Dementia with Lewy bodies--from its finding to the present, including the CDLB guideline-revised]

The history of dementia with Lewy bodies (DLB) was introduced. In 1976 we reported our first autopsied case with "diffuse Lewy body disease (DLBD)", the term of which we proposed in 1984. In addition, we reported, for the first time, the detailed characteristics and distribution pattern of cortical Lewy bodies, based on our own three autopsied DLBD cases, in 1978. We also reported two German autopsied cases with DLBD in 1979, which were the first DLBD cases reported in Europe. In 1980 we proposed the term "Lewy body disease" and classified it into three types: a brain stem type, a transitional type and a diffuse type. The brain stem type is equal to Parkinson disease (PD), and the diffuse type was later designated as DLBD. Furthermore, we reviewed all DLBD cases reported in Japan and classified DLBD into two forms: a common form with more or less Alzheimer pathology and a pure form without it. Since then we have reported many papers concerning DLBD. Based on our reports the term "dementia with Lewy bodies" was proposed at the first international workshop in 1995. The CDLB guidelines were published in 1996, and the CDLB guidelines--revised were also reported in 2005. In the revised guidelines the term "Lewy body disease" was used as the generic term including DLB, PD and PDD as we had insisted since 1980.     

Pathological substrate of dementia in Parkinson's disease--its relation to DLB and DLBD

The pathological background of dementia in Parkinson's disease (PD) has been a matter of controversy. Recent studies have revealed the appearance of many Lewy bodies in the cerebral cortex of PD with dementia (PDD). This pathological change corresponds to the neocortical type, which was originally reported as diffuse Lewy body disease (DLBD), or a transitional type of dementia with Lewy bodies (DLB). Clinical differentiation between DLBD and the transitional type of Lewy body disease (LBD) is sometimes difficult because the symptoms overlap. Therefore, it is appropriate, at least at present, that DLB and PDD are used as clinical diagnoses and that DLBD and the transitional- and brainstem-types of LBD are used as neuropathological diagnoses.     

Diffuse Lewy body disease

Diffuse Lewy body disease (DLBD) has been studied from various viewpoints and, although clinical diagnostic criteria for DLBD have been proposed, diagnosis remains difficult. DLBD has been reported to be the second most common form of dementia in the aged, following Alzheimer‐type dementia. It has, however, been clinically under‐diagnosed. Therefore, the search for diagnostic markers for DLBD must continue. Very recently, ‘dementia with Lewy bodies’ (DLB) was proposed as a generic term for various forms of dementia with Lewy bodies, including DLBD and similar disorders. Cortical Lewy bodies are the most important pathologic marker for diagnosis of DLBD. At present, however, the mechanism responsible for cortical Lewy body formation has yet to be disclosed.     

Clinicopathological studies on diffuse Lewy body disease

With reports of dementia cases with numerous cortical Lewy bodies and our proposal that this be named ‘diffuse Lewy body disease’ (DLBD), this condition has received a great deal of attention, first in Japan and subsequently in Europe and North America. In the early 1990s, similar types of nomenclature were considered, and at the First International Workshop in 1995, it was proposed that ‘dementia with Lewy bodies’ be used as a generic term for Lewy body dementia, including the DLBD form. We review our previous clinicopathological findings and describe our recent immunohistochemical studies on DLBD.     

Prevalence and clinical associations of tau in Lewy body dementias: A systematic review and meta-analysis

IntroductionAlzheimer's disease neuropathologies (amyloid-β and tau) frequently co-exist to varying degrees in Lewy body dementias (LBD), which include dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD).ObjectivesTo investigate the prevalence of tau in DLB and PDD, and its associations with clinical outcomes.MethodsWe searched the major electronic databases using the search term: (“dementia with Lewy bodies” OR “diffuse Lewy body disease” OR “Lewy body variant of Alzheimer's disease”) AND (“tau protein” OR “tauopathy” OR “neurofibrillary tangle”), for relevant studies which evaluated tau in LBD. Forty-nine articles met the inclusion criteria for data extraction. Where appropriate, a random-effect meta-analysis was performed to obtain pooled estimates for prevalence and risk ratios (RR) or standardized mean differences (SMD) for clinical features, diagnostic accuracy and cognition.ResultsBraak neurofibrillary tangle stage ≥ III was observed in 66% (n = 1511, 95%CI 60%–73%) of DLB and 52% (n = 433, 95%CI 27%–76%) of PDD at autopsy. Abnormal CSF phosphorylated-tau levels were present in 28% (n = 925, 95%CI 25%–31%) of DLB and 15% (n = 172, 95%CI 5%–24%) of PDD cases. Higher tau burden in DLB was associated with reduced likelihood of manifesting visual hallucinations (RR 0.56; 95%CI 0.40–0.77) and motor parkinsonism (RR 0.62; 95%CI 0.40–0.98), lower diagnostic accuracy of DLB during life (RR 0.49; 95%CI 0.38–0.64) and worse cognition prior to death (SMD 0.63; 95%CI 0.46–0.81).ConclusionsTau is common in LBD and may reduce clinical diagnostic accuracy in people with DLB. Prospective longitudinal studies are needed to understand the roles of co-morbid neuropathologies in Lewy body dementias.     

