Dementia with Lewy bodies showing advanced Lewy pathology but minimal Alzheimer pathology--Lewy pathology causes neuronal loss inducing progressive dementia

The present study concerns an autopsied case of dementia with Lewy bodies (DLB) showing advanced Lewy pathology but minimal Alzheimer pathology. The patient was a 50-year-old Japanese male without inheritance. His initial symptoms at the age of 43 suggested the diagnosis ofjuvenile idiopathic Parkinson's disease (PD), but were followed by memory disturbance 1 year later. He showed parkinsonism, dementia, personality change, fluctuating cognition and visual hallucinations 3 years later. Neuroradiological examination revealed moderate brain atrophy, predominantly in the frontal and temporal lobes. Neuropathological examination demonstrated a widespread occurrence of Lewy bodies (LB) with LB-related neurites not only in the brainstem but also in the cerebrum. The present case showed Lewy pathology which corresponded to stage IV by our staging and was parallel to neuronal loss. There was marked neuronal loss with many LB-related neurites in the CA2 of the hippocampus. Neurofibrillary tangles (NFT) were almost restricted to the entorhinal cortex, while senile plaques were absent. Consequently, the present case was pathologically diagnosed as having DLB of the neocortical type, pure form. In the present study, we suggest that Lewy pathology in the cerebral cortex could be responsible for progressive dementia.     

Developmental stages of cortical Lewy bodies and their relation to axonal transport blockage in brains of patients with dementia with Lewy bodies

We investigated 10 dementia with Lewy bodies (DLB) brains showing various degrees of Lewy pathology using alpha-synuclein-immunohistochemistry, and morphologically divided cortical Lewy bodies (LB) into six developmental stages. Further, we demonstrated the ultrastructure of each stage of cortical LB using alpha-synuclein-immunoelectron microscopy. In the initial stage, alpha-synuclein accumulated in part of the neuronal cytoplasm without filamentous components, then formed LB and LB-related neurites composed of granulo-filamentous components. Finally, LB degraded to extracellular LB composed of loose filamentous components with involved astroglial processes. In addition, we immunohistochemically investigated the accumulation of axonal transported substances in cortical LB, and showed that APP, chromogranin-A, synphilin-1 and synaptophysin accumulated in cortical LB from stages 1, 2, 3 and 4, respectively. These findings suggest that chronic axonal transport blockage is implicated in the development of cortical LB in DLB brains.     

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.     

Dementia with Lewy bodies: Reclassification of pathological subtypes and boundary with Parkinson's disease or Alzheimer's disease

The present study is an attempt to reclassify the pathological subtypes of DLB based on both Lewy pathology and Alzheimer pathology, and to clarify the pathological boundary between DLB and Parkinson's disease (PD) or Alzheimer's disease (AD) in autopsied cases, using pathological and immunohistochemical methods. Dementia with Lewy bodies was classified into the limbic type and neocortical type according to the degree of Lewy pathology, including Lewy bodies (LB) and LB‐related neurites, by our staging and was classified into the pure form, common form and AD form according to the degree of Alzheimer pathology including 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. There were some similarities in both Lewy pathology and other DLB‐related pathologies between PD and DLB, although Lewy pathology of PD was below the lowest stage of Lewy pathology. In contrast, AD did not meet the stages of Lewy pathology, and there were also no similarities in other DLB‐related pathologies between AD and DLB. In addition, LB of AD showed the characteristics different from those of DLB on the coexistence of LB with NFT. These present findings suggest that DLB has pathological continuity with PD, but can be pathologically differentiated from AD. The present study clarified the pathological entity of DLB, compared with PD and AD.     

Lewy body variant of Alzheimer’s disease or cerebral type Lewy body disease? Two autopsy cases of presenile onset with minimal involvement of the brainstem

