Seeing the future

We are proud to announce another research paper from the Predict-PD stable. We have published our data from the imaging substudy of the first phase of our research.

50 individuals who had gone through the website had a scan showing dopamine-releasing areas in the brain (known as a DAT-SPECT or DATSCAN) and transcranial ultrasound. The DATSCAN is the closest we have to a scan that gives proof of Parkinson’s in the brain. Ultrasound shows an area in the region most affected by Parkinson’s that is brighter in people with Parkinson’s compared to healthy people.

Our findings show that the reductions in the dopamine scan were correlated with risk scores, worse movement scores both on clinical assessment and using the keyboard tapping test, and worse sense of smell. The ultrasound scan also correlated with risk score and motor score on clinical assessment.

These findings show that the risk score calculated from the responses on the website are associated with changes on brain scans that are associated with established Parkinson’s. This is exciting news, not just for us, but it has established that there are hard changes in the brains of those at the highest risk that are very likely to be the earliest signs of Parkinson’s. These scans may well be used to prove eligibility for people to be included  in future drug trials to slow, stop or prevent the diagnosis.

What are the next steps? I’ll be repeating this on a larger sample, and not just using DATSCAN and ultrasound but MRI too, which will give a highly detailed map of the strucutre of the brain. I look forward to sharing these results with you in the next few years.

RNR

http://onlinelibrary.wiley.com/doi/10.1002/mds.27282/abstract

Dopamine reuptake transporter–single-photon emission computed tomography and transcranial sonography as imaging markers of prediagnostic Parkinson's disease

Authors

Alastair J. Noyce MRCP, PhD, John Dickson PhD, Richard N. Rees MRCP, Jonathan P. Bestwick MSc, Ioannis U. Isaias MD, PhD, Marios Politis MD, PhD, Gavin Giovannoni FRCP, PhD, Thomas T. Warner FRCP, PhD, Andrew J. Lees FRCP, MD, Anette Schrag FRCP, PhD

• First published: 30 January 2018

ABSTRACT

Objective: The objective of this study was to examine whether prediagnostic features of Parkinson's disease (PD) were associated with changes in dopamine reuptake transporter–single-photon emission computed tomography and transcranial sonography.

Methods: Prediagnostic features of PD (risk estimates, University of Pennsylvania Smell Identification Test, Rapid Eye Movement Sleep Behavior Disorder Screening Questionnaire, and finger-tapping scores) were assessed in a large cohort of older U.K. residents. A total of 46 participants were included in analyses of prediagnostic features and MDS-UPDRS scores with the striatal binding ratio on dopamine reuptake transporter–single-photon emission computed tomography and nigral hyperechogenicity on transcranial sonography.

Results: The striatal binding ratio was associated with PD risk estimates (P = .040), University of Pennsylvania Smell Identification Test (P = .002), Rapid Eye Movement Sleep Behavior Disorder Screening Questionnaire scores (P = .024), tapping speed (P = .024), and MDS-UPDRS motor scores (P = .009). Remotely collected assessments explained 26% of variation in the striatal binding ratio. The inclusion of MDS-UPDRS motor scores did not explain additional variance. The size of the nigral echogenic area on transcranial sonography was associated with risk estimates (P < .001) and MDS-UPDRS scores (P = .03) only.

Conclusions: The dopamine reuptake transporter–single-photon emission computed tomography results correlated with motor and nonmotor features of prediagnostic PD, supporting its potential use as a marker in the prodromal phase of PD. Transcranial sonography results also correlated with risk scores and motor signs.

On the road to nowhere

This week brings the publication of the (much-anticipated) EXPEDITION 3 study. This reports the results of a very large drug trial of a drug that is hoped to reduce the progression of Alzheimer’s disease. As you might be able to tell by the name, it has been preceded by two previous similar studies.

What is unique about this study? Firstly, the people involved all had ‘early’ Alzheimer’s disease. Secondly, participants had to have ‘evidence’ of Alzheimers pathology – this is key because in the previous studies although all the participants had dementia, a significant number ended up having dementia of another cause.

What are the other notable aspects of the design? The scales they used assessed ‘everyday’ performance (as best as a validated scale can), rather than an abstract cognitive assessment; the study compared cognitive performace after 18 months of treatment, which is a reasonable time given the tradeoff of the cost of a trial such as this, and the rate of progression of the disease.

What are the results? Unfortunately, there was no significant difference when comparing the two groups after 18 months.

