Latest concept of Lewy body disease



We 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 brainstem 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, including Parkinson's disease, Parkinson's disease with dementia and dementia with Lewy bodies. LBD has neuropathological characteristics whereby numerous Lewy bodies are present in the central and sympathetic nervous systems, and it is a type of alpha-synucleinopathy because the main component of Lewy body is alpha-synuclein. In this paper we explain the most recent concept of LBD from the historical viewpoint.

We proposed the term Lewy body disease (LBD) in 1980.[1] LBD is now understood to be the generic term, including Parkinson's disease (PD), Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB).[2, 3] Many dementia specialists, however, misunderstand the relation between LBD and DLB. Therefore, we explain the concept of LBD from the historical points of view.

From the Discovery of Lewy Bodies to the Proposal of LBD

Fritz Heinrich Lewy,[4] who had studied neuropathology under the leadership of Alois Alzheimer at Munich University, reported eosinophilic intracytoplasmic inclusions in the dorsal vagal nuclei and substantia innominata of PD brains in 1912. These inclusions were dubbed ‘Lewy bodies’ by Tretiakoff[5] in 1919. From the 1920s to the 1950s the differences between PD and postencephalitic parkinsonism were topical not only clinically but also neuropathologically. Greenfield and Bosanque,[6] for the first time, disclosed in 1953 that Lewy bodies were always found in the brainstem nuclei in PD, while neurofibrillary tangles were present in postencephalitic parkinsonism. Bethlem and Den Haltog Jager[7] (1960) reported the detailed distribution of Lewy bodies in both the central and autonomic nervous systems.

Thus, the neuropathological base of PD, which had first been found by James Parkinson in 1817, was established. Since then, it was widely believed that only rare Lewy bodies were found in the cerebral cortex; however, Okazaki et al.[8] reported two autopsied cases in 1961 in which numerous Lewy bodies were found in the cerebral cortex. In 1976 we reported an autopsied case with progressive dementia and parkinsonism, of which I was the chief doctor.[9] At that time, I clinically diagnosed the case as atypical presenile Alzheimer's disease with parkinsonism, and dissected the case myself. As a result, I found numerous intracytoplasmic eosinophilic inclusions in small neurons at the deeper cortical layers and typical Lewy bodies in the brainstem nuclei (Fig. 1), in addition to Alzheimer pathology. I also found similar pathological findings in another older patient with depression, persecutive delusions, mild dementia and mild parkinsonism. In 1978, I reported the features of cortical Lewy bodies in comparison with brainstem type of Lewy bodies in three autopsied cases.[10] In addition, I also found and reported two German autopsied cases[11] when I was at Max-Planck Institute for Psychiatry in Munich. These were the first autopsied cases with diffuse Lewy body disease (DLBD) in Europe. In 1980, we proposed the term ‘Lewy body disease’ based on our 20 autopsied cases.[1] Subsequently, we classified the disease into three types: type A (brainstem type), type B (transitional type) and type C (diffuse type). The brainstem type is consistent with PD, and the diffuse type was later called DLBD.[12] In 1996, we added a cerebral type of LBD, in which Lewy pathology was widely present in the cerebral cortex, but rare in the brainstem.[13] In this case, no Parkinson symptoms were detected in any of the clinical stages.

Figure 1.

(a) Typical brainstem type Lewy body and (b) cortica Lewy body.

From the Proposal of Lewy Body Disease to the Proposal of Diffuse Lewy Body Disease

LBD is now defined as follows: LBD is a chronic progressive neuropsychiatric disorder, which is clinically characterized by Parkinson symptoms of presenile or senile, or often younger onset, usually followed by dementia at the later stages. Case by case, progressive dementia or various kinds of psychiatric symptoms, including characteristic visual hallucination and delusions, are the chief symptoms, frequently followed by Parkinson symptoms. It is neuropathologically characterized by numerous Lewy bodies and neuritis (Lewy pathology), and neuronal cell loss in the central and autonomic nervous systems.

Yoshimura[14] reconfirmed our study of LBD when he was in Vienna, and proposed the term DLBD in 1983. Based on our 11 autopsied cases with the diffuse type of LBD, we also proposed the term ‘DLBD’ in 1984.[12]

DLBD was defined as follows: DLBD is characterized clinically by progressive dementia and Parkinson symptoms of presenile or senile, or sometimes younger onset, and neuropathologically by numerous Lewy bodies and neuronal cell loss in the central and autonomic nervous systems, frequently followed by various degrees of Alzheimer pathology.

