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Synucleinopathies see advances in biomarkers and imaging

Improved diagnostics and insights into pathogenesis were presented in the ADPD session that considered the roles of neurogranin and brain-derived exosomes, along with gut biopsy and advances in imaging.

Neurogranin is a small post-synaptic neuronal protein. Increased CSF levels Neurogranin are thought to reflect loss or dysfunction of synapses and relate to rapid cognitive decline in AD. But this potential marker of disease severity has not been much investigated in Parkinsonian disorders.

Low neurogranin in motor impairment reflects synaptic dysfunction

So the Swedish  BioFINDER study has been breaking new ground by looking at neurogranin in a cohort of subjects with a range of synucleinopathies including 157 with Parkinson’s disease PD, 29 with Parkinson’s disease with dementia (PDD), 11 Lewy body dementia and 26 MSA.  Sara Hall, University of Lund, Sweden, presented the following results:

  • Compared with healthy controls, baseline levels of neurogranin are lower in people with Parkinsonian conditions
  • Lower baseline neurogranin correlates with worse motor function, implicating synaptic dysfunction in this aspect of disease
  • Low neurogranin also correlates with poorer verbal fluency. But, interestingly, neurogranin does not link to delayed memory recall or poorer scores on the MMSE
  • And low neurogranin in PD is not a predictor of conversion to dementia or of faster clinical progression over a median follow-up of five years.

Exosomal α-synuclein distinguishes MSA from PD

Identifying MSA in patients with an initial diagnosis of PD can take several clinicians and many months. So Gal Bitan and colleagues from UCLA, Los Angeles, USA, are excited by their data suggesting that we can tease the two conditions apart and at an early stage by looking at the ratio between α-synuclein concentrations in exosomes of neuronal versus oligodendroglial origin.

Exosomes in serum provide a window into the brain

Based on a simple blood sample, the ratio between α-synuclein concentrations in oligodendroglial and neuronal exosomes distinguishes between PD and MSA with a high sensitivity and specificity. It is also significantly correlated with PD progression.

Synuclein, amyloid and tau stick together in LBD

John Growdon, Massachusetts General Hospital, Boston, USA, and colleagues have validated imaging biomarkers of Lewy body disease (LBD) against postmortem neuropathology in 18 patients with a mean age at PET scanning of 74 years. All had cognitive impairment and low DAT concentrations.

At autopsy, all patients with elevated uptake of the amyloid PET tracer PiB were found to have amyloid-β deposits. Remarkably -- and to investigators’ surprise -- PiB retention correlated not only with neuritic and total plaque burden but also with the severity of neurofibrillary tangle distribution indicated by tau immunostaining and the extent of Lewy bodies as indicated by α-synuclein staining.

PiB retention accurately reflected cortical amyloid-β deposits but also tau and α-synuclein

Growdon and colleagues conclude that the three aggregated proteins – amyloid-β, tau and α-synuclein – all contribute to the clinical spectrum of cognitive impairment seen in LBD. This poses intriguing questions: is a single pathological process responsible for the aggregation of all three proteins, or does aggregation of one lead to aggregation of the others?

How should we look for gut α-synuclein?

The search is on for reliable peripheral tissue markers of prodromal PD. Given the idea that the disease may have its origins in the enteral nervous system, trying to detect it in the gut is a logical approach. However, if we are hoping to use immunohistochemistry to detect α-synuclein in the GI tract, we should probably not rely on biopsy specimens.

Compared with surgical specimens, biopsy tissue is of little use

Work from the Seoul National University Hospital, Republic of Korea, shows that concordance between biopsy and surgical specimens is poor. Presenting the data from a study of 33 patients with PD, Beomseok Jeon said that larger and full-depth tissue samples obtained during surgery provide more reliable information. The data also suggest that we should look to tissue from the stomach rather than the colon or rectum – which makes sense given the rostrocaudal gradient in α-synuclein deposition.

P2P grows out of PPMI

Valuable information on rates of change obtained through the Parkinson’s Progression Markers Initiative (PPMI) is informing the design of clinical trials. It is clear, for example, that the relatively slow deterioration on Montreal Cognitive Assessment (MoCA) means that large numbers of patients are required to identify a potential drug effect on cognition of modest magnitude.

The PPMI is also uniquely helpful in defining the dataset required to give us a comprehensive handle on the disease, a standardized approach to sample collection, storage, analysis, and open access to data.

“Progression” in PD is hard to define and hence hard to predict

But PPMI results are challenging established concepts of progression in PD. One example, discussed by Ken Marek, Institute for Neurodegenerative Disorders, New Haven, Connecticut, USA, is that people whose UPDRS scores deteriorate rapidly are not necessarily the same as those who show rapid change on DaTSCAN.

The Path to Prevention (P2P) initiative will increase the number of people with prodromal PD judged to be at high risk of conversion to motor disease who are followed longitudinally.

Outcome in subsets with genetic predisposition or clinical features such as olfactory or sleep disorder will be assessed, along with imaging and biologic markers, in order to establish a signature that indicates high risk of progression. This can then be used to select people for trials of potentially disease-modifying agents.

Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.

References
  1. Prakash N, Caspell-Garcia C, Coffey C, et al. Feasibility and safety of lumbar puncture in the Parkinson's disease research participants: Parkinson's Progression Marker Initiative (PPMI). Parkinsonism Relat Disord. 2019 Jan 31. pii: S1353-8020(18)30559-5. doi: 10.1016/j.parkreldis.2018.12.025. [Epub ahead of print]
  2. Gomperts SN, Marquie M, Locascio JJ, Bayer S, Johnson KA, Growdon JH. PET Radioligands Reveal the Basis of Dementia in Parkinson's Disease and Dementia with Lewy Bodies. Neurodegener Dis. 2016;16(1-2):118-24.
  3. Simonsen AH, Kuiperij B, El-Agnaf OM et al. The utility of α-synuclein as biofluid marker in neurodegenerative diseases: a systematic review of the literature. Biomark Med. 2016;10(1):19-34.
  4. Shahnawaz M, Tokuda T, Waragai M. Development of a Biochemical Diagnosis of Parkinson Disease by Detection of α-Synuclein Misfolded Aggregates in Cerebrospinal Fluid. JAMA Neurol. 2017 Feb 1;74(2):163-172.
  5. Hall S, Janelidze S, Surova Y et al. Cerebrospinal fluid concentrations of inflammatory markers in Parkinson's disease and atypical parkinsonian disorders. Sci Rep. 2018 Sep 5;8(1):13276.
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