Synucleinopathies see advances in biomarkers and imaging

At the 2019 Alzheimer’s and Parkinson’s Diseases Congress (ADPD) in Lisbon, researchers considered the potential role of neurogranin and brain-derived exosomes in differential diagnosis of Parkinson’s Disease (PD), along with disease detection via gut biopsy and advances in PD imaging.

Neurogranin is a small post-synaptic neuronal protein.1 Increased levels of neurogranin in the cerebrospinal fluid (CSF) are thought to reflect loss or dysfunction of synapses and relate to rapid cognitive decline in Alzheimer’s Disease.1 However, this potential marker of disease severity has not been investigated much in Parkinsonian disorders.

Low neurogranin in motor impairment reflects synaptic dysfunction

The Swedish BioFINDER study has been breaking new ground by looking at neurogranin in a range of synucleinopathies, including 157 subjects with PD, 29 subjects with Parkinson’s disease with dementia (PDD), 11 subjects with Lewy body dementia (LBD) and 26 subjects with multiple system atrophy (MSA).2–4 The following results were presented:4

  1. Compared with healthy controls, baseline levels of neurogranin are seen to be lower in people with Parkinsonian conditions
  2. Low baseline neurogranin level correlates with worse motor function, implicating synaptic dysfunction in this aspect of disease
  3. Low neurogranin level also correlates with poorer verbal fluency. However, interestingly, neurogranin does not link to delayed memory recall or poor scores on the Mini-Mental State Examination (MMSE)
  4. Low neurogranin levels 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

Exosomes in serum can provide a window into the brain

In the speaker’s experience, identifying MSA in patients with an initial diagnosis of PD can take several clinicians and many months. Data was presented 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.

Based on a simple blood sample, the ratio between α-synuclein concentrations in oligodendroglial and neuronal exosomes can help distinguish between PD and MSA with a high sensitivity and specificity.5 It is also significantly correlated with PD progression.5

Synuclein, amyloid and tau stick together in LBD

Another study that was presented at the congress validated imaging biomarkers of LBD against post-mortem neuropathology in 18 patients at positron emission tomography (PET) scanning.6 All patients had cognitive impairment and low direct antiglobulin test (DAT) concentrations.6

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

At autopsy, all patients with elevated uptake of the amyloid PET tracer Pittsburgh compound B (PiB) were found to have amyloid-β deposits.6 Remarkably - and to the 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.6

The speakers concluded that the three aggregated proteins – amyloid-β, tau and α-synuclein – can 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?

Compared with surgical specimens, biopsy tissue is of little use

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.7 However, if we are hoping to use immunohistochemistry to detect α-synuclein in the gastrointestinal tract, we should probably not rely on biopsy specimens.7,8

Work from the Seoul National University Hospital, Republic of Korea, shows that concordance between biopsy and surgical specimens is poor.9 Presenting their data from a study of 33 patients with PD,9 the speaker stated that larger and full-depth tissue samples obtained during surgery provided the most reliable information. The data also suggest that we should look to tissue from the stomach rather than the colon or rectum9 – which makes sense given the rostrocaudal gradient in α-synuclein deposition.7

The Path to Prevention (P2P) initiative grows out of the Parkinson’s Progression Markers Initiative (PPMI)

Valuable information on rates of change in clinical markers obtained through the Parkinson’s Progression Markers Initiative (PPMI) could inform the design of clinical studies10. The speaker commented that the relatively slow deterioration on Montreal Cognitive Assessment (MoCA) observed in PD can mean that large numbers of patients will be required to identify a potential drug effect.

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

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.10,11

PPMI results are challenging established concepts of progression in PD. One example that was discussed is that people whose Unified Parkinson Disease Rating Scale (UPDRS) scores deteriorate rapidly are not necessarily the same as those who show rapid change on DaTSCAN.10,12

This website has been developed by Lundbeck UK. Highlights from the symposia are a fair representation of the scientific content presented at the meeting and have been adapted for the use of UK healthcare professionals.
  1. Portelius E, et al. Brain. 2015;138:3373-3385.
  2. The Swedish BioFINDER Study. Available at: Accessed: June 2019.
  3. Hall S, et al. Sci Rep. 2018;8:13276.
  4. Hall S, et al. Cerebrospinal fluid levels of neurogranin in parkinsonian disorders. Presented at Alzheimer’s and Parkinson’s Diseases Congress (ADPD), 2019, Lisbon, Portugal. Available at:!abstractdetails/0000246090. Accessed: June 2019.
  5. Bitan G, et al. Alpha-synuclein in brain-derived exosomes distinguishes parkinson’s disease from multiple system atrophy. Presented at Alzheimer’s and Parkinson’s Diseases Congress (ADPD), 2019, Lisbon, Portugal. Available at:!abstractdetails/0000253720. Accessed: June 2019.
  6. Growdon J, et al. Moleclar PET scans reveal the basis of dementia in Parkinson Disease. Presented at Alzheimer’s and Parkinson’s Diseases Congress (ADPD), 2019, Lisbon, Portugal. Available at:!abstractdetails/0000078500. Accessed: June 2019.
  7. Ruffman C & Parkkinen L. Mov Disord. 2016;31:193-202.
  8. Jeon B. Peripheral tissue biomarker of Parkinson’s Disease. Presented at Alzheimer’s and Parkinson’s Diseases Congress (ADPD), 2019, Lisbon, Portugal. Available at:!abstractdetails/0000078610. Accessed: June 2019.
  9. Shin C, et al. Parkinsonism Relat Disord. 2017;44:73-8.
  10. Marek K, et al. Ann Clin Transl Neurol. 2018;5:1460-77.
  11. Parkinson’s Progression Markers Initiative. Study goals. Available at: Accessed: June 2019.
  12. Simuni T, et al. Mov Disord. 2018;33:771-82.
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