Lewy bodies (LB) usually extend from the brainstem to the cerebrum in patients with Parkinson’s disease. However, whether the patterns of progression of LB and neuronal loss in Parkinson’s disease are identical to those in other Lewy body diseases (LBD) remains unclear. In addition, pathological data on the autonomic nervous system involvement in LBD are limited. We present here the clinicopathological characteristics of two autopsy cases with both Alzheimer’s disease and dementia with Lewy bodies (DLB), possibly diagnosed as having Lewy body variant of Alzheimer’s disease (LBV/AD). Our patients presented clinically with dementia without parkinsonism. Histopathologically, phosphorylated α‐synuclein‐positive LB and Lewy neurites were abundant in the limbic system, especially in the amygdala, and to a lesser degree, in the neocortex, including the primary motor cortex. The amygdala was also most severely affected by neuronal loss, and the other limbic areas and neocortex were affected to a lesser degree. Despite the existence of a small number of LB and many Lewy neurites, neurons in the brainstem nuclei were relatively well preserved. The Braak stages of concurrent neurofibrillary changes and senile plaques were stage V and C, respectively, in both cases. Tyrosine hydroxylase‐positive nerve fibers were relatively well spared in one case examined compared with Parkinson’s disease cases. Furthermore, many Lewy neurites immunopositive for phosphorylated α‐synuclein were found in the nerve fascicles of the epicardium in one case examined and in Parkinson’s disease cases to a lesser degree. These findings suggest that: (i) in at least some LBV/AD cases, the amygdala develops neuronal loss and Lewy‐related pathology prior to the brainstem nuclei; and (ii) the depletion of nerves in the heart tissue of LBV/AD is not necessarily complete despite the development of Lewy‐related pathology.     

Immunohistochemical study of the expression of cytokines and nitric oxide synthases in brains of patients with dementia with Lewy bodies

Regional expression of cytokines (IL‐1α, TNF‐α), inducible nitric oxide synthase (iNOS) and neuronal NOS (nNOS) was immunohistochemically investigated in the brains of patients with dementia with Lewy bodies (DLB), compared with those of patients with Alzheimer's disease (AD) and non‐demented elderly persons. It has been reported that inflammatory responses by cytokines and oxygen free radicals such as nitric oxide (NO) are associated with damaged neurons, degenerative neurites or amyloid deposits in AD brains. In the present study, overexpression of IL‐1α, TNF‐α and iNOS was demonstrated in the amygdala, hippocampus, entorhinal and insular cortices of DLB brains, which are pathologically the most vulnerable regions in DLB brains as well as AD brains. In addition, some Lewy body (LB)‐bearing neurons were involved by the processes of IL‐1α‐ and TNF‐α‐positive microglia, and most extracellular LB were associated with the processes of TNF‐α‐ and iNOS‐positive astroglia. Glial involvement was also found around neuritic plaques and extracellular neurofibrillary tangles. In contrast, the expression of nNOS was reduced in the amygdala of DLB brains showing severe Lewy pathology. These findings suggest that cytokines and NO are significantly implicated in neuronal damage and death including LB formation in DLB brains.     

Non‐uniformity in the regional pattern of Lewy pathology in brains of dementia with Lewy bodies

We examined the regional pattern of Lewy pathology in brains of dementia with Lewy bodies (DLB) to clarify whether Lewy pathology uniformly progresses or not. Thirty‐five autopsied DLB cases were examined using α‐synuclein‐immunohistochemistry, and the regional degree of Lewy pathology in the brainstem, diencephalon and cerebral cortex was quantitatively evaluated. Consequently, we found that the regional pattern of Lewy pathology differed according to the pathological subtype, and was divided into three types: type 1 showed a brainstem‐predominant pattern, type 2 was almost equal for the brainstem and cerebral cortex, and type 3 showed a cerebral cortex‐predominant pattern. The limbic type/pure and common forms were mainly composed of type 1, whereas the neocortical type/common and Alzheimer's disease (AD) forms were mainly composed of type 3. These findings suggest the possibility that Lewy pathology of the limbic type/pure and common forms mainly progresses from the brainstem to the cerebrum, whereas that of the neocortical type/common and AD forms mainly progresses from the cerebrum to the brainstem. Cases with type 1 Lewy pathology mainly developed parkinsonism, whereas those with type 3 Lewy pathology mainly developed dementia. This corresponded to most of the limbic type/pure and common forms which developed parkinsonism, whereas most of the neocortical type/common and AD forms developed dementia. Type 1 cases may thus be clinically diagnosed as having Parkinson's disease (PD) with dementia. These findings suggest that PD has clinico‐pathological continuity with DLB, and that the regional pattern of Lewy pathology is not uniform.     