From the Proposal of DLBD to the Proposal of DLB

Since we intensified in our paper of 1984 that DLBD had been overlooked in European and American countries, many autopsied cases with DLBD were also reported in those countries. Furthermore, in 1990 I indicated in my review of 36 autopsied DLBD cases reported in Japan that DLBD could be classified into two forms: a common form and a pure form, and that clinical features were different in the two forms.[15] In the common form, the onset was usually after 65 years of age (presenile or senile onset), and the chief symptom was cognitive impairment, followed by parkinsonism in 70% of the cases, while no parkinsonism was detected in 30% of the cases. On the other hand, in the pure form, the onset was usually much earlier and the initial symptoms were usually those of parkinsonism followed by dementia. Thereafter, when I was invited at the 150th Annual Meeting of the German Psychiatry Association, on the basis of a comparative study between Japanese and European–American autopsied cases with DLBD, I reported that no apparent differences of the clinical features in the common form were present between the two groups, but that in the pure form Japanese cases had much earlier onset and Parkinsonism preceded dementia, while most European–American cases were of presenile or senile onset and dementia preceded parkinsonism.[16] Perry et al.[17] proposed ‘senile dementia of Lewy body type’, and Hansen et al.[18] proposed the term ‘Lewy body variant of Alzheimer's disease’. In 1995 the first International Workshop on DLB was held in New Castle upon Tyne, England. Then, the title of my lecture was ‘Diffuse Lewy body disease within the spectrum of Lewy body disease’.[19] In this International Workshop, DLB was proposed.[20] The results of the Workshop were reported in Neurology in 1996.[21] Then, the clinical and pathological guidelines for DLB (CDLB guidelines)[21] were published, and the clinical diagnosis of DLB became possible. Thereafter, clinical studies were developed further.

From the Proposal of DLB to the Present

The Second International Workshop on DLB was held in Amsterdam in 1998, and the results of the workshop[22] were published in 1999. The Third Workshop was again held in Newcastle upon Tyne in 2003, and the CDLB Guidelines-Revised[2] were published in 2005. A symposium titled ‘A Cross-road at DLB and PDD’ was held in Washington DC in 2005, and the results[3] were published in 2007. In 2006, I held the fourth International Workshop on DLB and PDD in Yokohama, Japan. Since 2007, I have held the Japan DLB Research Meeting in Yokohama every November. In the Second Japan Annual Meeting, I organized the DLB Family Association in Japan. In 2012 we published ‘Front Line of DLB Research in Japan’.[23]

Over the last 18 years many important reports on DLB have been published. For example, DLB has been reported to be the second most frequent dementia following AD.[24] Some biological markers for the diagnosis of DLB have also been developed, such as brain single-photon emission computed tomography (SPECT)/positron emission tomography (PET), dopamine transporter imaging[25] (FP-CIT SPECT or DaT scan), and metaiodobenzylguanidine (MIBG) myocardial scintigraphy.[26] Alpha-synuclein gene mutations[27-29] were found in familial PD and DLB in 1997–2004. Alpha-synuclein was defined as the main component of Lewy bodies in 1997.[30] Alpha-synuclein is a 149-kDa protein encoded by the SNCA gene, rich in nuclei and presynaptic areas, but its function is not understood yet. In 2000, alpha-synuclein-positive inclusions were produced in transgenic animals.[31, 32] Braak et al.[33] hypothesized that Lewy pathology initiates in the brainstem and propagates upward to the cerebral cortex. However, in the cerebral type of LBD,[13] in which numerous Lewy bodies were found in the cerebral cortex in spite of only a few in the brainstem nuclei, Lewy pathology was thought to occur in the cerebral cortex and to propagate downward to the brainstem. Lewy pathology might also start from Auerbach's plexus of the lower esophagus[34] or the olfactory bulb.[33, 35] Very recently, aggregation of alpha-synuclein might spread in a transcellular manner throughout the brain in a prion-like way.[36]

Some therapeutic trials of galantamine[37] and donepezil[38, 39] to DLB patients have been reported. Recently, PD, PDD and DLB have usually been called Lewy body disease[2, 3, 40] as we have used since 1980.[1, 12]

We expect that the mechanism of alfa-synuclein aggregation will be solved, and that the essential therapy to LBD will be developed in the near future.