There are many lessons for researchers in the Parkinson’s world to learn from this study. A potential reason for failure is that even at the stage of ‘mild’ dementia, there may be too much ‘toxic protein’ in the brain for the process to be reversed, or slowed. To overcome this would require recruiting people with evidence of the disease, but without symptoms. Fortunately, this is exactly whom we hope to identify in PREDICT-PD. Another potential reason for the failure of this drug in three trials is that with solenizumab, they’re barking up the wrong tree. The drug has been specifically designed to reduce the amount of abnormal amyloid protein in the brain. However, although there is strong evidence for the Amyloid Hypothesis, the lack of efficacy of anti-amyloid treatments has brought many in the field to challenge the concept. In Parkinson’s there is less doubt over the Synuclein Hypothesis, and the challenge remains to find a compound that can reduce it, or stop it accumulating and causing brain destruction.

RNR

http://www.nejm.org/doi/full/10.1056/NEJMoa1705971?query=BUL

Trial of Solanezumab for Mild Dementia Due to Alzheimer’s Disease

Abstract

BACKGROUND

Alzheimer’s disease is characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles. The humanized monoclonal antibody solanezumab was designed to increase the clearance from the brain of soluble Aβ, peptides that may lead to toxic effects in the synapses and precede the deposition of fibrillary amyloid.

METHODS

We conducted a double-blind, placebo-controlled, phase 3 trial involving patients with mild dementia due to Alzheimer’s disease, defined as a Mini–Mental State Examination (MMSE) score of 20 to 26 (on a scale from 0 to 30, with higher scores indicating better cognition) and with amyloid deposition shown by means of florbetapir positron-emission tomography or Aβ1-42 measurements in cerebrospinal fluid. Patients were randomly assigned to receive solanezumab at a dose of 400 mg or placebo intravenously every 4 weeks for 76 weeks. The primary outcome was the change from baseline to week 80 in the score on the 14-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog14; scores range from 0 to 90, with higher scores indicating greater cognitive impairment).

RESULTS

A total of 2129 patients were enrolled, of whom 1057 were assigned to receive solanezumab and 1072 to receive placebo. The mean change from baseline in the ADAS-cog14 score was 6.65 in the solanezumab group and 7.44 in the placebo group, with no significant between-group difference at week 80 (difference, −0.80; 95% confidence interval, −1.73 to 0.14; P=0.10). As a result of the failure to reach significance with regard to the primary outcome in the prespecified hierarchical analysis, the secondary outcomes were considered to be descriptive and are reported without significance testing. The change from baseline in the MMSE score was −3.17 in the solanezumab group and −3.66 in the placebo group. Adverse cerebral edema or effusion lesions that were observed on magnetic resonance imaging after randomization occurred in 1 patient in the solanezumab group and in 2 in the placebo group.

CONCLUSIONS

Solanezumab at a dose of 400 mg administered every 4 weeks in patients with mild Alzheimer’s disease did not significantly affect cognitive decline. (Funded by Eli Lilly; EXPEDITION3 ClinicalTrials.gov number, NCT01900665.)

Association of Polygenic Risk Score With Cognitive Decline and Motor Progression in Parkinson Disease.

Polygenic (or genetic) risk scores have become widely used in the study of common genetic variation and its role in disease... these risk scores are derived by combining the effects of the genetic variants identified in genome wide association (GWA) studies. GWA studies themselves are usually a comparison between the genetic variants that exist in a particular disease group (for example Parkinson's disease) compared with the variants seen in a healthy control group. Stringent levels of 'statistical significance' are applied to rule out false positive results and the regions that are identified are independent of one another. This independence means that the odds of the disease attributed to each variant/region can be multiplied together to give an overall genetic risk score for that disease. You can see how this might be useful for predicting who might get Parkinson's.

One can also calculate how much of the disease that the genetic risk score explains (usually only a very small amount). The genetic risk score for the present study came from here. There is now a bigger GWA study for Parkinson's that has been published too.

In the present study, the authors set out to see if the original genetic risk score that predicted the odds of getting PD also predicted the rate of disease progression in those that already have the disease, using cognitive and motor scores. It is not always the case that risk factors that are associated with getting a disease are also associated with more aggressive disease, but here we see evidence that this might be the case. Whether this is a reflection of common mechanisms underpinning risk and progression, or whether the original GWAS study contained an excess of patients with more aggressive forms of PD remains to be determined...

- Alastair Noyce


JAMA Neurol. 2018 Jan 16. doi: 10.1001/jamaneurol.2017.4206. [Epub ahead of print]
Paul KC, Schulz J, Bronstein JM, Lill CM, Ritz BR.

https://jamanetwork.com/journals/jamaneurology/article-abstract/2669922?redirect=true

IMPORTANCE: Genetic factors have a well-known influence on Parkinson disease (PD) susceptibility. The largest genome-wide association study (GWAS) identified 26 independent single-nucleotide polymorphisms (SNPs) associated with PD risk. Among patients, the course and severity of symptom progression is variable, and little is known about the potential association of genetic factors with phenotypic variance.