Frequency and distribution of TUNEL‐positive neurons in brains of dementia with Lewy bodies: Comparison with those in brains of Alzheimer's disease

The present study investigated the frequency and distribution of TUNEL‐positive neurons in brains of dementia with Lewy bodies (DLB) in comparison with those in brains of Alzheimer's disease (AD), Down syndrome (DS) and non‐demented elderly persons. In DLB brains, TUNEL‐positive neurons were increased in frequency compared with those in non‐demented elderly brains, and showed a distribution similar to those in AD and DS brains. DLB cases with TUNEL‐positive neurons showing severe Lewy pathology were all neocortical type, while DLB cases of the limbic type showing mild Lewy pathology did not demonstrate TUNEL‐positive neurons. In addition, we investigated the relationships between TUNEL‐positive neurons and pathological hallmarks of DLB or AD brains. TUNEL‐positive neurons had no Lewy bodies or neurofibrillary tangles, and were not located within amyloid deposits. These findings suggest that neuronal damage showing DNA fragmentations occurs in DLB brains as well as in AD and DS brains, and that it is accelerated by progression of Lewy pathology as well as Alzheimer pathology, although it is not directly related to their pathological hallmarks.     

Cyclin-dependent kinase 5 (Cdk5) associated with Lewy bodies in diffuse Lewy body disease

We investigated the cyclin-dependent kinase (Cdk) 5 distribution pattern in diffuse Lewy body disease brains using immunohistochemistry. Cdk5 immunoreactivity was detected in both brainstem-type Lewy bodies (LBs) and cortical LBs. The number of Cdk5-positive LBs was less than that of ubiquitin- or α-synuclein-positive LBs, and more than that of phosphorylated neurofilament-positive LBs. Immunoelectron microscopy revealed Cdk5-immunolabeled granulo-filamentous components in LBs and LB-related neurites. These data suggest that Cdk5 may be associated with LB formation.     

Lewy body-related alpha-synucleinopathy in aging

To clarify the significance of Lewy body (LB)-related alpha-synucleinopathy in aging, we investigated the incidence of LBs in 1,241 consecutive autopsy cases (663 males and 578 females). LB pathology was identified histologically in sections stained with hematoxylin and eosin and with anti-ubiquitin and anti-alpha-synuclein antibodies. Cases without LBs were classified as LB stage 0 (987 cases). Cases with LBs were classified as follows: LB stage I = incidental LBs (149 cases); LB stage II = LB-related degeneration without attributable clinical symptoms (47 cases); LB stage III = Parkinson disease without dementia (10 cases); LB stage IV = dementia with Lewy bodies (DLB) transitional (limbic) form (25 cases); and LB stage V = DLB neocortical form (23 cases). The average age at death was greater for those cases with LBs. There were no gender differences in the LB pathology. G842A polymorphism in the paraoxonase I gene was associated with men in LB stage II or above and suggests a gender-specific risk factor. LB stage V had higher stages of neurofibrillary tangle and senile plaque involvement and also had a higher frequency of apolipoprotein E epsilon4. Our findings indicate that LBs are associated with cognitive decline, either independently or synergistically with neurofibrillary tangles and senile plaques.     

Localization of MAP1-LC3 in vulnerable neurons and Lewy bodies in brains of patients with dementia with Lewy bodies

There is emerging evidence implicating a role for the autophagy-lysosome pathway in the pathogenesis of Lewy body disease. We investigated potential neuropathologic and biochemical alterations of autophagy-lysosome pathway-related proteins in the brains of patients with dementia with Lewy bodies (DLB), Alzheimer disease (AD), and control subjects using antibodies against Ras-related protein Rab-7B (Rab7B), lysosomal-associated membrane protein 2 (LAMP2), and microtubule-associated protein 1A/1B light chain 3 (LC3). In DLB, but not in control brains, there were large Rab7B-immunoreactive endosomal granules. LC3 immunoreactivity was increased in vulnerable areas of DLB brains relative to that in control brains; computerized cell counting analysis revealed that LC3 levels were greater in the entorhinal cortex and amygdala of DLB brains than in controls. Rab7B levels were increased, and LAMP2 levels were decreased in the entorhinal cortex of DLB brains. In contrast, only a decrease in LAMP2 levels versus controls was found in AD brains. LC3 widely colocalized with several types of Lewy pathology; LAMP2 localized to the periphery or outside of brainstem-type Lewy bodies; Rab7B did not colocalize with Lewy pathology. Immunoblot analysis demonstrated specific accumulation of the autophagosomal LC3-II isoform in detergent-insoluble fractions from DLB brains. These results support apotential role for the autophagy-lysosome pathway in the pathogenesis of DLB.     

