This neurocognitive disease is only tends to get publicity when a celebrity dies from it. Yet it is a common disease (and one of the most common forms of dementia), in France alone it affects about 250,000 people, which makes it the country’s second most widespread neurodegenerative disease, after Alzheimer’s, putting on a par with Parkinson’s. It is estimated that dementia with Lewy bodies (commonly known as “DLB”) affects more than 10 million patients worldwide.
What causes the disease? What symptoms should we look out for? How is it treated? Here is what you need to know.
A long-ignored illness
Dementia with Lewy bodies owes its name to inclusions that develop inside patients’ neurons called “Lewy bodies”, after the German-born doctor Friedrich Heinrich Lewy, who first discovered their existence in 1912.
However, it was only in 1976 that the first clinical case was formally described, while the first international clinical criteria were defined much later in 1996.
In its earliest stages (the prodromal stage before full-blown dementia develops, followed by the early, milder stage), dementia with Lewy bodies is characterised by the dysfunction of certain parts of the outer layers of the brain, such as the insula and the olfactory bulbs (OB). The insula is involved in cognition, emotions, self-awareness, pain, the autonomic nervous system, taste, while the olfactory bulbs are, as their name suggests, involved in olfaction (sense of smell).
These dysfunctions occur due to the accumulation of abnormal deposits of a protein called alpha-synuclein inside neurons. In its usual state, this protein adopts a more helical conformation (also known as the “alpha helix”; it is the way the protein organises itself in space). In its toxic form, its conformation changes, and alpha-synuclein folds instead into “a mille-feuille cake” (a layered conformation called “beta sheet”).
The accumulation of these misfolded alpha-synucleins results in the development of Lewy bodies inside neurons throughout the course of the disease.
However, alpha-synuclein is important for neuronal function. It is a key element in the transmission between neurons. This transmission element is called a synapse. Alpha-synuclein regulates the synaptic vesicles which are kinds of small “bulls” filled with chemical messengers called neurotransmitters, brain hormones secreted by neurons, such as acetylcholine, noradrenaline, serotonin or dopamine.
The accumulation of the toxic form of alpha-synuclein disrupts neuronal function, as neurons are less able to secrete synaptic vesicles that allow them to communicate with each other.
This phase (called “neurofunctional”, because it affects neurotransmitters) lasts at least fifteen to twenty years. Subsequently, Lewy body disease then enters a more aggressive stage: patients’ experience not only neuronal malfunction but also neuronal cell death.
It is worth pointing out that although Lewy bodies are also found in patients with Parkinson’s disease, they differ in appearance, where they are located in the brain and the alpha-synuclein conformation that develops with Lewy body disease.
What do we know about the causes of dementia with Lewy bodies and its risk factors?
Some work suggests that dementia with Lewy bodies may be linked to our environment.
Chronic contact with certain toxic substances, such as phthalates or air pollution (in the form of ultrafine particles), as well as some infections, could promote alpha-synuclein conformational changes during aging, and trigger dementia with Lewy bodies, particularly in the olfactory bulbs, which are the only parts of the brain in contact with the outside, at the nose level.
Known risk factors for the condition include anxiety and depression. Often, patients are found to have suffered from depression for a few years prior; for this reason, it is thought that this disease constitutes a mode of entry into dementia with Lewy bodies.
Other identified risk factors are high blood pressure, diabetes, “bad” cholesterol, stroke, family history of dementia with Lewy bodies or Parkinson’s disease, or mutations in certain genes (including the GBA or ApoE4 genes, which are however not the cause of the disease).
Numerous symptoms
In France, French weathercaster and writer Catherine Laborde spoke out extensively on her illness: she was very embarrassed by her difficulty in concentrating, as well as the fluctuations in her cognitive ability and overall vigilance. She was also prone to great fears for no apparent reason, which together paints a very common clinical picture of this disease.
Cognitive difficulties are the main symptom of the condition, resulting in lower concentration, slowness as well as organisational difficulties. In addition to cognitive impairment, there are various so-called “core features”:
- Cognitive and alertness fluctuations that associate moments of drowsiness, long naps, staring or difficulties at certain times to focus (the cognitive and expressive difficulties experienced by Joe Biden during the televised debate with Donald Trump, which were at the root of his withdrawal from the race for the US presidency, beg us to raise questions about cognitive fluctuations).
- Behavioural disorders during REM sleep: the so-called “REM” phase of sleep is the dream sleep phase (with rapid eye movement); normally, during this phase, the body is naturally paralysed. This is not the case for patients with Lewy’s disorder: some of them are restless sleepers, they clearly enact their dreams by moving, screaming, while sleeping with their eyes closed.
- Visual hallucinations, which affect 70 to 80% of patients. In the prodromal stage (the early stage of the disease), these hallucinations consist of simple sensations of someone going by or someone being present. Then, they become real hallucinations: patients see people, animals, or scenes arise before their eyes.
- Parkinsonism: this is most often manifested by a body part that becomes slower or stiff. Unlike Parkinson’s disease, dementia with Lewy bodies is rarely associated with hand tremors when resting.
