Dementia with Lewy bodies and Parkinson's disease with dementia: are they different?

The relationship of dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD) is debated. In DLB, dementia antedates Parkinsonism; in PDD, Parkinsonism antedates dementia. Other than presenting features, diagnostic measures fail to distinguish DLB from PDD. There are few or no pathologic differences between DLB and PDD. In most cases cortical Lewy bodies (LBs) are widespread and there is coexistent Alzheimer type pathology, insufficient to diagnose Alzheimer's disease. Given the predominance of Parkinsonism in PDD, neuronal loss in the substantia nigra is more severe in PDD than DLB. Further clinicopathologic studies are needed to define other pathologic differences between DLB and PDD and to explore the role of neuritic, basal forebrain and striatal pathology in these clinical syndromes.     

Neuropathological investigation of the hypometabolic regions on positron emission tomography with [18F] fluorodeoxyglucose in patients with dementia with Lewy bodies

We performed a quantitative neuropathological examination of the hypometabolic regions on FDG PET in dementia with Lewy bodies (DLB), Alzheimer's disease (AD) and control cases. When the DLB cases were divided into two groups according to concomitant AD pathology (ADP), neuronal loss in the temporo-parietal association area was milder in the DLB groups than in the AD group, although there were no differences between the two DLB groups. Tau and Aβ immunoreactivities were observed in the AD group and the DLB group with ADP, but were rare in the DLB group without ADP. Tau and Aβ immunoreactivities as well as numbers of neurofibrillary tangles (NFTs) and neuritic plaques (NPs) were more common in the AD group than in the DLB group with ADP. There was no difference in neuronal loss in the occipital area among the three groups. α-Synuclein immunoreactivity was observed in the DLB groups but not in the AD group. There were no differences in α-synuclein immunoreactivity and number of Lewy bodies (LBs) between the two DLB groups. These findings indicate that the neuropathological bases of the hypometabolic regions in the temporo-parietal association and occipital area in DLB may be AD pathology and Lewy pathology, respectively.     

Depletion of cholinergic neurons in the nucleus of the medial septum and the vertical limb of the diagonal band in dementia with Lewy bodies

The cholinergic basal forebrain is divided into four subregions (Ch1–4), and cholinergic neuronal loss in the nucleus basalis of Meynert (Ch4) has been correlated with cognitive impairments in both Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). However, the Ch1–2 regions, which provide the major cholinergic innervation to the hippocampus, have not been investigated in DLB. The purpose of this study was to reveal the cholinergic neuronal changes in the medial septum (Ch1) and the nucleus of the vertical limb of the diagonal band (Ch2) of DLB brains. Using choline acetyltransferase (ChAT) immunohistochemistry, we showed that the number of ChAT-immunoreactive neurons in DLB brains was significantly lower than the numbers in AD and non-demented (control) brains. No significant difference in the number of ChAT-immunoreactive neurons was found between the AD and control brains. Moreover, the size of the ChAT-immunoreactive neurons was significantly smaller in the AD and DLB brains than in the control brains. These results show that cholinergic neurons of the Ch1-2 regions are more severely affected in DLB than in AD. Our DLB cases did not fulfill the neuropathologic criteria for definite AD. Furthermore, some Lewy bodies were observed in the Ch1-2 regions. Thus, cholinergic neuronal loss in the Ch1-2 regions might be specific to the pathology of DLB. Taking the distribution of cholinergic fibers in the hippocampus into consideration, this study suggests a possibility that hippocampal cholinergic projection is involved in Lewy-related neurites in the CA2–3 regions, the origin of which remains unclear.     

