1. Presymptomatic HD Disease onset currently defined by clinical detection of motor abnormalities Questions: 1) Are more subtle but clinically important signs or symptoms present earlier? Detecting early signs and symptoms may assist patients in obtaining help Example: subtle cognitive problems causing failure at work 2) When does the pathological process begin? At what age will it be necessary to start medicine to prevent neuronal toxicity? Important in treatment trials. 3) For studies of treatments designed to prevent or slow the onset of clinical disease: A) Can we find patients who will develop clinical disease in the next few years? (Therefore desired effect of medicine—delay in disease onset—can be detected B) Are there markers of disease that can be measured to determine if a treatment is working even if the patient has no clinical signs or symptoms?

2. start experimental treatment Based on current clinical definitions of onset age, determining the effect of an experimental treatment designed to slow disease onset will take many years. End of study Total study length Example of a study designed to test the effect of a treatment to delay the onset of clinical disease. Assumption: treatment slows onset, but not disease progression. Study ends when patients receiving treatment have all developed clinical disease. Using clinical onset of disease to determine effect of preventive treatments: Studies take too much time (years)

3. start treatment Based on current clinical definitions of onset age, determining the effect of an experimental treatment designed to slow disease onset will take many years. End of study Total study length Example of a study designed to test the effect of a treatment to delay the onset of clinical disease. Assumption: treatment slows onset, but not disease progression. Study ends when there is a difference in a biomarker (MRI scan, cognitive test, or other measure) Using biomarkers for disease progression: may greatly increase efficiency of trials to prevent disease progression Change in measure of disease severity (years)

4. Early signs of abnormal movements Dr. Shadmehr’s group at Johns Hopkins built a robotic arm that precisely measures upper extremity movement Subject holds the robotic arm Subject is instructed by graphics on a computer monitor where to move the robotic arm Smith, Brandt, and Shadmehr, Nature, 2000 Reza Shadmehr Johns Hopkins University Biomedical engineer Neuroscientist

5. Early signs of abnormal movements: results Normal control Measurement of hand movements from center to a target presymptomatic Presymptomatic individuals make more errors at the end of the movement, suggesting dysfunction of error correction Detectable at least 7 years prior to disease onset This test was never made clinically practical: robot expensive, takes too long Smith, Brandt, and Shadmehr, Nature, 2000

6. Changes in cognition in preclinical disease Dr. Jason Brandt Neuropsychologist Baltimore Huntington’s Disease Center Methods: 1. Assessment of individuals requesting presymptomatic testing at Johns Hopkins 2. N = 75 gene positive, N = 128 gene negative 3. Given a battery of neuropsychological tests 4.Gene positive cases split into two groups: A. Fewer than 8 years until predicted age of onset N = 37; mean of 4 years before predicted onset age B. 8 years or more until predicted age of onset (N= 38) N = 38, mean of 13 years before predicted onset age

7. Preclinical changes in cognition: results of Brandt et al Group that was close to disease did significantly worse on 6 of the 15 neuropsychological variables: Symbol Digit Modalities Test, WAIS–R Block Design subtest Road-Map Test of Directional Sense Stroop Color-Word Test (all three trials). This suggests impairment prior to onset of clinical disease in tasks requiring: spatial analysis constructional praxis response inhibition rapid response execution.

8. Changes in striatum in preclinical disease NEUROLOGY 2004;63:66–72 Methods 1)Measurement of atrophy: caudate and putamen volumes obtained by MRI scan 2)Predicted age of onset derived from the onset ages of 50 sets of affected parents and their affected offspring: = [-.81 x repeat length] + [.51 x parental onset age] + 54.87 3) Population: 19 gene positive presymptomatic patients with multiple MRI scans and 19 matched controls (additional cases with only a single scan were also added) Dr. Elizabeth Aylward--neuroimaging Univ of Washington and Baltimore HD Center

9. Neuroimaging: caudate volume loss MRI scans from all cases studied Clear correlation between caudate volume and estimated years to onset Control caudate volume Solid line = mean Dashed lines = 1 std dev

10. Progression of caudate atrophy prior to onset of clinical disease Each color represents an Individual patient scanned in mulitple years Dashed line represents best fit for the data Control caudate volume Solid line = mean Dashed lines = 1 std dev control

