Introduction 

Lewy body dementia and Parkinson's disease share more than just their devastating effects on the brain. Both conditions are linked by the presence of abnormal protein deposits, known as Lewy bodies, leading to overlapping symptoms like cognitive decline, movement issues, and hallucinations.

Understanding lewy body dementia

Dementia is defined as an acquired disruption of multiple cognitive domains, severe enough to affect proper everyday function. Dementia is a pressing global health concern, with Alzheimer's disease garnering significant attention. However, Lewy body dementia (LBD), encompassing both dementia with Lewy bodies and Parkinson's disease dementia, is the second most common type of degenerative dementia.¹ 

What is lewy body dementia

Lewy body dementia (LBD) is a progressive neurodegenerative brain disorder with characteristic symptoms, including dementia, psychosis, and parkinsonism. It encompasses two clinical entities: dementia with Lewy bodies and Parkinson's disease dementia, and the relationship between them continues to be a debate which we will explain further later, especially when it comes to differential diagnosis. It is an under-diagnosed and poorly understood disease because of the overlapping symptomatology.² 

An age-associated disorder, it produces progressive cognitive decline limiting the normal life of individuals. 

It seems to be underdiagnosed, mainly because of the standardised assessment that shows a lack of focus on the core features of the disease. Furthermore, neuroimaging and other 

It usually affects people over 65 years old, and early signs include various cognitive disturbances, such as thinking, movements and sleep problems, mood swings and hallucinations. As the disease worsens, patients become severely disabled and might even experience death within eight years post-diagnosis, in individuals over 65. Despite their prevalence, LBD often remains underrecognised and misdiagnosed, leading to suboptimal care.³

Genetics do play a role in the disorder onset and it might be inherited, and studies have found that mutations of the alpha-synuclein gene might contribute to disease onset. Genetic research has identified several genes that play a role in Lewy body dementia. These genes, including the GBA gene, which is involved in cell function, are associated with an increased risk of developing the disease. Mutations in these genes can affect the way cells function, potentially contributing to the development of Lewy body dementia.⁴

Pathophysiology 

The neuropathology of LBD is characterised by the accumulation of α-synuclein in Lewy bodies and Lewy neurites, which are abnormal clumps that accumulate in the brain, containing disaggregated oligomers of cellular proteins. Even though it is unclear whether they have a neurotoxic or neuroprotective role and the degree of contribution to the LBD clinical picture because of the individual differences in pathophysiology (some individuals have severe α-synuclein aggregates but no clinical symptoms of LBD), hence understanding the pathophysiology is multifactorial and should also take into consideration other factors that contribute to neural loss. 

Despite cortical α-synuclein aggregations being the strongest candidate substrate for Parkinson’s disease, amyloid β seems to have a more prominent role in LBD, but the pathologic basis is not fully established.⁵ Many neuropathological studies reflect that many LBD patients have Alzheimer’s disease-related pathology,⁶ with over 70% of cases having Alzheimer’s disease-related pathology. Thus, patients with concomitant AD-related pathology have shown faster brain atrophy and cognitive decline, mainly located in the medial temporal lobe.⁷ Moreover, neuroimaging and cerebrospinal fluid analysis show that the presence of AD-related biomarkers is found in older patients with worse cognitive performance and shorter disease duration. 

Understanding parkinson’s disease 

What is parkinson’s disease 

A neurodegenerative disease characterised by motor and nonmotor disturbances, it has a significant impact on patients' everyday functioning. It is one of the most common neurodegenerative disorders. First described as a “shaking palsy” in 1817, it has progressive effects on mobility and muscle control. The main clinical characteristic is parkinsonism, which refers to various motor symptoms such as tremors, rigidity and bradykinesia.⁸ Parkinson’s disease (PD) is the most common cause, but we should be aware that secondary causes also contribute to the pathophysiology of PD. The foremost motor manifestations of PD are postural instability, cogwheel rigidity and resting tremor. Primarily known as a disease affecting the elderly, patients developing it in their 30s and 40s do exist.⁹ There are significant gender differences with a delayed onset present in females which is attributed to the presence of estrogen and its effects on the nigrostriatal dopaminergic system, which is neuroprotective.¹⁰

Oxidative stress, free radicals and environmental toxins along with genetic mutations are considered risk factors, despite biomedical research continuing.¹¹ Other risk factors include: 

• Head trauma
• High caloric intake
• Increased BMI (body mass index) 
• Inflammation associated with microglia activation 
• Mitochondrial dysfunction 
• Post-infection states 
• Signal-mediated apoptosis

It has been found that SNCA (alpha-synuclein gene) has a role in Lewy body dementia and is also associated with PD, along with the GBA gene (glucocerebrosidase gene).¹²