Accumulation of phosphorylated alpha-synuclein in aging human brain

Alpha-synuclein in Lewy bodies (LBs) is phosphorylated at Ser129. We raised monoclonal and polyclonal antibodies to this phosphorylation site (psyn) and examined 157 serial autopsy brains from a geriatric hospital. Anti-psyn immunoreactivity was observed in 40 of these cases (25.5%). Immunohistochemistry revealed 4 novel types of pathology: diffuse neuronal cytoplasmic staining (pre-LB); neuropil thread-like structures (Lewy threads); dot-like structures similar to argyrophilic grains (Lewy dots); and axons in the white matter (Lewy axons). This novel pathology was abundantly present around LBs and also involved the limbic subcortical white matter, the cerebral cortical molecular layer, and the spongiform changes of the medial temporal lobe associated with cases of dementia with LBs (DLB). The phosphorylated alpha-synuclein was limited to the temporal lobe in cases of Parkinson disease, spread from the temporal lobe to the frontal lobe in cases of DLB transitional form and further spread to the parietal and occipital lobes in DLB neocortical form. Our findings suggest that LB-related pathology initially involves the neuronal perikarya, dendrites, and axons, causes impairment of axonal transport and synaptic transmission, and later leads to the formation of LBs, a hallmark of functional disturbance long before neuronal cell death.     

Nuclear factor kappa-B p50 and p65 subunits expression in dementia with Lewy bodies

Dementia with Lewy bodies (DLB) is the second most common cause of neurodegenerative dementia after Alzheimer's disease (AD). Parkinsonism in DLB is mainly caused by neuronal loss with Lewy bodies (LBs) in the substantia nigra, thereby inducing degeneration of the nigrostriatal dopaminergic pathway similar to that in Parkinson's disease (PD). To clarify the pathogenesis of DLB, it is important to investigate the mechanisms involved in the degenerative process of LB-bearing neurones. Several reports suggest a role for nuclear factor kappa-B (NFkappaB) in the manifestation of neurodegenerative conditions such as AD and PD. The aim of the present study was to investigate whether NFkappaB subunits are involved in the pathogenesis of neurodegeneration in DLB by measuring tyrosine hydroxylase (TH), NFkappaB p65 and p50 protein expression in frontal cortex and substantia nigra pars compacta of DLB and control human brains. An increase, although not statistically significant, in nigral TH expression in DLB cases was observed. There were no differences in the cortical and nigral expression levels of NFkappaB p65 subunit between control and DLB cases. Western blots of the frontal cortex showed no differences in the expression levels of NFkappaB p50 subunit. However, NFkappaB p50 levels were significantly decreased (P < 0.05) in the pars compacta of the substantia nigra in the DLB cases in comparison with controls. The decrease in the expression of the p50 subunit in the substantia nigra of DLB cases achieved in the present study may increase the vulnerability of the dopaminergic neurones to a possible neurotoxic effect of p65 subunit. Thus, normal levels of NFkappaB p65 might be toxic in neurones with a low expression of the NFkappaB p50 subunit.     

Neuritic pathology as a correlate of synaptic loss in dementia with lewy bodies

Synaptic loss is present in Alzheimer's disease and correlates with the severity of dementia. Loss of synapses in dementia with Lewy bodies (DLB) does not correlate as clearly with cognitive status and its cause is unclear. To begin to understand the relationship between cognition and synaptic loss in DLB, we assessed immunoreactivity for the synaptic-terminal specific protein, synaptophysin, in the hippocampus in 14 DLB cases. Quantitative synaptic data were obtained using an Image-Pro semiautomated analysis system. We determined Braak stage, beta-amyloid, Lewy bodies (LBs), and Lewy neurites (LN). We found significant correlations (r = 0.617, P < .01) between Braak stage and synaptophysin score and marginal correlation between LN score and synaptophysin loss ( r = 0.694, P < .06). Correlations of beta-amyloid and of LB density with synaptophysin score were unimpressive. These data support the hypothesis that synaptic loss in DLB is related to neuritic degeneration.     

