"They might have dementia, let's act QuIC!".
- pietrococchiara
- Jul 7
- 5 min read
In medicine, thanks to more recent advancements, it is becoming easier to determine whether a patient may suffer of dementia. However, many types of dementia have been described in the past and the new technologies are helping medical doctors in providing patients with a more accurate diagnosis and at an earlier stage of the disease. It is easy to understand the growing importance of new methodologies aiming to improve the earlier-stages of these diseases, as world-wide population is getting older, with serious implications on many countries' health system and welfare. In this article, a specific type of dementia will be described, called Lewy Body Dementia (LBD).
Lewy Body Disease (LBD): what is it and how does it originate?
LBD is an age-associated neurodegenerative disorder which produces a progressive cognitive decline in affected patients, that interferes with their normal life and daily activities through psychosis episodes and parkinsonian-like symptoms. This symptomatology is the results of the accumulation of a protein aggregates of α-synuclein in clumpy structures defined as Lewy bodies and/or Lewy neurites, abnormal thread-like extensions of neurons containing α-synuclein. This group of symptoms present some resemblance to those described in presence of Parkinson's disease, which makes the clear diagnosis of this disorder quite difficult.
Since LBD is caused by α-synuclein, this disorder can be classified as a synucleinopathy. This is a group of neurodegenerative disorders, characterized by accumulation and malfunctioning of synuclein protein in brain cells. Many known diseases belong to this group, such as LBD, Parkinson's disease (PD) and Multiple System Atrophy (MSA).
Although many studies have been carried out and many hypothesis have been developed, currently the aetiology of LBD is still unknown; however, genetics, environmental factors, and changes linked to aging may have a role and still require further research and confirmation.
Pathophysiology and biomarkers associated to LBD.
An important clinical feature of LBD symptomatology is the acetylcholine deficiency, which is also present in Alzheimer's disease, although more pronounced in LBD. Decreased levels of this neurotransmitter (a chemical messenger that transmits signals between neurons or from neurons to other cells) in the temporal and parietal cortex result in visual hallucinations (a prominent feature of LBD), while up-regulation of muscarinic M1 receptor in the temporal lobe results in delusions. Additionally, another neurotransmitter whose levels are diminished in LBD is dopamine, which is connected with nigrostriatal dopaminergic neuron loss observed LBD patients. Post-mortem examinations (which in the past used to be the most common way to diagnose this disorder via immunohistochemistry) have revealed that LBD affects specific regions of the brain, such as the substantia nigra, dorsal raphe, locus ceruleus, and the dorsal motor nucleus of the vagus nerve.
Since no specific exam can diagnose this disease, the presence of an indicative biomarker in combination with a single core clinical feature of this pathology is sufficient for a diagnosis of probable DLB. For example, by SPECT or PET imaging, it is possible to detect nigrostriatal dopaminergic neuron loss by using a ligand binding to pre-synaptic dopamine transporters. Another indicative biomarker is represented by the polysomnography, which has the merit of allowing for the objective identification of RBDs (REM sleep behaviour disorders) by measuring EEG, eye movements and muscle movement during sleep, which are common in both LBD and PD. Also genetic history of the family helps in diagnosis, since it has been shown an increased risk of developing this disorder if other members of the family have been affected by this disease.
A new potential strategy: RT-QuIC for α-Synuclein
As previously mentioned in this article, several research lines have tried to develop novel systems and technologies to detect early stages of synucleinopathies. New potential diagnostic tools have been moved to the next phase of their development (which means the possibility of these to be included in common guidelines for diagnose these disorders), thanks to their specificity and accuracy. These parameters were studied and positively observed (above 95% accuracy and/or specificity) when samples from patients, which were blindly diagnosed with LBD, resulted positive to some of these test.
One of the most promising test for these disorders is the RT-QuIC (Real Time-Quaking Induced Conversion). This consists of a highly sensitive and specific test. which was originally developed and used to detect the presence of misfolded prion proteins, specifically in the context of prion diseases like Creutzfeldt-Jakob disease (CJD). In the case of CJD, this assay requires using a sample (which in most of the cases is cerebrospinal fluid, but sometimes other tissues have been tested as well) containing potentially misfolded prion protein (PrPSc) and mixes it with a solution of normal, recombinant prion protein (rPrP). The PrPSc acts as a "seed," inducing the conversion and aggregation of the rPrP into a similar misfolded form. This process is monitored by a fluorescence plate reader in real-time by using a fluorescent dye that binds to the newly formed aggregates of misfolded PrP, which, in case of fluorescence signal increase, represents an ongoing aggregation process. This principles together with the assay and the potential result expected for positive patients are shown in Figure 1 below.
This system has been adapted also for LBD, where instead of the prion protein, the α-synuclein aggregates formation is measured. Indeed, in several clinical trials, this assay showed a sensitivity and a specificity equal, respectively, to 95% and 83% (study in which LBD versus controls were analyzed), and also 100% and 94% in a second study (LBD with symptoms vs no symptoms).
Conclusions
Therefore, considering what has been previously described relatively to pathology and diagnosis of LBD, it can be considered an important success the development of an assay such as the RT-QuIC for synucleinopathies. Indeed, α-syn RT-QuIC of CSF samples is highly sensitive (ability to correctly identify individuals who have the disease) and specific (ability to correctly identify individuals who do not have the disease) for identifying cases with clinicopathologically-defined Lewy body disorders. However this technique shows a lower sensitivity for non-standard cased of LBD patients or in presence of asymptomatic LBD patients, where the early-phase diagnosis can still represent an important goal to achieve to improve their life expectancy and quality.
References
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