Dementia with Lewy bodies

The etiology of DLB is not known. Possible causative mechanisms include:[11]

Toxic protein aggregation
Abnormal phosphorylation
Other molecular mechanisms such as nitration, inflammation, oxidative stress, and lysosomal dysfunction.

Almost all DLB cases are sporadic. However, familial clusters have been reported. It is likely that genetic factors contribute to DLB pathogenesis. Most are autosomally dominantly inherited, although autosomal recessive inheritance has also been implicated.[12][13] Genes identified in families with DLB include the alpha-synuclein gene on chromosome 4, and the apolipoprotein E e4 allele.[12][14] Other genes implicated include SNCA and glucocerebrosidase.[15] There does not appear to be an association with the MAPT locus, unlike that found in Parkinson disease.[1]

DLB is a degenerative disease of the central nervous system characterized by an accumulation of Lewy bodies in vulnerable sites. Lewy bodies were first described in idiopathic Parkinson disease. The pathology of DLB mimics that of idiopathic Parkinson disease. Lewy body inclusions are composed of the protein alpha-synuclein, a cytoplasmic protein associated with synaptic vesicles.[11] The normal function of this protein includes roles in transportation of synaptic vesicles and synaptic plasticity. Other proteins in the Lewy bodies include neurofilament light and ubiquitin. The distribution and density of Lewy bodies are thought to be correlated with clinical symptoms, although the distribution of Alzheimer disease (AD) pathology in patients with DLB may have some bearing on phenotype.[16][17]

Coexisting AD pathology is common in patients with DLB, especially amyloid pathology. Neurofibrillary tangles tends to be less severe than in typical cases of AD.[11] If neurofibrillary pathology is severe, the clinical features are less likely to resemble DLB.[1] Other pathologic features include focal vacuolization in the temporal lobe and Lewy neurites.

At the biochemical level, a significant cholinergic deficit is present when compared with AD. A dopaminergic deficit is also common.

Pathologic classification at time of autopsy: Lewy body type pathology[1]

The neuropathologic classification is based on the distribution and density of Lewy bodies at the time of autopsy:

In nigral predominant disease, most Lewy bodies are in the brainstem pigmented nuclei (e.g., locus ceruleus, substantia nigra).
For limbic (transitional type) disease, Lewy bodies extend into the basal forebrain/limbic regions (e.g., transentorhinal, cingulate cortex).
In diffuse neocortical disease, Lewy body involvement diffusely extends into the neocortical areas (e.g., frontal and temporal cortices).

Clinical presentation may be complicated by mixed dementias. Concomitant AD pathology is common. This often results in an atypical clinical syndrome.[1] There is also a crossover with vascular dementias, with vascular pathology present in up to one third of DLB patients. This adds to the heterogeneity of presentation and the complexity of diagnosis and care.

Differentiation from Parkinson disease dementia (PDD) may be complicated and clinically depends on relationship of timing of dementia to motor symptom onset: DLB is diagnosed if dementia was present at symptom onset or within 1 year of parkinsonism onset; PDD is diagnosed if a patient had a diagnosis of PD for at least 1 year before the onset of dementia. This timing is useful in clinical practice, but it is arbitrary and based on expert opinion, so it may be modified in the future when more data become available.[1]

This pathologic assessment continues to be used in the fourth report of the DLB consortium, with only a few modifications which predict the likelihood that the pathologic findings will be associated with a typical DLB clinical syndrome (i.e., cases with high likelihood are expected to fulfill clinical criteria for probable DLB, whereas low-likelihood cases may have few or no DLB clinical features).[1]

Diagnostic and statistical manual of mental disorders, 5th ed., text revision (DSM-5-TR) classification of criteria for major and or mild vascular neurocognitive disorders[3][4]

DSM-5-TR defines major and mild neurocognitive disorders as being due to:

Alzheimer disease
Frontotemporal degeneration
Lewy body disease
Vascular disease
Traumatic brain injury
Substance/medication use
HIV infection
Prion disease
Parkinson disease
Huntington disease
Another medical condition
Multiple etiologies
Unknown etiology.

Severity is defined for major neurocognitive disorders as mild, moderate or severe; and the presence or absence of behavioral and psychological symptoms is also specified.

Specific criteria relating to Lewy body disease are given in Diagnostic criteria.

Pathophysiology

Classification

Pathologic classification at time of autopsy: Lewy body type pathology[1]

Diagnostic and statistical manual of mental disorders, 5th ed., text revision (DSM-5-TR) classification of criteria for major and or mild vascular neurocognitive disorders[3][4]