Striatal β-amyloid in dementia with Lewy bodies but not Parkinson’s disease

Professor Jellinger first identified that striatal Aβ deposition at postmortem seemed to differentiate cases of dementia with Lewy bodies (DLB) from those with Parkinson’s disease dementia (PDD), a finding subsequently questioned. Our replication study in 34 prospectively studied cases assessed the ability of striatal Aβ deposition to differentiate DLB from PDD, and also assessed the relationship between striatal and cortical Aβ deposition and α-synuclein-immunoreactive pathologies, using previously published protocols. Cases with DLB had significantly shorter durations and greater dementia severities compared with cases with PDD. Striatal Aβ-immunoreactive plaques were only consistently found in cases with DLB and correlated with both the severity (positive correlation) and duration (negative correlation) of dementia. Striatal Aβ-immunoreactive plaques also positively correlated with the severity of α-synuclein-immunoreactive pathologies as well as cortical Aβ-positive plaques. Striatal Aβ deposition positively predicted dementia in Lewy body cases with high specificity and had the greatest sensitivity to differentiate DLB from PDD with 100% negative predictive value. These data suggest that striatal Aβ deposition in Lewy body diseases contributes to early dementia and in these cases may impact on the efficacy of treatments targeting the striatum.     

Parkinson's disease, dementia with Lewy bodies, multiple system atrophy and alpha-synuclein]

Lewy bodies (LBs) are hallmark lesions of degenerating neurons in the brains of patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). DLB is the second most common neurodegenerative dementia after Alzheimer's disease, which is characterized clinically by fluctuating cognitive impairments, visual hallucinations and parkinsonism, and pathologically by the appearance of cortical LBs. To characterize the components of LBs, we have developed a purification procedure for LBs from cortices of patients with DLB using sucrose density separation followed by fluorescence-activated particle sorting. We then raised monoclonal antibodies (mAbs) to purified LBs, and obtained a mAb (LB509) that intensely immunolabeled LBs and specifically reacted with a approximately 18kDa brain protein, which was identified as alpha-synuclein. LB509 as well as other antibodies to alpha-synuclein, but not to beta-synuclein, immunostained brainstem and cortical LBs in sporadic PD and DLB brains. Recently, a point mutation in alpha-synuclein gene was identified in some autosomal-deminantly inherited familial PD pedigrees. Moreover, glial cytoplasmic inclusions in the brains of patients with multiple system atrophy (MSA) were shown to be alpha-synuclein positive. Taken together, our data strongly implicate alpha-synuclein in the formation of LBs and the selective neuronal degeneration in PD, DLB and MSA.     

Biochemical staging of synucleinopathy and amyloid deposition in dementia with Lewy bodies

The primary feature of dementia with Lewy bodies (DLB) is the aggregation of alpha-synuclein into characteristic lesions: Lewy bodies (LBs) and Lewy neurites. However, in most of DLB cases, LBs are associated with neurofibrillary tangles and amyloid plaques (both Alzheimer disease [AD]-related lesions). We wanted to determine if this overlap of lesions is statistical, as a result of the late onset of both diseases, or results from a specific physiopathological synergy between synucleinopathy and either tauopathy or amyloid pathology. All patients with DLB from our prospective and multidisciplinary study were analyzed. These cases were compared with cases with pure AD and patients with Parkinson disease and controls. All cases were analyzed thoroughly at the neuropathologic and biochemical levels with a biochemical staging of aggregated alpha-synuclein, tau, and Abeta species. All sporadic cases of DLB were associated with abundant deposits of Abeta x-42 that were similar in quality and quantity to those of AD. Amyloid precursor protein (APP) dysfunction is a risk factor for AD as demonstrated by pathogenic mutations and Abeta accumulation. The constant and abundant Abeta x-42 deposition in sporadic DLB suggests that synucleinopathy is also promoted by APP dysfunction. Therefore, we conclude that APP is a therapeutic target for both AD and DLB.     

Cognitive burden and excess Lewy-body pathology in the Lewy-body variant of Alzheimer disease.

