Substantia nigra fractional anisotropy changes confirm the PD at-risk status of patients with idiopathic smell loss

In my opinion idiopathic anosmics are an under-researched group (PARS study aside). It is good to see others taking a particular interest in them... at PREDICT-PD we are very in interested in idiopathic anosmia and are about to start reassessing the people that we have recruited with unexplained smell loss. Particularly interesting that there are MRI differences between the groups....

Parkinsonism Relat Disord. 2018 Feb 17. pii: S1353-8020(18)30076-2. doi: 10.1016/j.parkreldis.2018.02.026. [Epub ahead of print]
Haehner A, Schöpf V, Loureiro A, Linn J, Reichmann H, Hummel T, Kitzler HH.

INTRODUCTION: Individuals with unexplained smell loss constitute an at-risk population for the development of Parkinson's disease (PD). Currently, no specific MRI patterns are known for early PD diagnosis. In this study, we measured the fractional anisotropy (FA) in the substantia nigra (SN) in PD patients, in patients with idiopathic smell loss, and in healthy controls.

METHODS: All subjects underwent extensive olfactory testing and MR imaging data were obtained to explore SN diffusion characteristics. The SN regions were manually identified by two independent raters on the individual imaging data.

RESULTS: FA measurements in the SN revealed significant group differences, with reduced values clearly distinguishing PD patients and patients with idiopathic smell loss from healthy controls.

CONCLUSION: These findings indicate a reduced intrinsic integrity of the SN in PD at-risk subjects and support the risk status of patients with idiopathic smell loss.

Do subjects with minimal motor features have prodromal PD?

This is a study of potentially vital importance to our understand of the prodrome(s) of PD. Here the authors show that people with mild parkinsonian signs (subtle bradykinesia, tremor, rigidity, gait disturbance) have Parkinson's disease pathology at post-mortem. The authors observed no PD pathology in participants without mild parkinsonian signs, moderate PD pathology in those with mild parkinsonian signs and frank PD pathology in those with a clinical diagnosis of PD. Some caution should be exercised that the group with mild parkinsonian signs was significantly older than the other two groups, but the pattern of pathology was not typically age-related.

Their observation add further weight the notion that there is a significant motor aspect to the phase of PD before diagnosis, as suggested by our group and others... (the citations in this paper relating to the previous literature on prodromal motor symptoms are a little light if you ask me ! 😀)... 

However this new study could turn out to be a landmark one. I (and some others) have long been asserting that the term 'premotor' may not be an appropriate one. Unless we have laid eyes on people with idiopathic anosmia, RBD or other non-motor prodromal features, then we can't be sure that there are no motor signs. The really important thing to work on now is characterising what specifically starts to change in terms of motor function in those that will eventually go on to get a diagnosis of PD? This is a major focus of the PREDICT-PD study over the next 3 years... and we are exploring this in a variety of ways...

Ann Neurol. 2018 Feb 8. doi: 10.1002/ana.25179. [Epub ahead of print]
Chu Y, Buchman AS, Olanow CW, Kordower JH.

http://onlinelibrary.wiley.com/doi/10.1002/ana.25179/full

BACKGROUND: Understanding the pathological changes underlying mild motor features of the eldery and defining a patient population with prodromal Parkinson's disease (PD) are of great clinical importance. It remains unclear, however, how to accurately and specifically diagnose prodromal PD. We examined whether older adults with minimal parkinsonian motor features have nigrostriatal degeneration and α-synuclein pathology consistent with prodromal PD.

METHODS: Brain sections were obtained from older adults with a clinical diagnosis of PD (N=21) and without a clinical diagnosis of PD (N=27) who underwent motor examination proximate to death. Cases without PD were further dichotomized into no motor deficit (n=9) or minimal motor features (n-18) groups using a modified Unified Parkinson's Disease Rating Scale. We performed quantitative unbiased stereological analyses of dopaminergic neurons/terminals and α-synuclein accumulation in the nigrostriatal system.

RESULTS: In all subjects with minimal motor features, there were significant reductions in dopaminergic neurons and terminals in the substantia nigra and putamen that was intermediate between subjects with no motor deficit and PD. Phosphorylated α-synuclein inclusions were observed in the substantia nigra that were of similar density to what was seen in PD. Furthermore, there was greater Lewy neuritic pathology in the putamen relative to PD patients. Lastly, neurons with α-synuclein inclusions displayed reductions in tyrosine hydroxylase expression that was comparable in subjects with both minimal motor features and PD.