Pathophysiology 

The underlying pathological process has a slow progression and involves multiple neuronal systems. A disorder of the extrapyramidal system, the hallmark of PD is the loss of dopaminergic function. Neuroanatomically, midbrain dopaminergic neurons found in the substantia nigra pars compacta and ventral tegmental area are responsible for the regulation of extrapyramidal movements. Selective degeneration of dopaminergic neurons in substantia nigra pars compacta is the neuropathological hallmark in PD.¹³ Additional evidence indicates that Parkinson's disease (PD) may originate in the dorsal motor nuclei of the vagal and glossopharyngeal nerves, as well as in the anterior olfactory nucleus, hinting at a disease progression that begins in the brainstem and advances to higher cortical regions. Histopathologically, PD is characterised by the loss of pigmented dopaminergic neurons and the presence of Lewy bodies (LBs).

The progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc), which project to the striatum via the nigrostriatal pathway, leads to a decline in dopaminergic function in PD patients. Motor symptoms typically appear only after 50% to 80% of these neurons are lost, implying the presence of compensatory mechanisms during the early stages of the disease.¹⁴ Another key histopathological feature of Parkinson's disease (PD) is the presence of Lewy bodies (LBs), which are intracellular cytoplasmic aggregates made up of proteins, lipids, and other materials.¹⁵  

The connection between lewy body dementia and parkinson’s disease 

DLB and PDD are clinically and neuropathologically similar diseases, sharing the same hallmark as the deposition of alpha-synuclein. 

Shared pathology

While LBD and Parkinson's disease both involve Lewy body pathology, they have distinct clinical features. In LBD, Lewy bodies are found in various brain regions, including the limbic system and neocortex, leading to cognitive impairments such as memory loss, confusion, and difficulty with problem-solving. In contrast, Parkinson's disease typically begins with Lewy body formation in the brainstem, resulting in motor symptoms like tremors, rigidity, and slow movements. As the disease progresses, Lewy bodies may spread to other brain areas, leading to cognitive decline. Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) share a common underlying pathology marked by the accumulation of Lewy bodies, abnormal aggregates primarily composed of α-synuclein. These protein aggregates are found in the cytoplasm of neurons and are present in the brainstem, limbic system, and neocortical areas in both conditions. Pathologically, both DLB and PDD show widespread Lewy body distribution throughout the brain, affecting dopamine-producing neurons in the midbrain and cholinergic neurons in the basal forebrain, leading to cognitive decline and motor impairments. In addition to α-synuclein deposition, amyloid plaques and neurofibrillary tangles, commonly associated with Alzheimer’s disease (AD), can also be present in both PDD and DLB, further complicating the disease process​. 

Overlapping symptoms 

PDD and DLB manifest with a similar constellation of cognitive and motor symptoms. In both conditions, patients experience progressive cognitive decline, particularly in executive function, visual-spatial abilities, and attention. Memory impairment, although present, tends to be more related to retrieval difficulties than encoding problems, unlike Alzheimer’s disease. Neuropsychiatric symptoms, such as visual hallucinations, fluctuations in attention and alertness, and REM sleep behaviour disorder, are also hallmark features shared by both diseases. Motor symptoms resembling Parkinsonism, including bradykinesia, rigidity, and tremors, are seen in both PDD and DLB, although the timing of their onset relative to cognitive symptoms is a key differentiator between the two conditions​

Diagnosis 

The primary distinction between PDD and DLB lies in the timing of cognitive impairment relative to motor symptoms. In PDD, cognitive decline arises after a well-established history of motor symptoms, typically occurring after at least a year of Parkinsonism. In contrast, DLB is diagnosed when cognitive impairment occurs concurrently with or precedes the development of motor symptoms. The clinical diagnosis for both conditions can involve neuroimaging, such as SPECT or PET, to evaluate dopaminergic activity, and assessments for Lewy body-related features such as visual hallucinations, cognitive fluctuations, and REM sleep behaviour disorder. Despite these diagnostic criteria, differentiating PDD from DLB remains challenging due to their overlapping features, leading to the hypothesis that they may represent different clinical expressions of the same underlying synucleinopathy​. 

Summary

Lewy body dementia (LBD) is a progressive neurodegenerative disorder affecting individuals over 65, characterised by cognitive decline, psychosis, and parkinsonism. It includes dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), involving the accumulation of α-synuclein in Lewy bodies within the brain. Despite being the second most common type of dementia after Alzheimer’s, LBD remains underdiagnosed due to overlapping symptoms and insufficient focus on core diagnostic features. While early symptoms include cognitive disturbances, mood changes, and hallucinations, the disease progresses rapidly, often leading to severe disability and death within eight years post-diagnosis. Genetics, including mutations in the alpha-synuclein gene, contribute to its onset.