OBJECTIVES: Authors compared the degrees of cognitive deficit among individuals with Alzheimer disease (AD), the Lewy-body variant of AD (LBV), and "pure" dementia with Lewy bodies (DLB); and compared cortical Lewy body (LB) counts in LBV versus DLB and neuritic plaque and neurofibrillary tangle severity in LBV versus AD. METHODS: Authors examined brain specimens from consecutive autopsies of elderly nursing home subjects. Numbers and densities of plaques, Lewy bodies, and tangle severity were determined in multiple cortical regions, and demographic and clinical variables were compared among the three groups. RESULTS: The three groups did not differ in demographic or clinical variables. The LBV group was significantly more impaired than the other groups. Cortical LB counts were significantly higher in LBV than in DLB. There was no evidence of increased plaque or tangle severity in LBV than in AD. CONCLUSION: The co-occurrence of AD and LB pathology is associated with higher numbers of LBs and more severe dementia than when classical AD or LB lesions occur alone.     

Neurofilament-immunoreactive neurons in Alzheimer's disease and dementia with Lewy bodies

The cortical neurons thought to be selectively affected in dementia with Lewy bodies (DLB) are those containing nonphosphorylated 200-kDa neurofilament (NF) protein. As these neurons are largely spared in Alzheimer's disease (AD), DLB and AD may impact on different cortical neuronal populations. The present study quantifies the NF-containing neurons in frontal and temporal cortex of 8 AD, 8 DLB, and 8 control cases. Formalin-fixed paraffin-embedded tissue was immunohistochemically stained with antibodies against nonphosphorylated and phosphorylated NF. Immunoreactive neurons were quantified by areal fraction analysis and corrected for cortical volume. As expected, nonphosphorylated and phosphorylated NF accumulated in the pathological hallmarks of AD and DLB. However, rather than a decrease in NF-containing neurons, a doubling of this population was observed in DLB, compared with AD and controls. This increased number of cortical NF-containing neurons reveal novel widespread cortical changes, beyond those explained by Lewy body formation, that are specific for DLB.     

Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases

Here, we investigated if TAR-DNA-binding protein-43 (TDP-43), the disease protein in frontotemporal lobar degeneration and ubiquitin inclusions with or without motor neuron disease as well as amyotrophic lateral sclerosis, also formed inclusions in Lewy body (LB) disorders including Parkinson’s disease (PD) without or with dementia (PDD), and dementia with LBs (DLB) alone or in association with Alzheimer’s disease (AD). Immunohistochemical analyses of TDP-43 in clinically well characterized and pathologically confirmed cases of DLB + AD, PD and PDD demonstrated TDP-43 pathology in the following percentage of cases: DLB + AD = 25/80 (31.3%); PD = 5/69 (7.2%); PDD = 4/21 (19%), while DLB and normal controls exhibited no (0/10, 0%) and one cases (1/33, 3%) presenting TDP-43 pathology, respectively. Significant differences in the prevalence of TDP-43 lesions were noted between disease versus normal brains (P < 0.001) as well as demented versus non-demented brains (P < 0.001). Statistical analyses revealed a positive relationship between TDP-43 lesions and several clinical and pathological parameters in these disorders suggesting the TDP-43 pathology may have co-morbid effects in LB diseases. This study expands the concept of TDP-43 proteinopathies by implicating TDP-43 lesions in mechanisms of neurodegeneration in LB disorders. Hanae Nakashima-Yasuda and Kunihiro Uryu are equally contributed first authors.     