Fulminant Lewy body disease.

The clinical distinction between Parkinson's disease (PD) with dementia (PDD) and dementia with Lewy bodies (DLB) is challenged by most neuropathological studies showing nearly identical changes in both conditions. We report an unusual case of PD evolving into a rapidly progressive dementia leading to death within 3 months that showed nearly all clinical features of DLB. At autopsy, numerous Lewy bodies and Lewy neurites were found in several areas of the brainstem, the limbic system, and the neocortex, consistent with pure DLB. This case demonstrates that Lewy body disease may exhibit a dramatic course without any coexisting pathology and exemplifies that PD, PDD, and DLB may sometimes represent sequential, yet overlapping, phenotypes of a same clinicopathological entity.     

Amyloid imaging of Lewy body‐associated disorders

Clinicopathologic studies of Parkinson disease dementia (PDD) and dementia with Lewy bodies (DLB) commonly reveal abnormal β‐amyloid deposition in addition to diffuse Lewy bodies (α‐synuclein aggregates), but the relationship among these neuropathologic features and the development of dementia in these disorders remains uncertain. The purpose of this study was to determine whether amyloid‐β deposition detected by PET imaging with Pittsburgh Compound B (PIB) distinguishes clinical subtypes of Lewy body‐associated disorders. Nine healthy controls, 8 PD with no cognitive impairment, 9 PD with mild cognitive impairment, 6 DLB, and 15 PDD patients underwent [¹¹C]‐PIB positron emission tomography imaging, clinical examination, and cognitive testing. The binding potential (BP) of PIB for predefined regions and the mean cortical BP (MCBP) were calculated for each participant. Annual longitudinal follow‐up and postmortem examinations were performed on a subset of participants. Regional PIB BPs and the proportion of individuals with abnormally elevated MCBP were not significantly different across participant groups. Elevated PIB binding was associated with worse global cognitive impairment in participants with Lewy body disorders but was not associated with any other clinical or neuropsychological features, including earlier onset or faster rate of progression of cognitive impairment. These results suggest that the presence of fibrillar amyloid‐β does not distinguish between clinical subtypes of Lewy body‐associated disorders, although larger numbers are needed to more definitively rule out this association. Amyloid‐β may modify the severity of global cognitive impairment in individuals with Lewy body‐associated dementia. © 2010 Movement Disorder Society     

Imaging amyloid in Parkinson's disease dementia and dementia with Lewy bodies with positron emission tomography

Although Parkinson's disease with later dementia (PDD) and dementia with Lewy bodies (DLB) are pathologically characterized by the presence of intraneuronal Lewy inclusion bodies, amyloid deposition is also associated to varying degrees with both these disorders. Fibrillar amyloid load can now be quantitated in vivo with positron emission tomography (PET) using imaging biomarkers. Here the reported findings of ¹¹C‐PIB PET studies concerning the amyloid load associated with PD and its influence on dementia are reviewed. It is concluded that the presence of amyloid acts to accelerate the dementia process in Lewy body disorders, though has little influence on its nature. Anti‐amyloid strategies could be a relevant approach for slowing dementia in a number of DLB and PDD cases. © 2009 Movement Disorder Society     

Clinical evaluation of Parkinson's disease dementia: association with aging and visual hallucination

OBJECTIVES: In order to explore factors associated with the development of dementia in Parkinson's disease (PD) and Dementia with Lewy bodies (DLB), we systematically investigated the clinical evaluation of PD and DLB patients hospitalized in the Department of Neurology at Tottori University Hospital, Japan. RESULTS: There were 208 patients diagnosed as having PD and 39 patients diagnosed with DLB in this study. Of the patients with PD, 67 (32%) developed dementia and only five PD+ patients were considered to have cognitive impairment attributable to Alzheimer's disease (AD) or vascular dementia (VaD). Fifty-four (81%) PDD patients had visual hallucinations (VH) with or without cognitive fluctuation. The onset age of parkinsonian motor symptoms of patients with PD dementia (PDD) did not differ from that of PD patients without dementia. There was a significant inverse correlation between the onset age of motor symptoms in PD and the onset of their dementia in PDD. Seventy-five (36%) patients with PD had experienced VH and most of the PDD patients had experienced VH within 1 year before or after diagnosis of PDD. CONCLUSIONS: These results indicate that aging and VH are important factors associated with dementia in PD.     

