Not listed
VASCULAR CONTRIBUTION TO WHITE MATTER LESIONS AND MOTOR DYSFUNCTION IN AD AND ADRD - MOST ALZHEIMER'S DISEASE (AD) PATIENTS EXPERIENCE SEVERE MOTOR IMPAIRMENT AT THE LATER STAGE OF DISEASE AND 10 - 40% OF AD PATIENTS EXHIBIT SIGNS OF MOTOR DYSFUNCTION AT EVEN EARLIER STAGES OF AD. FURTHERMORE, CHANGES IN MOTOR FUNCTION OFTEN PRECEDE OTHER SYMPTOMS OF AD AS WELL AS CORRELATE WITH INCREASED SEVERITY AND MORTALITY. DESPITE THE FREQUENT OCCURRENCE OF MOTOR DYSFUNCTION IN AD PATIENTS, LITTLE IS KNOWN ABOUT THE MECHANISMS BY WHICH THIS BEHAVIOR IS ALTERED. IN SEVERAL OTHER NEUROLOGICAL DISEASES, SUCH AS STROKE AND VASCULAR PARKINSONISM (VP), CEREBROVASCULAR LESIONS UNDERLIE MOTOR DYSFUNCTION DURING THE PROGRESSION OF THESE DISEASES, ESPECIALLY IN THE BASAL GANGLIA. IN ADDITION, WHITE MATTER LESIONS (WMLS), WHICH ARE PRIMARILY CONSIDERED A SMALL VESSEL DISEASE AND CHARACTERIZED AS FOCAL ABNORMAL MYELINATION, ARE HIGHLY CORRELATED WITH MOTOR DEFICITS IN VP. MOREOVER, WMLS ARE STRONGLY ASSOCIATED WITH THE CLINICAL RISK OF AD AND MAY ACCELERATE THE CLINICAL MANIFESTATION OF THE DISEASE. FAMILIAL DANISH DEMENTIA (FDD) IS ANOTHER AD-LIKE FAMILIAL NEURODEGENERATIVE DISEASE ASSOCIATED WITH MOTOR DYSFUNCTION, WML, AND VASCULAR IMPAIRMENT. HOWEVER, IT IS UNCLEAR WHICH PATHOGENIC MECHANISMS PRODUCE VASCULAR IMPAIRMENT, WML, MOTOR DYSFUNCTION IN AD AND FDD. SINCE SEVERAL CLINICAL STUDIES SUGGEST A STRONG CONNECTION BETWEEN VASCULAR DEFICITS IN BASAL GANGLIA AND MOTOR DYSFUNCTION IN SEVERAL NEUROLOGICAL DISEASES, WE INVESTIGATED THESE PATHOLOGIC CORRELATIONS IN AD MOUSE MODEL. WE FOUND A SIGNIFICANT INCREASE IN FIBRIN DEPOSITS, DEMYELINATION, AND AXONAL DEGENERATION AS WELL AS A DECREASE IN BLOOD VESSEL DENSITY IN THE STRIATUM OF THE AGED AD MICE WHICH EXHIBITED MOTOR DEFICITS. FURTHERMORE, WE FOUND THE DEPLETION OR DESTABILIZATION OF FIBRIN IN AD MICE IMPROVED THEIR MOTOR PERFORMANCE. BASED ON THESE FINDINGS, WE HYPOTHESIZE THAT FIBRIN DEPOSITS AND VASCULAR DEGENERATION LEAD TO BLOOD BRAIN BARRIER (BBB) DAMAGE, AGGRAVATE INFLAMMATION AND DEMYELINATION, AS WELL AS CAUSE AXONAL DEGENERATION, FINALLY LEADING TO MOTOR DYSFUNCTION IN AD AND FDD. IN THIS PROPOSAL WE WILL ANALYZE POSTMORTEM BRAIN TISSUES OF AD PATIENTS WHO CLINICALLY EXHIBITED MOTOR DEFICITS IN THE EARLY DISEASE STATE AND INVESTIGATE THE PATHOGENIC MECHANISM OF MOTOR DYSFUNCTION IN RODENT MODELS OF AD AND FDD USING BIOCHEMICAL, HISTOLOGICAL, AND GENETIC METHODS (EXPERTISE BY MPI AHN). WE WILL ALSO INVESTIGATE HOW STRIATAL FIBRIN DEPOSITS CAUSE DEMYELINATION AND MOTOR DYSFUNCTION IN AD BY INDUCTION OF RESISTANT FIBRIN CLOTS OR DEPLETING THE COAGULATION FACTOR FXIII. FURTHERMORE, WE WILL EMPLOY ADVANCED MAGNETIC RESONANCE IMAGING (MRI) TECHNIQUES IN A MOUSE MODEL OF AD, FXIII DEFICIENT AD MICE AND A KNOCK-IN RAT MODEL OF FDD (EXPERTISE BY MPI DYKE). OUR TECHNIQUES WILL INTERROGATE THE PERMEABILITY OF THE BBB AND ASSESS CEREBRAL BLOOD FLOW, AND WMLS SEEN IN WHITE MATTER HYPERINTENSITIES AS WELL AS DEMYELINATION. OUR LONG-TERM OBJECTIVE IS TO TRANSLATE OUR FINDINGS IN THIS PROPOSAL FOR THE DIRECT CLINICAL MRI USE IN ASSESSING PERMEABILITY, DEMYELINATION AND NEURODEGENERATION IN HUMAN SUBJECTS AND DEVELOPING THERAPEUTICS FOR AD AND FDD.