The Lewy body variant of Alzheimer's disease: a clinical and pathologic entity

Thirty-six clinically diagnosed and pathologically confirmed Alzheimer's disease (AD) patients included 13 with cortical and subcortical Lewy bodies (LBs). The patients with LBs appeared to constitute a distinct neuropathologic and clinical subset of AD, the Lewy body variant (LBV). The LBV group showed gross pallor of the substantia nigra, greater neuron loss in the locus ceruleus, substantia nigra, and substantia innominata, lower neocortical ChAT levels, and fewer midfrontal tangles than did the pure AD group, along with a high incidence of medial temporal lobe spongiform vacuolization. Analysis of neuropsychological tests from 9 LBV subjects and 9 AD patients matched for age and degree of dementia revealed greater deficits in attention, fluency, and visuospatial processing in the LBV group. Similar comparisons of neurologic examinations showed a significant increase in masked facies; in addition there was an increase in essential tremor, bradykinesia, mild neck rigidity, and slowing of rapid alternating movements in the LBV group. Extremity rigidity, flexed posture, resting tremor, or other classic parkinsonian features were not characteristic of the LBV patient. In some cases, it may be possible to diagnose LBV premortem on the basis of the clinical and neuropsychological features.     

Pathological entity of dementia with Lewy bodies and its differentiation from Alzheimer’s disease

We reclassified the pathological subtypes of dementia with Lewy bodies (DLB), based on both Lewy pathology and Alzheimer pathology, to clarify the pathological entity of DLB and the boundary between DLB and Alzheimers disease (AD) in autopsied cases, using both pathological and immunohistochemical methods. DLB was classified as either limbic type or neocortical type according to the degree of Lewy pathology including Lewy bodies (LB) and LB-related neurites by our staging, and was classified as pure form, common form or AD form according to the degree of Alzheimer pathology including neurofibrillary tangles (NFT) and amyloid deposits by Braak staging. These combined subtypes were lined up on a spectrum, not only with Lewy pathology but also with other DLB-related pathologies including Alzheimer pathology, neuronal loss in the substantia nigra, spongiform change in the transentorhinal cortex and LB-related neurites in the CA2–3 region. In contrast, the Lewy pathology of AD did not meet the stages of Lewy pathology in DLB, and there were scarcely any similarities in other DLB-related pathologies between AD and DLB. In addition, the Lewy pathology of AD had characteristics different from that of DLB, including the coexistence rate of LB with NFT, and the immunohistochemical and immunoelectron microscopic findings of LB and LB-related neurites. These findings suggest that DLB is a distinctive pathological entity that can be differentiated from AD, although it shows some pathological subtypes.     

Lewy bodies and dementia

The discovery of widely distributed Lewy bodies (LBs) in the brains of patients with dementia has stimulated much clinical and pathologic inquiry. This clinico-pathologic syndrome is now referred to as dementia with Lewy bodies (DLB). Diagnostic criteria for DLB proposed at a workshop in 1995 are receiving detailed scrutiny. The criteria are complex to apply, and appear to have high specificity, but variable sensitivity. Neuropathologic studies have been aided by the development of probes against a-synuclein, a key component of LBs. Widespread LBs in limbic or cortical areas contribute to dementia. Pharmacologic management of cognitive and behavioral symptoms in patients with DLB is being explored. There is evidence that cholinesterase inhibitors may have beneficial effects.     

Active, phosphorylation-dependent mitogen-activated protein kinase (MAPK/ERK), stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and p38 kinase expression in Parkinson's disease and Dementia with Lewy bodies

Summary. The expression of mitogen-activated protein kinases, extracellular signal-regulated kinases (MAPK/ERK), stress-activated protein kinases, c-Jun N-terminal kinases (SAPK/JNK), and p38 kinases is examined in Parkinson disease (PD), in Dementia with Lewy bodies (DLB), covering common and pure forms, and in age-matched controls. The study is geared to gaining understanding about the involvement of these kinases in the pathogenesis of Lewy bodies (LBs) and associated tau deposits in Alzheimer changes in the common form of DLB. Active, phosphorylation dependent MAPK (MAPK-P) is found as granular cytoplasmic inclusions in a subset of cortical neurons bearing abnormal tau deposits in common forms of DLB. Phosphorylated p-38 (p-38-P) decorates neurons with neurofibrillary tangles and dystrophic neurites of senile plaques in common forms of DLB. Phosphorylated SAPK/JNK (SAPK/JNK-P) expression occurs in cortical neurons with neurofibrillary tangles in the common form of DLB. Lewy bodies (LBs) in the brain stem of PD and DLB are stained with anti-ERK-2 antibodies, but they are not recognized by MAPK-P, SAPK/JNK-P and p-38-P. Yet MAPK-P, p-38-P and SAPK/JNK-P immunoreactivity is found in cytoplasmic granules in the vicinity of LBs or in association with irregular-shaped or diffuse α-synuclein deposits in a small percentage of neurons, not containing phosphorylated tau, of the brain stem in PD and DLB. MAPK-P, p-38-P and SAPK-P are not expressed in cortical LBs or in cortical neurons with α-synuclein-only inclusions in DLB. MAPK-P, p-38-P and SAPK/JNK-P are not expressed in α-synuclein-positive neurites (Lewy neurites) in PD and DLB as revealed by double-labeling immunohistochemistry. These results show that MAPKs are differentially regulated in neurons with α-synuclein-related inclusions and in neurons with abnormal tau deposits in DLB. Moreover, different kinase expression in brain stem and cortical LBs suggest a pathogenesis of brain stem and cortical LBs in LB diseases. Finally, no relationship has been observed between MAPK-P, p-38-P and SAPK/JNK-P expression and increased nuclear DNA vulnerability, as revealed with the method of in situ end-labeling of nuclear DNA fragmentation, and active, cleaved caspase-3 expression in neurons and glial cells in the substantia nigra in PD and DLB. Received June 27, 2001; accepted July 26, 2001     

Immunohistochemical localization of spatacsin in α‐synucleinopathies

Spatacsin (SPG11) is a major mutated gene in autosomal recessive spastic paraplegia with thin corpus callosum (ARHSP‐TCC) and is responsible for juvenile Parkinsonism. To elucidate the role of spatacsin in the pathogenesis of α‐synucleinopathies, an immunohistochemical investigation was performed on the brain of patients with Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) using anti‐spatacsin antibody. In PD, Lewy bodies (LBs) in the brain stem were positive for spatacsin. These LBs showed intense staining in their peripheral portions and occasionally in the central cores. Lewy neurites were also spatacsin‐positive. In DLB, cortical LBs were immunolabeled by spatacsin. In MSA, glial cytoplasmic inclusions (GCI) and a small fraction of neuronal cytoplasmic inclusions (NCI) were positive for spatacsin. The widespread accumulation of spatacsin observed in pathologic α‐synuclein‐containing inclusions suggests that spatacsin may be involved in the pathogenesis of α‐synucleinopathies.     

Clinical and neuropathological correlates of Lewy body disease

We investigated distribution of neuronal and glial inclusions in 30 brains obtained at autopsy from patients with Lewy bodies (LBs) disease, which was clinically diagnosed as Parkinson's disease (PD), dementia with Lewy bodies (DLB), or pure autonomic failure (PAF). The cases were classified, according to the guidelines for the pathological diagnosis of DLB, into three types: the neocortical type, the limbic type, and the brain stem-predominant type. All postmortem brains had coil-like glial inclusions as well as LBs, and the distribution pattern and density of glial inclusions and LBs varied. The distribution of glial inclusions was strikingly similar to that of LBs. In the cerebral cortex in particular, the number of glial inclusions was fairly well correlated with the number of LBs, irrespective of the three pathological types. In the brain stem, distribution was similar between glial inclusions and LBs, and there was no distinct pathological difference among the three types. Glial inclusions and LBs were immunohistopathologically similar with respect to ubiquitin, alpha-synuclein, and Gallyas-Braak staining. The clinical features of the three types of LB disease were also similar; i.e., parkinsonism, some dementia, and/or autonomic failure. The inclusions in neurons and glial cells occurred in parallel with respect to tissue distribution and immunohistochemical features, suggesting that accumulation of neuronal and glial inclusions in the LB diseases have a common pathological feature. Our findings suggest that DLB, PD with and without dementia, and PAF share one clinicopathological entity.     