Cerebral amyloid angiopathy in Lewy body disease

Summary. While Alzheimer and Lewy body pathologies are discussed as major substrates of dementia in Parkinson’s disease (PD/Lewy body disease of brainstem type), the incidence and impact of cerebral amyloid angiopathy (CAA) and its association with cognitive decline in PD and dementia with Lewy bodies (DLB) are unknown. The severity of CAA and other Alzheimer lesions were assessed in 68 cases of autopsy-confirmed PD, 32 of them with dementia (PDD), and in 20 cases of DLB. PDD patients were significantly older than those without dementia (mean age 84.5 vs 77.6 years; p < 0.01), the age of DLB patients was in between both groups (mean 80.0 years), while duration of disease was DLB < PDD < PD (mean 6.5 vs 8.5 and 14.3 years). PDD patients had a significantly higher neuritic Braak stage (mean 4.2 vs 2.4, p < 0.01), significantly higher cortical amyloid β (Aβ) load, capillary cerebral amyloid angiopathy (CapCAA) and generalized CAA than those without dementia (mild CapCAA in 22% vs moderate to severe CapCAA in 87%; mild generalized CAA in 5.5% vs moderate to severe generalized CAA in 82%). Mean PD stage was higher in both DLB and PDD than in PD (mean 5.2 vs 4.5 and 4.0, respectively): Mean neuritic Braak stage in DLB was 3.4, severe Aβ plaque load was seen in 95%, moderate to severe CapCAA in 90% and mild to severe generalized CAA in 70%. This and other recent studies imply an association of CAA with cognitive decline in both PD/PDD and DLB, particularly in cases with concomitant AD-type pathology. Correspondence: Kurt A. Jellinger, Institute of Clinical Neurobiology, Kenyongasse 18, 1070 Vienna, Austria     

Parkinson's disease dementia – A diminished role for the Lewy body

The literature currently views Lewy bodies as central in the pathogenesis of Parkinson's disease dementia (PDD) when Alzheimer's disease (AD) or vascular pathology is not present. Because the neuropathology of PDD is not well understood, the pathological features of PDD were characterized in eighteen PD brain specimens using published criteria for AD, Diffuse Lewy Body Disease (DLBD), and Vascular Disease as a framework. Among the PD dementia (n = 16) subjects, 3 (19%) did not have LBs outside of the brain stem, nor AD or vascular pathology. In two additional cases, one did have rare LBs in the neocortex and cingulate gyrus. However, these two cases did not meet the diagnostic criteria for DLBD. Beyond these 5 cases, the remaining PD dementia subjects fitted a classical pathological profile consistent with AD (38%), vascular disease (12.5%), DLBD (6%), or a combination of these pathologies (12.5%). The findings from this study do not support the hypothesis that LBs are the main substrate for dementia in PD. More research with a larger sample size is needed to determine whether the LB may be a secondary phenomenon and/or an “innocent-bystander”. The entire role of the LB in PD dementia is again brought into question.     

β‐amyloid in lewy body disease is related to Alzheimer's disease‐like atrophy

The aim of this study was to investigate whether amyloid deposition is associated with Alzheimer's disease (AD)‐like cortical atrophy in Lewy body (LB) disease (LBD). Participants included 15 LBD with dementia patients (8 with dementia with Lewy bodies [DLB] and 7 with Parkinson's disease [PD] with dementia [PDD]), 13 AD patients, and 17 healthy controls. Age, gender, and Mini–Mental State Examination scores were matched between patient groups. All subjects underwent PET scans with [¹¹C]Pittsburgh Compound B to measure brain amyloid deposition as well as three‐dimensional T1‐weighted MRI. Gray‐matter volumes (GMVs) were estimated by voxel‐based morphometry. Volumes‐of‐interest analyses were also performed. Forty percent of the 15 DLB/PDD patients were amyloid positive, whereas all AD patients and none of the healthy controls were amyloid positive. Amyloid‐positive DLB/PDD and AD patients showed very similar patterns of cortical atrophy in the parahippocampal area and lateral temporal and parietal cortices, with 95.2% of cortical atrophy distribution being overlapped. In contrast, amyloid‐negative DLB/PDD patients had no significant cortical atrophy. Compared to healthy controls, parahippocampal GMVs were reduced by 26% in both the amyloid‐positive DLB/PDD and AD groups and by 10% in the amyloid‐negative DLB/PDD group. The results suggest that amyloid deposition is associated with AD‐like atrophy in DLB/PDD patients. Early intervention against amyloid may prevent or delay AD‐like atrophy in DLB/PDD patients with amyloid deposition. © 2012 Movement Disorder Society     

