In 1817, James Parkinson described the symptoms of the shaking palsy, a disease that was subsequently defined in greater detail, and named after Parkinson, by Jean-Martin Charcot. Parkinson expected that the publication of his monograph would lead to a rapid elucidation of the anatomical substrate of the shaking palsy; in the event, this process took almost a century. In 1912, Fritz Heinrich Lewy identified the protein aggregates that define Parkinson disease (PD) in some brain regions outside the substantia nigra. In 1919, Konstantin Nikolaevich Tretiakoff found similar aggregates in the substantia nigra and named them after Lewy. In the 1990s, α-synuclein was identified as the main constituent of the Lewy pathology, and its aggregation was shown to be central to PD, dementia with Lewy bodies, and multiple system atrophy. In 2003, a staging scheme for idiopathic PD was introduced, according to which α-synuclein pathology originates in the dorsal motor nucleus of the vagal nerve and progresses from there to other brain regions, including the substantia nigra. In this article, we review the relevance of Lewy's discovery 100 years ago for the current understanding of PD and related disorders.

Dementia with Lewy bodies (DLB) is the second most common type of degenerative dementia following Alzheimer's disease (AD). DLB is clinically and pathologically related to Parkinson's disease (PD) and PD dementia, and the three disorders can be viewed as existing on a spectrum of Lewy body disease. In recent years there has been a concerted effort to establish the phenotypes of AD and PD in the prodromal phase (before the respective syndromes of cognitive and motor impairment are expressed). Evidence for the prodromal presentation of DLB is also emerging. This paper briefly reviews what is known about the clinical presentation of prodromal DLB before discussing the pathology of Lewy body disease and how this relates to potential biomarkers of prodromal DLB. The presenting features of DLB can be broadly placed in three categories: cognitive impairment (particularly nonamnestic cognitive impairments), behavioural/psychiatric phenomena (for example, hallucinations, rapid eye movement sleep behaviour disorder (RBD)) and physical symptoms (for example, parkinsonism, decreased sense of smell, autonomic dysfunction). Some noncognitive symptoms such as constipation, RBD, hyposmia and postural dizziness can predate the onset of memory impairment by several years in DLB. Pathological studies of Lewy body disease have found that the earliest sites of involvement are the olfactory bulb, the dorsal motor nucleus of the vagal nerve, the peripheral autonomic nervous system, including the enteric nervous system, and the brainstem. Some of the most promising early markers for DLB include the presence of RBD, autonomic dysfunction or hyposmia, I-123-metaiodobenzylguanidine cardiac scintigraphy, measures of substantia nigra pathology and skin biopsy for a-synuclein in peripheral autonomic nerves. In the absence of disease-modifying therapies, the diagnosis of prodromal DLB is of limited use in the clinic. That said, knowledge of the prodromal development of DLB could help clinicians identify cases of DLB where the diagnosis is uncertain. Prodromal diagnosis is of great importance in research, where identifying Lewy body disease at an earlier stage may allow researchers to investigate the initial phases of dementia pathophysiology, develop treatments designed to interrupt the development of the dementia syndrome and accurately identify the patients most likely to benefit from these treatments.

Two patients with pathologically confirmed dementia with Lewy bodies (DLB) had electroencephalogram recordings reported to show periodic discharges suggestive or typical of Creutzfeldt-Jakob disease. These findings caused diagnostic confusion and necessitated appropriate precautions for prion disease at postmortem examination. Periodic sharp wave complexes have occasionally been reported in DLB and should not therefore dissuade one from the diagnosis when other clinical and neuropsychological features are consistent with validated diagnostic criteria.