$2.0m 9/14/22 Not listed
VASCULAR CONTRIBUTION TO WHITE MATTER LESIONS AND MOTOR DYSFUNCTION IN AD AND ADRD - MOST ALZHEIMER'S DISEASE (AD) PATIENTS EXPERIENCE SEVERE MOTOR IMPAIRMENT AT THE LATER STAGE OF DISEASE AND 10 - 40% OF AD PATIENTS EXHIBIT SIGNS OF MOTOR DYSFUNCTION AT EVEN EARLIER STAGES OF AD. FURTHERMORE, CHANGES IN MOTOR FUNCTION OFTEN PRECEDE OTHER SYMPTOMS OF AD AS WELL AS CORRELATE WITH INCREASED SEVERITY AND MORTALITY. DESPITE THE FREQUENT OCCURRENCE OF MOTOR DYSFUNCTION IN AD PATIENTS, LITTLE IS KNOWN ABOUT THE MECHANISMS BY WHICH THIS BEHAVIOR IS ALTERED. IN SEVERAL OTHER NEUROLOGICAL DISEASES, SUCH AS STROKE AND VASCULAR PARKINSONISM (VP), CEREBROVASCULAR LESIONS UNDERLIE MOTOR DYSFUNCTION DURING THE PROGRESSION OF THESE DISEASES, ESPECIALLY IN THE BASAL GANGLIA. IN ADDITION, WHITE MATTER LESIONS (WMLS), WHICH ARE PRIMARILY CONSIDERED A SMALL VESSEL DISEASE AND CHARACTERIZED AS FOCAL ABNORMAL MYELINATION, ARE HIGHLY CORRELATED WITH MOTOR DEFICITS IN VP. MOREOVER, WMLS ARE STRONGLY ASSOCIATED WITH THE CLINICAL RISK OF AD AND MAY ACCELERATE THE CLINICAL MANIFESTATION OF THE DISEASE. FAMILIAL DANISH DEMENTIA (FDD) IS ANOTHER AD-LIKE FAMILIAL NEURODEGENERATIVE DISEASE ASSOCIATED WITH MOTOR DYSFUNCTION, WML, AND VASCULAR IMPAIRMENT. HOWEVER, IT IS UNCLEAR WHICH PATHOGENIC MECHANISMS PRODUCE VASCULAR IMPAIRMENT, WML, MOTOR DYSFUNCTION IN AD AND FDD. SINCE SEVERAL CLINICAL STUDIES SUGGEST A STRONG CONNECTION BETWEEN VASCULAR DEFICITS IN BASAL GANGLIA AND MOTOR DYSFUNCTION IN SEVERAL NEUROLOGICAL DISEASES, WE INVESTIGATED THESE PATHOLOGIC CORRELATIONS IN AD MOUSE MODEL. WE FOUND A SIGNIFICANT INCREASE IN FIBRIN DEPOSITS, DEMYELINATION, AND AXONAL DEGENERATION AS WELL AS A DECREASE IN BLOOD VESSEL DENSITY IN THE STRIATUM OF THE AGED AD MICE WHICH EXHIBITED MOTOR DEFICITS. FURTHERMORE, WE FOUND THE DEPLETION OR DESTABILIZATION OF FIBRIN IN AD MICE IMPROVED THEIR MOTOR PERFORMANCE. BASED ON THESE FINDINGS, WE HYPOTHESIZE THAT FIBRIN DEPOSITS AND VASCULAR DEGENERATION LEAD TO BLOOD BRAIN BARRIER (BBB) DAMAGE, AGGRAVATE INFLAMMATION AND DEMYELINATION, AS WELL AS CAUSE AXONAL DEGENERATION, FINALLY LEADING TO MOTOR DYSFUNCTION IN AD AND FDD. IN THIS PROPOSAL WE WILL ANALYZE POSTMORTEM BRAIN TISSUES OF AD PATIENTS WHO CLINICALLY EXHIBITED MOTOR DEFICITS IN THE EARLY DISEASE STATE AND INVESTIGATE THE PATHOGENIC MECHANISM OF MOTOR DYSFUNCTION IN RODENT MODELS OF AD AND FDD USING BIOCHEMICAL, HISTOLOGICAL, AND GENETIC METHODS (EXPERTISE BY MPI AHN). WE WILL ALSO INVESTIGATE HOW STRIATAL FIBRIN DEPOSITS CAUSE DEMYELINATION AND MOTOR DYSFUNCTION IN AD BY INDUCTION OF RESISTANT FIBRIN CLOTS OR DEPLETING THE COAGULATION FACTOR FXIII. FURTHERMORE, WE WILL EMPLOY ADVANCED MAGNETIC RESONANCE IMAGING (MRI) TECHNIQUES IN A MOUSE MODEL OF AD, FXIII DEFICIENT AD MICE AND A KNOCK-IN RAT MODEL OF FDD (EXPERTISE BY MPI DYKE). OUR TECHNIQUES WILL INTERROGATE THE PERMEABILITY OF THE BBB AND ASSESS CEREBRAL BLOOD FLOW, AND WMLS SEEN IN WHITE MATTER HYPERINTENSITIES AS WELL AS DEMYELINATION. OUR LONG-TERM OBJECTIVE IS TO TRANSLATE OUR FINDINGS IN THIS PROPOSAL FOR THE DIRECT CLINICAL MRI USE IN ASSESSING PERMEABILITY, DEMYELINATION AND NEURODEGENERATION IN HUMAN SUBJECTS AND DEVELOPING THERAPEUTICS FOR AD AND FDD.
$2.0m 9/14/22