The Synucleinopathies: Twenty Years On.

In 2017, it is two hundred years since James Parkinson provided the first complete clinical description of the disease named after him, fifty years since the introduction of high-dose D,L-DOPA treatment and twenty years since α-synuclein aggregation came to the fore. In 1998, multiple system atrophy joined Parkinson's disease and dementia with Lewy bodies as the third major synucleinopathy. Here we review our work, which led to the identification of α-synuclein in Lewy bodies, Lewy neurites and Papp-Lantos bodies, as well as what has happened since. Some of the experiments described were carried out in collaboration with ML Schmidt, JQ Trojanowski and VMY Lee.

Lewy body disease and dementia with Lewy bodies.

In 1976 we reported our first autopsied case with diffuse Lewy body disease (DLBD), the term of which we proposed in 1984. We also proposed the term "Lewy body disease" (LBD) in 1980. Subsequently, we classified LBD into three types according to the distribution pattern of Lewy bodies: a brain stem type, a transitional type and a diffuse type. Later, we added the cerebral type. As we have proposed since 1980, LBD has recently been used as a generic term to include Parkinson's disease (PD), Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB), which was proposed in 1996 on the basis of our reports of DLBD.DLB is now known to be the second most frequent dementia following Alzheimer's disease (AD).In this paper we introduce our studies of DLBD and LBD.

100 years of Lewy pathology.

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.

Parkinson's disease with dementia, lewy-body disorders and alpha-synuclein: recent advances and a case report.

The advance in research on the dementia syndrome associated with Parkinson's disease recently gains momentum in part because Parkinson's disease inevitably causes declined cognition and then lead to poor quality of life. More importantly, dementia of Lewy bodies, now known as the second most common neurodegenerative disorder, shares the common neuropathological hallmark with Parkinson's disease and yet exhibits a unique clinical syndrome. Recent genetic, neurochemical and neuropsychological experiments robustly confirm a link between dementia associated with Parkinson's disease and dementia with Lewy bodies. Meanwhile, controversial issues regarding diagnostic criteria and proper treatments remain unresolved. Here I review milestone research conclusions and report a typical case with pathological data in order to clarify different aspects of these two dementia disorders.

Did Immanuel Kant have dementia with Lewy bodies and REM behavior disorder?

Immanuel Kant, one of the most brilliant minds of the XVIII century and of western philosophy, suffered from dementia in his late years. Based on the analysis of testimonies of his close friends, in this report we describe his neurological disorder which, after 8years of evolution, led to his death. His cognitive decline was strongly associated with a parasomnia compatible with a severe rapid eye movement (REM) behavior disorder (RBD) and dementia with Lewy bodies.

[Kosaka's disease].

The author proposed the terms "diffuse Lewy body disease(DLBD)" in 1984 and "Lewy body disease(LBD)" in 1980. Some Japanese researchers have called DLBD "Kosaka' s disease". On the other hand, "dementia with Lewy bodies (DLB)", which was proposed by the consortium of DLB in 1996, has been sometimes called "Kosaka's disease" by some researchers. Recently DLB, Parkinson disease (PD) and PD with dementia(PDD) are understood within the spectrum of LBD. In this paper the author reviews the concepts of DLBD, DLB and LBD, and discusses on the suggestion of the editorial board of "BRAIN and NERVE" that DLBD or DLB might be called "Kosaka's disease". According to the opinion of the author, DLBD, but not DLB, had better be called "Kosaka's disease", since the term DLB had been proposed based upon the concept of DLBD.

Common inflammatory mechanisms in Lewy body disease and Alzheimer disease.

Cortical Lewy body disease as a cause of dementia has been recognized for more than 40 years. Only in the past 15 to 20 years, however, has the true frequency of this entity come to be appreciated, primarily because of the advent of sensitive and specific immunohistochemical diagnostic techniques. We now know that there is frequent and extensive overlap, both clinically and pathologically, between Lewy body and Alzheimer diseases. Although some of this overlap may be attributable to common genetic and environmental risk factors, it is also now apparent that the 2 diseases share common neuroinflammatory mechanisms involving activation of microglia, overexpression of interleukin-1 and other inflammatory mediators, and inflammatory toxicity to neurons. Activated microglia are found in association with alpha-synuclein-containing neurons and glia in Parkinson disease, in dementia with Lewy bodies, and in multiple system atrophy, and these associations are reminiscent of microglial associations with neurofibrillary tangle-containing neurons in Alzheimer disease. In vitro and in vivo experimental work has shown reciprocal induction between alpha-synuclein and injured neurons on one hand and activated microglia and cytokine overexpression on the other. These neuroinflammatory processes may be a common link driving progression in both diseases and explaining the frequent overlap between the 2 diseases.

[Dementia with Lewy bodies].

"Dementia with Lewy bodies (DLB)" was proposed at the first international workshop in 1995. It has received much attention since we had proposed "Lewy body disease" in 1980 and "diffuse Lewy body disease" in 1984. In the CDLB guidelines, which were reported in 1996, the clinical and pathological diagnostic criteria for DLB were shown for the first time. At present, DLB as well as Alzheimer's disease (AD) and vascular dementia (VD) are known as the three major dementing illnesses. The second international workshop was held in 1998, and the third in 2003. One of the authors, K. Kosaka, presented a paper on DLB at each international workshop, based on series of our papers which we had reported since 1976. The revised CDLB guidelines will be reported soon. In addition, the fourth international workshop on DLB will be held by Kosaka in Yokohama in 2007. In this article, we review the history, the clinical, therapeutic, neuropathological, neurochemical and molecular biological issues, based on our previous papers and other important reports on DLB.

Dementia with Lewy bodies and the neurobehavioral decline of Mervyn Peake.

Mervyn Peake (1911-1968) was an accomplished British artist, poet, novelist, and playwright. He was a prolific and talented illustrator and wrote hundreds of poems, 4 novels, and several plays. His exceptional career was prematurely ended by a neurodegenerative illness variously ascribed to Alzheimer disease, Parkinson disease, or postencephalitic parkinsonism. However, a detailed review of biographical accounts produces substantial evidence in support of a probable diagnosis of dementia with Lewy bodies, a clinical entity remaining undiagnosed outside specialty dementia clinics. Peake developed signs of parkinsonism and insidious cognitive decline during his fifth decade. A breakdown in his writing style has frequently been cited as reflecting his encroaching dementia. Visual hallucinations are portrayed in sketches, and together with paranoid delusions are apparent in poetry composed during his illness. His deterioration was progressive and punctuated by well-described episodes of confusion and psychosis. His occasional preservation of insight is poignantly captured in drawings of figures with dunce caps or pointed heads, often with expressions of fear and apprehension etched with an economy of strokes. Peake spent his final years in various psychiatric institutions but continued to exhibit lucid intervals even late into his illness. His tragic deterioration remained undiagnosed at the time, but in retrospect, his progressive dementia with parkinsonism, visual hallucinations, and marked cognitive fluctuations likely represents one of the earliest recognized historical cases of dementia with Lewy bodies.