11. Progression of putamen loss prior to onset of clinical disease Each color represents an Individual patient scanned in mulitple years Dashed line represents best fit for the data Control caudate volume (Solid line = mean) (Dashed lines = 1 std dev control

12. Conclusions of Aylward et al, 2004 Striatum is smaller than normal until 10 years before the estimated year of disease onset Possible reasons why: –Striatum in HD fails to normally develop—it is always small –atrophy begins early, but is very slow for many years Striatal atrophy rate becomes significant at 10 years prior to estimated disease onset –4.5%/year loss of caudate volume –3.1%/year loss of putamen volume

13. Functional measures of presymptomatic HD Pilot study of 7 presymptomatic HD cases and 6 controls Behavioral task in the MRI scanner: distinguish either the big letter or the little letter: Dr. Sarah Reading Psychiatrist Neuroimager Baltimore HD Center Ann Neurol, 2004

14. Functional measures of presymptomatic HD Reading et al, 2004 Results: 1.Test performance was not impaired in the presymptomatic HD subjects 2. However, less activation in presymptomatic individuals in the left anterior cingulate (Brodmann areas 24 and 32; corrected p 0.013). Conclusions: 1. Deficits in brain function can be detected even with unimpaired cognition. 2. The deficit detected may reflect abnormalities in the anterior cingulate circuit of the corticostriatal pathway

15. White matter changes in presymptomatic HD Reading et al, Psychiatric Research, 2005 Results: 1. Numerous regions of White matter abnormality in presymp HD 2.Maximal difference from control is in Superior frontal white matter Conclusion: White matter damage is present presymptomatically and can be detected and measured. Method: Diffusion tensor images obtain from 7 presym patients and 7 controls. Fractional anisotropy, a measure of water movement in a white matter tract, was Used to determine white matter tract disruption.

16. The PREDICT-HD Study: Large study of gene positive presymptomatic HD 24 sites in U.S., Canada, and Australia. Still collecting. Results from 505 patients reported in 2006 Performed by the Huntington Study Group Information flow of Predict study. Data collected at all sites Analysis done at specific centers Goal is to confirm previous studies of presymptomatic change, and find other changes

17. PREDICT-HD: Initial results Paulsen, J. S. et al. Arch Neurol 2006;63:883-890. 1. Confirmation of loss of striatum volume prior to disease onset MRI scans showed greater volume loss as the probability of developing HD in the next 5 years increased. Adapted from Table 1, Paulsen et al, 2006. Study looking at entry level examinations, MRIs, and test scores of gene positive presymptomatic individuals.

18. PREDICT-HD: Initial results Paulsen, J. S. et al. Arch Neurol 2006;63:883-890. 2.Cognitive decline as patients get closer to onset age (measured by clinicians certainty of whether a patient had HD: 0= 0% certainty: 1 = 15%, 2 = 50%, 3 = 75-90% certain) Detected in multiple domains: psychomotor speed timing and movement sequencing learning and memory working memory face and emotion recognition executive function As certainty of diagnosis of HD increases (= decreasing time before clinical onset) cognitive function declines in multiple regions. Example: trails B test B A C D 1 2 3 4

19. PREDICT-HD: Initial results Duff et al. Biol Psychiatry 2007 3. Psychiatric symptoms are present presymptomatically Using the SCL-90 rating scale, elevations of depression hostility obsessive–compulsiveness anxiety interpersonal sensitivity phobic anxiety psychoticism

20. Presymptomatic clinical trials For the first time, serious efforts to delay disease onset Two trials –Creatine –Coenzyme Q (PREQUEL) Primary outcome measure will be delay of predicted onset of disease

21. Conclusion: presymptomatic disease Subtle abnormalities of cognition, movement, and affect occur 7-10 years prior to disease diagnosis At present, this requires specialized assessment Brain abnormalities can be detected early –Striatal atrophy –White matter –Function Implications –Possible markers for study of presymptomatic illness –Probable need to start treatment early First clinical trials for presympotmatic individuals –A milestone in neurodegenerative disease –Will probably lead to more interest in genetic testing