary:

Failure of memory and other higher mental functions (dementia) is increasingly recognized as a major source of disability in Parkinson disease (PD) and related conditions.  Symptoms of these problems do not respond effectively to available medications, and there are no approaches to slowing or preventing their development.  A major limitation to discovery of new treatment approaches is the underlying complexity of brain pathology in PD with dementia subjects.  Individual patients may have various combinations of abnormal protein depositions, including proteins called alpha-synuclein, beta-amyloid, and tau.  These proteins may indicate different types of brain injury, and are unlikely all to respond to the same type of treatment.  Thus, progress in the field of PD with dementia will require methods to identify the involved pathways and protein depositions in individual patients.  In this project, we will apply recently-developed research brain imaging methods that can reveal the major degenerating pathways and protein accumulations in PD with dementia.  We will evaluate whether this approach identifies different types of symptoms or symptom progression in individual patients, depending on their imaging results.  Ultimately, we expect that this brain imaging approach will permit the future design and testing of new targeted treatments to slow or halt the development of dementia in PD patients.

Abstract:

Cognitive impairment and dementia are common and disabling problems in patients with neurodegenerations characterized by intraneuronal α-synuclein (α-Syn) aggregates. These patients are classified clinically as either Parkinson disease with dementia (PDD) or as dementia with Lewy bodies (DLB). This labeling distinction is based on the order of presentation of parkinsonism versus dementia – in PDD, the movement disorder occurs first, while in DLB, the cognitive impairment occurs first or within 1-year of parkinsonism onset. PDD and DLB exhibit virtually identical pathological findings at autopsy. Abnormalities found include pathological depositions of α-Syn, Aβ-amyloid, and tau proteins, the latter as intraneuronal paired helical filaments or “neurofibrillary tangles” (NFT). In individual brains, α-Syn alone may be present in cell bodies (Lewy bodies) or in synaptic terminals (Lewy neurites). In other brains, α-Syn deposits are present together with Aβ-amyloid plaques. In still other brains, α-Syn, Aβ-amyloid and tau NFT pathologies are all present, often diagnosed neuropathologically as Alzheimer disease (AD) with PD. The neuropathologic findings do not, however, correlate substantially with subject clinical classification as PDD versus DLB. The future development of effective therapy for dementia in α-synucleinopathy will likely require targeting of the pathologic pathways involved, and this in turn, necessitates ability to determine the type(s) of pathology present in individual patients and assessment of which pathologies most strongly drive progression of cognitive impairments. To be effective in disease modification, therapies will require testing and application in patients with only mild symptoms. In the present proposal, we will determine endophenotypes of mild dementia in patients with α-synucleinopathy, employing multi-tracer molecular brain imaging with positron emission tomography (PET). We will determine the presence of α- Syn neuropathology on the basis of [11C]dihydroteterabenazine (DTBZ) PET imaging of nigrostriatal projection integrity. We will identify the presence of Aβ-amyloid plaque deposition with [11C]Pittsburgh compound-B (PiB) PET imaging, and the presence of tau NFT pathology with [18F]AV1451 (formerly designated T807) PET imaging. Together, these imaging results will permit classification of each subject as: “pure” synucleinopathy, or synucleinopathy with Aβ-amyloid, or as synucleinopathy with both Aβ-amyloid and tau. We will test the hypothesis that the progression of cognitive decline will be more rapid in the synucleinopathy with both Aβ-amyloid and tau endophenotype, and that the progression of cognitive impairment in subjects with this endophenotype will correlate with the progression of NFT pathology as determined in follow-up [18F]AV1451-PET. The development of reliable trait biomarkers of neurodegenerative pathologies in PDD and DLB will enable progress in the development and assessment of new therapeutic interventions desperately needed in these syndromes. PUBLIC HEALTH RELEVANCE: Failure of memory and other higher mental functions (dementia) is increasingly recognized as a major source of disability in Parkinson disease and related conditions. Symptoms of these problems do not respond effectively to available medications, and there are no approaches to slowing or preventing their development. A major limitation to discovery of new treatment approaches is the underlying complexity of brain pathology in PD with dementia subjects. Individual patients may have various combinations of abnormal protein depositions, including proteins called alpha-synuclein, beta-amyloid, and tau. These proteins are potentially hallmarks of differing pathways and types of brain injury, and are unlikely all to respond to the same type of treatment intervention. Thus, progress in the field of PD with dementia will require methods to identify involved pathways and protein depositions in individual patients. In the present research proposal, we will apply recently-developed research brain imaging methods that can reveal the major degenerating pathways and protein accumulations in PD with dementia. We will evaluate whether this approach results in differing types of symptoms or of symptom progression in individual patients, depending on their imaging results. Ultimately, we expect this brain imaging approach will permit the future design and testing of new specifically-targeted treatments to slow or halt the development of dementia in PD patients.

Goals of Project:

  • Recruitment: Enroll 100 patients with Dementia with Lewy Bodies (DLB) / Parkinson’s Disease with Dementia (PDD), confirmed with PET imaging, as well as 20 elderly patients without dementia.
  • Assessment: We will evaluate cognitive deficits in patients over 3-years and will compare global cognitive decline amongst the 3 anticipated patient classifications.
  • Discovery: We will compare neuropsychometric cognitive deficit profiles amongst the 3 anticipated patient classifications.
  • Discovery: We will perform repeat PET imaging at 3-years, and will compare the progression of neuropsychometric deficits with changes in NFT-tau accumulation.

Enrollment Goals:

  • 100 patients with Dementia with Lewy Bodies (DLB) / Parkinson’s Disease with Dementia (PDD) (varying stages of disease)
  • 20 elderly patients without dementia

To participate in this study, contact: