Presymptomatic HDDisease 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?

Threshold for clinical detection

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Threshold for clinical detection

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start experimental treatment

Based on current clinical definitions of onset age, determining the effect ofan experimental treatment designed to slow disease onset will take many years.

End of study

Total study length

Example of a studydesigned 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)

Threshold for clinical detection

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Normal coursetreated course

Threshold for clinical detection

Mea

sure

of

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y

time

Normal coursetreated course

start treatment

Based on current clinical definitions of onset age, determining the effect ofan experimental treatment designed to slow disease onset will take many years.

End of study

Total study length

Example of a studydesigned 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)

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 ShadmehrJohns Hopkins UniversityBiomedical engineerNeuroscientist

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

Changes in cognition in preclinical disease

Dr. Jason BrandtNeuropsychologistBaltimore Huntington’s Disease Center

Methods: 1. Assessment of individuals requesting presymptomatic testing at Johns Hopkins2. N = 75 gene positive, N = 128 gene negative3. Given a battery of neuropsychological tests4. 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

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 subtestRoad-Map Test of Directional SenseStroop Color-Word Test (all three trials).

This suggests impairment prior to onset of clinical disease in tasks requiring:

spatial analysisconstructional praxisresponse inhibitionrapid response execution.

Changes in striatum in preclinical disease

NEUROLOGY 2004;63:66–72

Methods1) Measurement of atrophy: caudate and putamen volumes obtained by MRI scan2) 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--neuroimagingUniv of Washington and Baltimore HD Center

Neuroimaging: caudate volume loss

MRI scans from all cases studied

Clear correlation between caudate volume and estimated years to onset

Control caudate volumeSolid line = meanDashed lines = 1 std dev

Progression of caudate atrophy prior to onset of clinical disease

Each color represents anIndividual patient scanned in mulitple years

Dashed line represents best fit for the data

Control caudate volumeSolid line = meanDashed lines = 1 std dev

control

Progression of putamen loss prior to onset of clinical disease

Each color represents anIndividual 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

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

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 ReadingPsychiatristNeuroimagerBaltimore HD Center

Ann Neurol, 2004

Functional measures of presymptomatic HDReading 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

White matter changes in presymptomatic HDReading et al, Psychiatric Research, 2005

Results:

1. Numerous regions ofWhite 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, wasUsed to determine white matter tract disruption.

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 2006Performed 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

PREDICT-HD: Initial resultsPaulsen, 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.

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Probablity of developing HD in the next 5 years

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PREDICT-HD: Initial resultsPaulsen, 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 speedtiming and movement sequencinglearning and memoryworking memoryface and emotion recognitionexecutive function

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As certainty of diagnosis of HD increases (= decreasing time before clinical onset)cognitive function declines in multiple regions. Example: trails B test

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PREDICT-HD: Initial resultsDuff et al. Biol Psychiatry 2007

3. Psychiatric symptoms are present presymptomatically

Using the SCL-90 rating scale, elevations of depression

hostilityobsessive–compulsivenessanxietyinterpersonal sensitivityphobic anxietypsychoticism

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

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