Prevalence and impact of vascular and Alzheimer pathologies in Lewy body disease

Whereas the prevalence and impact of vascular pathology in Alzheimer diease (AD) are well established, the role of vascular and Alzheimer pathologies in the progression of neurodegeneration and cognitive impairment in Parkinson disease (PD) is under discussion. A retrospective clinico-pathologic study of 100 patients with autopsy proven PD (including 44 cases with dementia/PDD) and 20 cases of dementia with Lewy bodies (DLB) confirmed essential clinical (duration of illness, Mini-Mental State Examination/MMSE, age at death) and morphologic differences between these groups; Lewy body Braak scores and Alzheimer pathologies (neuritic Braak stage, cortical Aβ plaque load, and generalized cerebral amyloid angiopathy or CAA) were significantly higher/more severe in DLB and PDD than in PD without dementia. Duration of illness showed no association to any of the examined pathologic parameters, while there was a moderate association between LB scores and neuritic Braak stages, the latter significantly increasing with age. Significant association between cerebrovascular lesions and neuritic Braak stage was seen in PDD but not in PD subjects without dementia. These data suggest an influence of Alzheimer-related lesions on the progression of the neurodegenerative process and, in particular, on cognitive decline in both PDD and DLB. On the other hand, both these factors in PD and DLB appear to be largely independent from coexistent vascular pathology, except in cases with severe cerebrovascular lesions or those related to neuritic AD pathology. Assessment of ApoE genotype in a small number of cases showed no significant differences in the severity of Aβ plaque load and CAA except for much lower intensities in non-demented ε3/3 patients. Despite increasing evidence suggesting synergistic reactions between α-synuclein (αSyn), tau and Aβ-peptides, the major protein markers of both AD and Lewy body diseases, and of both vascular pathology and AD, the molecular background and pathophysiological impact of these pathologies on the progression of neurodegeneration and development of cognitive decline in PD await further elucidation. Dedicated to the memory of Professor Dr. Franz Seitelberger, a pioneer of modern neuropathology and neurosciences.     

Cell type specific sequestration of choline acetyltransferase and tyrosine hydroxylase within Lewy bodies

Lewy bodies (LBs), the pathological hallmark of Lewy body disease (LBD), contain α-synuclein, as well as other proteins. In this study, we examined the relationship of α-synuclein to two rate-limiting enzymes in neurotransmitter synthesis, tyrosine hydroxylase (TH) and choline acetyltransferase (ChAT). Double-labeling immunohistochemistry for α-synuclein and TH revealed TH immunoreactivity within LBs in catecholaminergic neurons in the substantia nigra and locus coeruleus, but not within LBs in cholinergic neurons in the pedunculopontine nucleus and nucleus basalis of Meynert. In contrast, ChAT immunoreactivity within LBs was detected in cholinergic, but not within LBs in catecholaminergic neurons. The amygdala was devoid of TH and ChAT positive LBs, although a few Lewy neurites contained ChAT immunoreactivity. Further analysis revealed two distinct patterns of neurotransmitter immunoreactivity within LBs. One pattern had diffuse co-localization of TH or ChAT with α-synuclein as in cortical-type LBs, while the other had intense TH or ChAT immunoreactivity in the LB core surrounded by a peripheral rim of α-synuclein as in brainstem-type LBs. Levels of both TH and ChAT were higher in brainstem-type LBs than in the cytoplasm of the same neuron or in neurons from the same case devoid of LBs. Given the fact that LB-containing neurons have decreases in cytoplasmic TH and ChAT immunoreactivity, these results suggest LBs may disrupt cholinergic and catecholaminergic neurotransmitter production by sequestration of the rate-limiting enzymes for acetylcholine and catecholamine synthesis.