OBJECTIVE: To assess whether GWAS-identified PD risk SNPs also have a cumulative association with the progression of cognitive and motor symptoms in patients with PD.

DESIGN, SETTING, AND PARTICIPANTS: This longitudinal population-based cohort study of 285 patients of European ancestry with incident PD genotyped 23 GWAS SNPs. One hundred ninety-nine patients were followed up for a mean (SD) of 5.3 (2.1) years for progression (baseline: June 1, 2001, through November 31, 2007; follow-up: June 1, 2007, through August 31, 2013, with mortality surveillance through December 31, 2016); 57 patients had died or were too ill for follow-up, and 29 withdrew or could not be contacted. Movement disorder specialists repeatedly assessed PD symptom progression.

MAIN OUTCOMES MEASURES: The combined association of PD risk loci, after creating a weighted polygenic risk score (PRS), with cognitive decline, motor progression, and survival, relying on Cox proportional hazards regression models and inverse probability weights to account for censoring.

RESULTS: Of the 285 patients undergoing genotyping, 160 were men (56.1%) and 125 were women (43.9%); the mean (SD) age at diagnosis was 69.1 (10.4) years. The weighted PRS was associated with significantly faster cognitive decline, measured by change in the Mini-Mental State Examination (hazard ratio [HR] per 1 SD, 1.44; 95% CI, 1.00-2.07). The PRS was also associated with faster motor decline, measured by time to Hoehn & Yahr Scale stage 3 (HR, 1.34; 95% CI, 1.00-1.79) and change in Unified Parkinson's Disease Rating Scale part III score (HR, 1.42; 95% CI, 1.00-2.01).

CONCLUSIONS AND RELEVANCE: Susceptibility SNPs for PD combined with a cumulative PRS were associated with faster motor and cognitive decline in patients. Thus, these genetic markers may be associated with not only PD susceptibility but also disease progression in multiple domains.

Comparing apples and apples

Drug trials (or trials of any new treatment for that matter) are designed by comparing a group on the new treatment against a group on something else. That may be no treatment, the best available treatment, or placebo (or dummy treatment). In order to make a fair comparison, it is essential to compare like with like.

An extreme example of this would be to say that “men are faster than women”, having compared the Jamaican mens olympic sprint team, against a selection of girls from the local secondary school. This is obviously ridiculous in so many ways: adult men vs teenage girls, trained atheletes vs untrained and so on…

In studies of Parkinson’s, it is also important that we compare like with like. For the past 50 years, researchers have used the “Hoehn and Yahr Scale” to create standardised definitions. (The scale is named after Margaret Hoehn and Melvin Yahr who pioneered research into progression and epidemiology of Parkinson’s in the 1960s.) Designed to give researchers a simple and global assessment of disease severity, this is probably the most widely used Parkinson’s staging system in use. According to the latest version of this scale there are 6 stages from 0= Asymptomatic to 5 = wheelchair bound or bedridden unless unaided.

Despite its widespread use, until now there have been no systematic attempts to prove how useful and reproducible it is. The researchers in this study assessed the acceptability, reproducibility, content and validity of the scale. They compared how different raters scored people (known as inter-rater reliability), and how that compared with other scoring systems of stiffness, tremor and other features of Parkinson’s. They also looked at whether the same assessor gave the same patient the same score at different times (known as test-retest reliability).

The good news is that inter-rater reliability and test-retest reliability are incredibly high. In other words, if one clinician judges a person to have stage II, so will almost every other (trained) clinician. It also correlated quite well with other physical assessment scores.

As ever, it is not a perfect test. The difference between stages is not the same (in other words, going from I to II is not the same as going from III-IV). Nor does it correlate at all well with quality of life. It also does not take into account non-motor features of Parkinson’s. Furthermore, only 2.9% of more than 3000 participants were at the most advanced stage V, so may not be quite as reliable for these people.

In summary, we have a pretty good measure of giving a number to the amount that an individual is affected by Parkinson’s. Until we have a blood test/scan/marker of progression, this is the best we have, and we need to make sure we have ways of addressing its weaknesses. Using it we can compare like with like, and, hopefully, get ever closer to preventing people advancing through the scale.

RNR

http://onlinelibrary.wiley.com/doi/10.1002/mds.27242/abstract;jsessionid=A596451DCF79B33BF34C1802EFD6E2CF.f04t03

Martinez-Martin P, Skorvanek M, Rojo-Abuin JM, Gregova Z, Stebbins GT, Goetz CG, et al. Validation study of the hoehn and yahr scale included in the MDS-UPDRS. Mov Disord. 2018 Jan 11;17:427.