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.