Lewy Body Dementia (LBD) is a progressive degenerative brain disorder marked by features of dementia, psychosis, and traits of parkinsonism. Lewy bodies are named after Dr. Friedrich Heinrich Lewy (1885-1950), a German neurologist who discovered Lewy bodies in the brain of a deceased Parkinson’s patient. LBD is an umbrella term for 2 neurodegenerative disorders; Dementia with Lewy bodies (DLB) and Parkinson's Disease Dementia (PDD). Symptoms will often fluctuate after the onset of the disorder and many of its markers overlap with other neurodegenerative disorders; namely Dementia; therefore diagnosis of DLB requires meticulous clinical investigation.
DLB is the most common type of Dementia after Alziehmers, yet analogous to most synucleinopathies, the condition remains idiopathic. This, however, has not stopped scientists from associating the impact with speculated causes. The most agreed mutual consensus remains to be genetic mutations.
In this article I’ll be clarifying 5 questions regarding DLB:
1) What is it?
2) What are the Symptoms?
3) What is the Prognosis?
4) What are the Risk Factors?
5) What are the Speculated Causes?
Dementia with Lewy Bodies
DLB is a condition characterized by abnormal aggregation of protein clusters. Although the reason for the accumulation is idiopathic, its effects on the cells have been monitored and deduced. Protein inclusions, containing disaggregated oligomers of many cellular proteins, accumulate throughout the brain in the synaptic terminals and axonal processes. These are primarily alpha-synuclein (αSyn) clusters. αSyn plays a role in interneuronal communication and helps to regulate the release of neurotransmitters. This abnormal accumulation of protein impairs cell function and ultimately causes cell death, especially in the dopaminergic regions; however, the localization of Lewy bodies (LB) in DLB tends to be random and progressively affects the entire brain.
The aggregates draw in mitochondria from the periphery and cause a loss in peripheral microtubules, meaning a decrease in axonal trafficking as well as ATP production. Damage to the DNA, depleted ATP supplies and reduced neuronal trafficking lead to neuronal loss (Power et al., 2015). This accumulation also affects a basement membrane protein that maintains the integrity of dopaminergic neurons (Cabrero et al., 2022). Different conformers of the proteins also play a role in the toxicity of αSyn. The toxicity of the fibrils increases with the amount of αSyn that penetrates the neuronal cells and this causes calcium uptake, ROS formation, membrane permeabilization, caspase-3 activation and mitochondrial dysfunction (Cascella et al., 2022).
However, It is not yet fully understood whether this aggregation is the reason or consequence of the degeneration of brain cells.
Diagram illustrating how different gene mutations result in an accumulation of αSyn and the effect on the cell. Created with information from Power et al. (2016), Cascella et al. (2022), and MedlinePlus-Genetics. (2021)
Symptoms and Prognosis
If LB is found in both DLB and PDD, what differentiates the 2 diseases? DLB is a condition that will progressively deposit LB around the brain, whereas in PDD, LB is mainly found in specific regions such as the substantia nigra. The onset of symptoms of DLB involves cognitive impairment whereas motor disabilities develop later on. In PDD, however, motor impairment develops first followed by or alongside relatively mild cognitive impairments. If individuals with DLB were to take a series of MMSEs (A mini-mental state examination scaled to 30 in which scores ≥ 25 are considered normal), the scores would drastically fluctuate. This is because cognitive fluctuations are a characteristic symptom of DLB. It is also common for neurologists to use the clock drawing method first introduced by British neurologist/psychiatrist Sir Henry Head to test the diagnoses and severity of neurodegenerative disorders. In DLB, patients will have moderate motor control but will fail to remember what a clock looks like as well as have difficulty with numbers. (Severe motor incapability could also be observed). In simpler terms; DLB affects the brain before the body, and PDD affects the body before the brain (This is a fairly standard pattern but anomalies exist.)
DLB affects the transmission of essentially 2 neurotransmitters; Dopamine and Acetylcholine. Visual hallucinations are typical for DLB patients (When protein clusters accumulate in the primary visual cortex in the occipital lobe; Broadmans area 17 is affected in mild hallucinations whereas Broadmans area 18 is affected in severe hallucinations). Erratic changes in focus, attention, alertness, and wakefulness from day to day are also fairly expected. Patients' ideas may be disorganized, unclear, or illogical, often accompanied by severe loss of thinking abilities that interfere with daily activities. Other changes related to thinking may include poor judgment, confusion about time and place, severe delusions and difficulty with language and numbers. Motor impairment may also develop later on (NIH, n.d.).
Unfortunately, even after hospice and supervising symptoms, most patients lose their battle with DLB within 6-12 years of diagnosis (This isn't always the case). The cause of death can vary considerably, but aspiration pneumonia tends to be a typical one. Patients have trouble swallowing or dysphagia (Which can be a consequence of either cognitive impairment or motor impairment or both) and this can oftentimes result in food and drinks entering the respiratory tract. This will act like an injurious stimulus resulting in an infection of the lung; pneumonia. A study at Fukushimura Hospital in Japan found that 93% of patients with DLB died from pneumonia during hospitalization (Manabe et al., 2016).