These symptoms result from neuronal dysfunction, and the resulting lack of neurotransmitters: a lack of acetylcholine promotes cognitive impairment, a lack of serotonin and norepinephrine promotes depression, the lack of melatonin promotes sleep disorders while the lack of dopamine favours slowing down.
It should be known that it is rare that one person may experience all four core symptoms, even though it can happen: patients generally tend to experience one or two of them.
In addition to the core features, many other symptoms can be bothersome for patients affected by the disorder. Thus, it is common for patients to experience behavioural symptoms, such as anxiety, depression, apathy (demotivation) or even delusion. Patients also often have difficulties expressing emotions or recognising other people’s emotions.
Many patients also have autonomis (neurovegetative) symptoms, such as a runny nose (rhinorrhoea), dryness, urinary problems or low blood pressure when standing up. There are also neurosensory symptoms, such as difficulty detecting smells, or light discomfort.
During the advanced stages of the disease, patients lose the ability to perform everyday activities: getting dressed, eating, washing, using the phone, television or remote control… Patients aren’t able to walk as well or lose weight, because some have difficulty swallowing.
When should I see a medical doctor?
The symptoms of dementia with Lewy bodies are highly variable from one patient to another, which explains why, despite its commonness, this condition remains rarely diagnosed, and largely undiagnosed. It is readily confused with so-called “normal aging”, or with other diseases such as Alzheimer’s disease, Parkinson’s disease, or certain psychiatric illnesses such as depression or bipolar disorder.
Patients usually seek medical help due to cognitive disorders, such as mental slowness or difficulty concentrating. However, it is also advisable to see a medical doctor when depression develops after 60 years without an obvious reason, similarly if a patient experiences vision difficulties, even though the eye exam showed no abnormalities.
Other reasons for seeking a medical opinion: starting to sleep a lot during the day, or having such bad nightmares that you struggle in your sleep while in bed.
In general, diagnosis based on clinical symptoms is enough. However, additional tests can be performed where necessary, such as a brain scan (DAT-scan for highlighting a decline in dopamine activity, a marker of parkinsonism) or an MIBG cardiac, or sleep monitoring (which may show a loss of atony during the REM sleep phase – in other words, the loss of normal paralysis in the dream state).
More recently, it has become possible to detect alpha-synuclein (that constitute Lewy bodies) in cerebrospinal fluid (body fluid that circulates in the brain and around the spinal cord) via a sample obtained by lumbar puncture. The technique used, which is called RT-QuIC synuclein, makes it possible to detect Lewy bodies even before the onset of symptoms of the disease.
Thanks to the Swedish Biofinder study, we know that 8% of the population aged 70 years on average has Lewy bodies which are detected using this technique.
Research is now focused on the identification of an equivalent biomarker that would work via a simple blood test.
Where are we in terms of treatment?
No treatment or cure exists yet for fighting the alpha-synuclein deposits that accumulate in the brain or for the actual disease itself. That said, symptomatic treatment does improve the levels of neurotransmitters in the brain.
At present, it is thought that treating patients from the prodromal to mild stages (the earliest stages) is worthwhile for preventing neuron death. Indeed, fighting neuronal dysfunction can probably prevent some of these neurons from dying.
In this respect, it is important to treat depression and anxiety early on as they are both prodromal symptoms and risk factors for dementia with Lewy bodies.
We know that medical attention (sessions with a speech therapist, neuropsychologist, psychologist, occupational therapist, physiotherapist, psychomotor therapist) for cognitive or physical remediation is beneficial to patients.
The early association of these two approaches, both human and pharmacological, allows to optimise patients’ quality of life and that of their relatives by extension. In France, we are fortunate to have an association of dynamic patients and caregivers: the A2MCL. It also contributes to better support for patients and their relatives, thanks to the availability of a telephone hotline, the services of committed psychologists, the dissemination of advice and the sharing of experiences between caregivers. There are many other associations in the world, such as the LBDA in the U.S. and the Lewy Body Society in the United Kingdom.
Regarding the curative aspects, therapeutic trials are underway in France and worldwide to try to develop effective treatments.
A promising drug is Neflamapimod, which reduces inflammation in the brain and promotes acetylcholine-mediated neuronal connections. Our team is also evaluating the effectiveness of a neuromodulation protocol using light (transcranial photobiomodulation), with the Clinatec Foundation.
Finally, research for better understanding and treating dementia with Lewy bodies is dynamic but while it is qualitatively excellent, quantitatively it is inadequate. In recent years, there have been 30 times fewer therapeutic trials on dementia with Lewy bodies than on Alzheimer’s disease. Yet, if we collectively make progress in the fight against the condition, it will be to the great benefit of patients, their families and society as a whole.
Frédéric Blanc, Professeur de gériatrie et neurologue, chef du service de Gérontologie Mobile-Neuro-Psy-Recherche et du Centre Mémoire de Ressources et de Recherche (CMRR), chercheur au sein de l'équipe IMIS du laboratoire ICube, Université de Strasbourg, Université de Strasbourg
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