INTERPRETATION: Minimal motor features in older adults may represent prodromal PD and identify at risk individuals for testing putative neuroprotective interventions that could slow or prevent PD progression.

This article is protected by copyright. All rights reserved. © 2018 American Neurological Association.

Parkinson's in the community

This article, which comes from a large UK study of Parkinson's Disease (PRoBaND), is an important snapshot of the impact of Parkinson's across the country today. The authors focus particularly on the most common genetic risk factor for Parkinson's - the GBA mutation. This mutation is of particular interest as it is associated with a rarer syndrome - Gaucher's Disease. In this disease, which is a lysosomal storage disorder, lipids accumulate in cells and there is disruption of the normal lysosomal function which is to digest and dispose of unwanted materials. The implication from this association is that a similar process may be involved in Parkinson's Disease.

However, most people with Parkinson's do not have this mutation. Here, over 2000 patients were recruited from across the country and of these, 1893 patients underwent genetic testing. In total a minority, 142 of these patients had mutations in the GBA gene. Of these, the majority, around 2/3 had mutations not linked with Gaucher's Disease, while the other 1/3 has mutations exactly the same as those seen in Gaucher’s disease. There were differences between carriers of these two different types of mutation, with those who had the Gaucher's Disease mutations more likely to have a severe form of the disease - younger at onset, with faster progression and higher medication requirements. While previous studies have reported more cognitive impairment in GBA carriers, this was not bourne out by this study.

We still have a long way to go in connecting the dots in genetics - a number of patients had mutations whose significance is unknown and only 10% of patients had any mutations in this gene. It may be that GBA-related Parkinson's represents a slightly different disease which may have different underlying pathology and treatment options from other forms. However, the connection between lysosomal storage disorders and Parkinson's is increasingly strong and the hope is that these connections will allow us to unlock mechanisms and develop specific treatments.

http://jnnp.bmj.com/content/early/2018/01/28/jnnp-2017-317348

J Neurol Neurosurg Psychiatry. 2018 Jan 29. pii: jnnp-2017-317348. doi: 10.1136/jnnp-2017-317348.

Features of GBA-associated Parkinson's disease at presentation in the UK Tracking Parkinson's study.

Malek N, Weil RS, Bresner C, Lawton MA, Grosset KA, Tan M, Bajaj N, Barker RA, Burn DJ, Foltynie T, Hardy J, Wood NW, Ben-Shlomo Y, Williams NW, Grosset DG, Morris HR; PRoBaND clinical consortium.

OBJECTIVES:

To examine the influence of the glucocerebrosidase (GBA) mutation carrier state on age at onset of Parkinson's disease (PD), the motor phenotype and cognitive function at baseline assessment in a large cohort of UK patients. We also analysed the prevalence of mood and behavioural problems that may confound the assessment of cognitive function.

METHODS:

We prospectively recruited patients with PD in the Tracking Parkinson's study. We fully sequenced the GBA gene in all recently diagnosed patients (≤3.5 years). We examined cognitive (Montreal Cognitive Assessment) and motor (Movement Disorder Society Unified Parkinson's Disease Rating Scale part 3) function at a baseline assessment, at an average of 1.3 years after diagnosis. We used logistic regression to determine predictors of PD with mild cognitive impairment and PD with dementia.

RESULTS:

We studied 1893 patients with PD: 48 (2.5%) were heterozygous carriers for known Gaucher's disease (GD) causing pathogenic mutations; 117 (6.2%) had non-synonymous variants, previously associated with PD, and 28 (1.5%) patients carried variants of unknown significance in the GBA gene. L444P was the most common pathogenic GBA mutation. Patients with pathogenic GBA mutations were on average 5 years younger at disease onset compared with non-carriers (P=0.02). PD patients with GD-causing mutations did not have an increased family risk of PD. Patients with GBA mutations were more likely to present with the postural instability gait difficulty phenotype compared with non-carriers (P=0.02). Patients carrying pathogenic mutations in GBA had more advanced Hoehn and Yahr stage after adjustment for age and disease duration compared with non-carriers (P=0.005). There were no differences in cognitive function between GBA mutation carriers and non-carriers at this early disease stage.

CONCLUSIONS:

Our study confirms the influence of GBA mutations on the age of onset, disease severity and motor phenotype in patients with PD. Cognition did not differ between GBA mutation carriers and non-carriers at baseline, implying that cognitive impairment/dementia, reported in other studies at a later disease stage, is not present in recently diagnosed cases. This offers an important window of opportunity for potential disease-modifying therapy that may protect against the development of dementia in GBA-PD.

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.