Risk Factors
Before we proceed to discuss the speculated causes, it’s important to note that although we’re unsure of the causes, it doesn’t imply that we have not concluded factors that can aggravate the symptoms or accelerate the onset of DLB. Age plays a massive part in DLB's manifestation. Most people show signs of neurodegenerative disorders at around 40 years old. Still, they don’t get diagnosed till way later, when symptoms have manifested far too long for the results not to be progressively destructive. Fortunately, there are many suitable treatment options and hospices that can manage those symptoms and sustain the patients for longer. These include Donepezil, Rivastigmine and Galantamine; these are AchE inhibitors which boost acetylcholine transmission in the brain so cells can communicate better (Haider et al., 2022). It is also noted that individuals older than 60 and male are more susceptible to DLB (Mayo Clinic, 2021). Being immunosuppressed, smoking and putting one's health at risk, (Whether it’s something you bring upon yourself, or a pre-existing medical condition) can make your body more liable to the symptoms.
“Speculated” Causes
The most common speculated cause for DLB is genetic mutations, particularly mutations concerning the following 4 genes; SNCA, SNCB, GBA, and APOE (allele 4).
SNCA expresses αSyn. Mutations in the SNCA gene will result in malformed αSyn that will be more susceptible to abnormal aggregation. In DLB, parts of the brain such as the amygdala contain forms of carboxy-truncated αSyn (Sorrentino et al., 2019). These are more prone to aggregation due to the loss of the carboxyl group.
SNCB expresses a protein called β-Synuclein (βSyn). βSyn is involved in a process that allows neurons to change and adapt over time, which is necessary for learning and memory (Neural Plasticity). Beta-synuclein may also prevent the harmful accumulation of αSyn in neurons by inhibiting the secondary nucleation of αSyn aggregation via competitive binding to the fibril surfaces. (W.P. Brown. 2016).
The GBA gene is responsible for producing an enzyme called β-glucocerebrosidase, which is found in lysosomes. β-glucocerebrosidase recycles proteins and other materials that are no longer required by the body. A mutation in the GBA gene will result in the disruption of the standard process of the lysosomes; therefore lysosomes will fail to break down excess αSyn adequately, leading to an abnormal aggregation.
The APOE gene provides instructions for making a protein called apolipoprotein E. This protein's role is to package cholesterol/ other fats and transport them through the bloodstream. One version of this gene mutation; concerning the e4 allele (APOE4), seems to raise an individual's risk of developing DLB, however, the definite biochemistry behind this is unclear. It is thought a mutation on this version of the gene will disrupt the transportation of αSyn into and out of cells, leading to its aggregation. It's interesting to note that APOE4 is also the strongest risk factor gene for Alzheimer’s disease, although inheriting APOE4 does not necessarily ensure a person will develop the disease (NIH, 2021).
Demand for further investigation into the defining cause of DLB is needed now more than ever, and this is certainly not to negate the efforts of the pharma companies, scientists and doctors who made consequential progress in the past couple of decades. We are still on the search for more concrete pathophysiological explanations and the advancement of treatment methods is still placed high on the agenda. DLB symptoms overlap with those of other neurodegenerative disorders such as Parkinson's, making it arduous to diagnose. Cognition therapeutics and Garvan Institute of Medical Research are only 2 of the thousands of firms endeavoring on this journey to describe DLB in conclusive terms.
Further reading:
Garvan Institute of Medical Research: https://www.garvan.org.au/news-events/news/clinical-trial-will-test-drug-treatment-for-dementia
References:
Cabrero, F.R. and Morrison, E.H. 2021. Lewy Bodies. PubMed. [Online]. [Accessed 13 October 2022]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK536956/
Cascella, R., Bigi, A., Cremades, N. and Cecchi, C. 2022. Effects of oligomer toxicity, fibril toxicity and fibril spreading in synucleinopathies. Cellular and Molecular Life Sciences. 79(3)
MedlinePlus-Genetics 2021. Dementia with Lewy bodies: MedlinePlus Genetics. medlineplus.gov. [Online]. Available from: https://medlineplus.gov/genetics/condition/dementia-with-lewy-bodies/.
Manabe, T., Mizukami, K., Akatsu, H., Hashizume, Y., Teramoto, S., Nakamura, S., Kudo, K. and Hizawa, N. 2016. Prognostic Factors Related to Dementia with Lewy Bodies Complicated with Pneumonia: An Autopsy Study. Internal Medicine. 55(19), pp.2771–2776.
Haider, A., Spurling, B.C. and Sánchez-Manso, J.C. 2022. Lewy Body Dementia. PubMed. [Online]. [Accessed 13 October 2022]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482441/#article-24236.s2.
Mayo Clinic 2021. Lewy Body Dementia - Symptoms and Causes. Mayo Clinic. [Online]. [Accessed 13 October 2022]. Available from: https://www.mayoclinic.org/diseases-conditions/lewy-body-dementia/symptoms-c auses/syc-20352025.
Sorrentino, Z.A., Goodwin, M.S., Riffe, C.J., Dhillon, J.-K.S., Xia, Y., Gorion, K.-M., Vijayaraghavan, N., McFarland, K.N., Golbe, L.I., Yachnis, A.T. and Giasson, B.I. 2019. Unique α-synuclein pathology within the amygdala in Lewy body dementia: implications for disease initiation and progression. Acta Neuropathologica Communications. 7(1).
Brown JW, Buell AK, Michaels TC, Meisl G, Carozza J, Flagmeier P, Vendruscolo M, Knowles TP, Dobson CM, Galvagnion C. β-Synuclein suppresses both the initiation and amplification steps of α-synuclein aggregation via competitive binding to surfaces. Sci Rep. 2016 Nov 3;6:36010. doi: 10.1038/srep36010. PMID: 27808107; PMCID: PMC5093550.
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