A comparison of cerebral glucose metabolism in Parkinson's disease, Parkinson's disease dementia and dementia with Lewy bodies

Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) share many similar aspects, and making a clinical diagnosis of one disorder over the other relies heavily on an arbitrary criterion, so-called 1-year rule. This study was designed to search for any difference of metabolic patterns in these two disorders using F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) images.
We enrolled 16 patients with PD, 13 patients with PDD, and seven patients with DLB. FDG PET was performed, and images were reconstructed by iterative reconstruction using the computed tomography (CT) images, and were normalized to a standard template. Statistical comparison between groups were performed on a voxel-by-voxel basis using t -statistics (two-sample t -test).
Compared with the patients with PD, both PDD and DLB patients showed similar patterns of decreased metabolism in bilateral inferior and medial frontal lobes, and right parietal lobe ( P _uncorrected < 0.001). In a direct comparison, DLB patients had significant metabolic decrease ( p _uncorrected < 0.005) in the anterior cingulate compared with those with PDD. These findings support the concept that PDD and DLB have similar underlying neurobiological characteristics, and that they can be regarded as a spectrum of Lewy body disorders.     

Arguing against the proposed definition changes of PD

As members of the Lewy Body Dementia Association Scientific Advisory Council, we aim to address some of the issues raised in the article titled “Time to Redefine PD? Introductory Statement of the MDS Task Force on the Definition of Parkinson's Disease.” In particular, we suggest that the 1‐year rule distinguishing Parkinson's disease dementia from dementia with Lewy bodies is worth maintaining because it serves an important purpose in clinical practice and clinical and basic science research and when helping the lay community understand the complexity of these different clinical phenotypes. Furthermore, we believe that adding an additional diagnostic label, “PD (dementia with Lewy bodies subtype),” will confuse rather than clarify the distinction between dementia with Lewy bodies and PD or PD dementia, and will not improve management or expedite therapeutic development. We present arguments supporting our contentions. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.     

Diffuse lewy body disease in Japan

Summary Thirty-seven Japanese autopsy cases with diffuse Lewy body disease (DLBD) were reviewed from a clinicopathological viewpoint. Based on the neuropathological finding of whether or not many concomitant senile plaques (SPs) and/or neurofibrillary tangles (NFTs) are present, DLBD is divided into two forms: a common form and a pure form. In the common form not only numerous Lewy bodies but also many SPs and/or NFTs are found in the cerebral cortex, whereas in the pure form there are no or few senile changes. Of the 37 cases, 28 cases had the common form, and 9 had the pure form of DLBD. In the common form all cases had shown progressive cortical dementia in the presenile or senile period. About 60% of the cases began with memory disturbance, while 25% showed Parkinson's or Shy-Drager syndrome initially. Parkinson's syndrome, consisting mainly of muscular rigidity and akinesia, was usually marked in the later stage, although there were also 8 cases (28.6%) in which no parkinsonian symptoms were detected even in the terminal stage. On the other hand, almost all cases with the pure form of DLBD showed juvenile Parkinson's syndrome, followed by progressive cortical dementia, although there was one presenile case with mild dementia and Parkinson's syndrome. These Japanese cases are compared with cases reported in Western countries.     

BuChE‐K and APOE ϵ4 allele frequencies in Lewy body dementias,and influence of genotype and hyperhomocysteinemia on cognitive decline

Apolipoprotein E (APOE) ε4 and butyrylcholinesterase‐K (BuChE‐K) are associated with an increased risk for Alzheimer's disease. The primary objective was to evaluate frequencies of these alleles in dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). A secondary objective was to evaluate influences on rate of cognitive decline. This analysis used data from participants consenting to pharmacogenetic testing in placebo‐controlled rivastigmine studies. Allele frequencies in DLB and PDD were compared using logistic regression. Within the PDD placebo sample, associations with cognitive decline were evaluated (the DLB sample was too small for these evaluations). Fifty‐seven DLB and 323 PDD subjects provided APOE and BuChE data. Allelic frequencies were higher in DLB, relative to PDD subjects, for BuChE‐K (P = 0.06), APOE ε4 (P < 0.001), or both alleles together (P < 0.001). More rapid cognitive decline was seen in PDD patients carrying both alleles, compared with other genotypes. Subjects with hyperhomocysteinemia were associated with more rapid decline in the presence of BuChE‐K, with or without APOE ε4. These results suggest that genetic and biochemical risk factors for AD and PDD pathology may be important in dementia onset and progression in these Lewy body disorders. © 2008 Movement Disorder Society     

Extrapyramidal features in Parkinson's disease with and without dementia and dementia with Lewy bodies: A cross-sectional comparative study.