To test for an association between the apolipoprotein E (APOE) ϵ4 allele and dementias with synucleinopathy.Genetic case-control association study.Academic research.Autopsied subjects were classified into 5 categories: dementia with high-level Alzheimer disease (AD) neuropathologic changes (NCs) but without Lewy body disease (LBD) NCs (AD group; n=244), dementia with LBDNCs and high-level ADNCs (LBD-AD group; n=224), dementia with LBDNCs and no or low levels of ADNCs (pure DLB [pDLB] group; n=91), Parkinson disease dementia (PDD) with no or low levels of ADNCs (n=81), and control group (n=269). MAIN OUTCOME MEASURE The APOE allele frequencies. RESULTS The APOE ϵ4 allele frequency was significantly higher in the AD (38.1%), LBD-AD (40.6%), pDLB (31.9%), and PDD (19.1%) groups compared with the control group (7.2%; overall χ(2)(4)=185.25; P=5.56 × 10(-39)), and it was higher in the pDLB group than the PDD group (P=.01). In an age-adjusted and sex-adjusted dominant model, ϵ4 was strongly associated with AD (odds ratio, 9.9; 95% CI, 6.4-15.3), LBD-AD (odds ratio, 12.6; 95% CI, 8.1-19.8), pDLB (odds ratio, 6.1; 95% CI, 3.5-10.5), and PDD (odds ratio, 3.1; 95% CI, 1.7-5.6). CONCLUSIONS The APOE ϵ4 allele is a strong risk factor across the LBD spectrum and occurs at an increased frequency in pDLB relative to PDD. This suggests that ϵ4 increases the likelihood of presenting with dementia in the context of a pure synucleinopathy. The elevated ϵ4 frequency in the pDLB and PDD groups, in which the overall brain neuritic plaque burden was low, indicates that apoE might contribute to neurodegeneration through mechanisms unrelated to amyloid processing.

One of the major challenges in diagnosing dementia with Lewy bodies (DLB) is the common co-morbid presence of amyloid pathology. To understand the putative role of altered amyloid-β (Aβ) metabolism in dementia with DLB, we analyzed levels of different cerebrospinal fluid (CSF) Aβ peptides (Aβ38, Aβ40, Aβ42) in DLB, Alzheimer's disease (AD), and cognitively normal controls.CSF from patients with DLB (n = 72; age 68 ± 6 years; 10%F; Mini-mental State examination (MMSE) 23 ± 4), AD (n = 38; age 68 ± 6 years; 8%F; MMSE 22 ± 5), and cognitively normal controls (n = 38; age 67 ± 7 years; 13%F; MMSE 29 ± 2) was analyzed using the Meso Scale Discovery assay for human Aβ peptides. We performed general linear models to compare CSF Aβ peptide levels between groups. Associations between CSF Aβ peptides and MMSE score at baseline and longitudinal changes over time were assessed with linear mixed models.For all three CSF Aβ peptides and compared to controls (Aβ38 2676 ± 703 pg/ml, Aβ40 6243 ± 1500 pg/ml, and Aβ42 692 ± 205 pg/ml), we observed lower levels in DLB (Aβ38 2247 ± 638, Aβ40 5432 ± 1340, and Aβ42 441 ± 185, p < 0.05), whereas AD patients showed only lower Aβ42 levels (304 ± 71, p < 0.001). The observed differences in Aβ38 and Aβ40 were independent of co-morbid AD pathology (CSF tau/Aβ42 > 0.52) and APOE genotype. Finally, lower Aβ peptide levels were associated with lower MMSE score (β = 1.02-1.11, p < 0.05).We demonstrated different profiles of CSF Aβ reduction in DLB and AD. In particular, while AD is characterized by an isolated drop in Aβ42, DLB comes with reductions in Aβ38, Aβ40, and Aβ42. This suggests that amyloid metabolism is affected in DLB, even in the absence of co-morbid AD pathology.

Individuals with Lewy body dementia (LBD) typically exhibit impairments in attentional and executive function. Current pharmacological treatments have limited efficacy, with associated side effects. Transcranial direct current stimulation (tDCS) may represent an alternative treatment, as cognitive improvements have been demonstrated in healthy individuals. However, no studies to date have assessed the feasibility of tDCS in an LBD population. The aim of this preliminary study, therefore, was to assess the tolerability of tDCS, as well as its effects upon attentional and visuoperceptual performance, in LBD patients.Thirteen participants completed attentional (simple reaction time, choice reaction time, and digit vigilance) and forced-choice visuoperceptual (angle and motion perception) tasks before and after one 20-min session of active tDCS (0.08 mA/cm2). The anodal electrode was applied to the left dorsolateral prefrontal cortex and the cathodal electrode was applied to the right deltoid. Attentional (task accuracy and reaction time to correct answers) and visuoperceptual (task accuracy and difficulty) outcome measures were compared using paired t-tests.All participants tolerated stimulation and did not report any side effects during or immediately after stimulation. Post-stimulation improvements were observed in the choice reaction time (increased percentage of correct answers; p = 0.01) and digit vigilance (reduced mean reaction time to correct answers; p = 0.02) attention tasks. Visuoperceptual task performance did not improve (all p-values > 0.05).Attentional, but not visuoperceptual, improvements were observed following stimulation in LBD patients. Larger-scale, placebo-controlled trials are needed to confirm whether tDCS is a useful treatment option for attentional deficits in LBD.