Risk factors predicting an increased risk of dementia in Parkinson's disease (PD) are not fully established. The dementia associated with PD (PDD) closely resembles dementia with Lewy bodies (DLB). Based upon a high frequency of non-dopaminergic mediated clinical features in DLB, we predicted that a motor subtype comprising postural instability and balance problems would be more common in PDD. We examined extrapyramidal, cognitive, and affective features in 38 PD, 43 PDD, and 26 DLB patients in a cross-sectional study design. Motor subtype was subdivided into postural-instability gait difficulty (PIGD) or tremor (TD) dominant. The PIGD-subtype was more common in PDD (88% of cases) and DLB (69% of cases) groups compared with the PD group (38% of cases), in which TD and PIGD sub-types were more equally represented (P < 0.001). Although the mean depression scores overall were modest, PDD patients scored significantly higher than PD, but not DLB patients (Cornell; P = 0.006, and Geriatric Depression scale, GDS-15; P = 0.001), while within the PD group, those patients with a PIGD subtype had greater depression scores than the TD subtype (GDS-15; P < 0.05). We conclude that non-dopaminergic motor features are frequent in PDD. Neurodegeneration within the cholinergic system is likely to mediate many of these motor problems, as well as playing a significant role in determining the neuropsychiatric symptomatology of both PDD and DLB.     

Plasma cytokine profile in synucleinophaties with dementia

Immune response may play a pivotal role in the pathogenesis of the common synucleinopathy as Parkinson’s disease (PD) and could be mediated with the accumulation of neurotoxic alpha-synuclein. There is limited evidence for immune response in another synucleinopathy as dementia with Lewy bodies (DLB). Recent data suggest that immune response may contribute to cognitive impairment. We aimed to estimate plasma cytokine profile in patients with synucleinopathies with dementia (PD dementia (PDD), DLB). Plasma cytokine levels (interferon-gamma (IFN-gamma), interleukin (IL)-4 (IL-4), IL-6, IL-10, tumor necrosis factor alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1)). were estimated in 16 patients with DLB, 19 patients with PDD, 28 patients with PD without dementia (PD) and 19 individuals without neurological disorders (controls) using Luminex array system. Cognitive status was assessed with the Mini–Mental State Examination (MMSE). TNF-alpha and IL-6 plasma levels were elevated in patients with synucleinopathies with dementia (DLB, PDD) compared to controls and IL-10 plasma level was increased in PDD compared to controls (p < 0.05). IFN-gamma levels were decreased in PD and PDD patients compared to controls (p < 0.001, p = 0.026, respectively) and in PD patients than in DLB patients (p = 0.032). Patients with PD, PDD, and DLB were characterized by increased plasma levels of MCP-1 compared to controls (p < 0.001). At the same time, no differences in TNF-alpha, IL-10, IL-6 plasma levels in PD patients compared to controls were found. Our study demonstrated more pronounced immune response in synucleinopathies associated with dementia compared to PD without demetia.     

Relationships between Lewy bodies and pale bodies in Parkinson's disease

Summary The prevalance of pale bodies and Lewy bodies was studied in the substantia nigra of 12 patients with typical Parkinson's disease (PD), in 5 patients with diffuse Lewy body disease (DLBD), and in a group of neurologically normal controls. Anti-ubiquitin antibodies labelled pale bodies and Lewy bodies in typical PD and DLBD, and there was a strong positive correlation between numbers of ubiquitin-immunoreactive pale bodies and Lewy bodies. BF10, a monoclonal antibody against a phosphate-dependent epitope of neurofilament 155-kDa polypeptide subunit, immunolabelled 57% of Lewy bodies and 15% of pale bodies in typical PD. Some pale bodies and Lewy bodies were seen in the substantia nigra of 2 of 5 neurologically normal, aged controls, probably representing incidental PD. We conclude that there is a close relationship between pale bodies and typical Lewy bodies in the substantia nigra in clinical varicties of PD, and that these inclusions share antigenic determinants. If pale bodies and Lewy bodies reflect separate aspects of the cellular pathology in PD, their formation probably occurs in parallel. Alternatively, these observations may suggest that pale bodies represent a stage in the formation of Lewy bodies.Supported by the Medical Research Council, the Wellcome Trust, and the Parkinson's Disease Society of Great Britain