Clinicopathological multiplicity of dementia with Lewy bodies

‘Dementia with Lewy bodies (DLB)’ is a generic clinicopathological concept characterized by progressive dementia and Lewy bodies (LB). We examined 23 autopsied DLB cases clinicopathologically and immunohistochemically. These cases were classified into the neocortical type (10 cases), the limbic type (seven cases), the cerebral type (one case) and the brainstem type (none) according to our pathological criteria, which were based on the regional incidence of LB and the degree of neuronal loss in the substantia nigra. Each subtype of DLB was further divided into the common form and the pure form on the basis of the degree of Alzheimer pathology. The remaining five cases were not classified by our pathological criteria, and were designated ‘the senile dementia of Alzheimer type (SDAT) or Alzheimer's disease (AD) type of DLB with neocortical or limbic LB’. We examined how each subtype was correlated with various clinical features, such as the age of disease onset, the clinical duration, the degree of dementia, and the presence or absence of parkinsonism, fluctuating cognition and visual hallucination. The results of this study indicate that DLB can be clinicopathologically divided into a number of subtypes, that each subtype is preferentially correlated with some clinical feature, and that the neocortical type, common form, is the major type of DLB.     

Lewy body-related α-synucleinopathy in the aged human brain

To clarify the significance of Lewy body (LB)-related alpha-synucleinopathy in aging and various neurodegenerative disorders, its incidence and topographic pattern were examined in 260 brains of elderly patients, including 116 autopsy-proven cases of Alzheimer disease (AD), 71 cases of clinically and autopsy-proven Parkinson disease (PD), 38 of dementia with Lewy bodies (DLB), 8 patients with progressive supranuclear palsy (PSP), one with senile tremor, and 26 age-matched controls without neuropsychiatric disorders. Using immunohistochemistry, alpha-synuclein (AS) positive lesions were assessed semiquantitatively. For technical reasons, the olfactory system was not systematically studied. All PD-brains showed AS-positive lesions in medullary, pontine and mesencephalic nuclei, with involvement of the nucleus basalis (90.1%), limbic cortex (58.9%), cingulate cortex (46%), amygdala, CA 2/3 hippocampal region (36.2%), neocortex (28.8%), and striatum (11%). 88% of clinical PD cases corresponded to LB pathology stages 4-6, 12% to stage 3 according to Braak et al. (2003). 84% of DLB brains were PD stage 5 or 6 and 17% stage 4, without significant differences between DLB with and without neuritic AD pathology, suggesting morphologic similarities betwee these disorders. 6/8 PSP and senile tremor cases, 49.1% of AD and 69% of aged controls were negative. AS-positive lesions in AD showed decreasing incidence from midbrain (24-28%), limbic cortex and amygdala (17-18%), nucleus basalis and medullary nuclei (13-17%), cingulate cortex (12%), CA 2/3 region (8%) to neocortex (2%), without gender differences or relationship to the severity of AD pathology (mean Braak stage 5.1). AD cases with AS positive lesions, particularly those with AS pathology in the amygdala, were older at death than negative ones (86.6 vs 83.3 yrs), but this difference was not statistically significant. 15 AD cases (seven of them with mild PD symptoms) and 3 aged controls without parkinsonian signs but LB pathology stages 3 (n=5) and 4 (n=13) were considered "incidental LB disease". 16 AD brains without parkinsonian symptoms had AS positive lesions in various areas without medullary involvement, suggesting deviation from the proposed stereotypic expansion pattern. Located AS-pathology in the midbrain and limbic cortex was seen in 31% of asymptomatic aged controls. These data 1. largely confirm Braak's staging of LB-pathology in PD; 2. suggest morphologic and pathogenic relations between PD (brainstem type) and DLB with and without coexistent AD pathology; 3. the occurrence of LB-related alpha-synucleinopathy in about 50% of AD brains and about 30% of aged controls. However, the basic mechanisms of LB-related AS-pathology and their pathogenic and clinical relevance in aged brain and neurodegenerative disorders await further elucidation.     

Formation and development of Lewy pathology: a critical update

Filamentous protein inclusions in neurons (Lewy bodies, LB) and dystrophic neurites containing pathologic α-synuclein (αSyn) are the morphologic hallmarks of sporadic Parkinson disease (PD) and dementia with Lewy bodies (DLB), but are also found in aged subjects and in a variety of neurogenerative disorders. They occur in the central, peripheral, and autonomic nervous system as an essential or coincident feature. Their formation runs through several phases from initial dust-like particles cross-linked with αSyn to aggregation of ubiquitinated dense filaments, formation of LBs, finally degradation and death of the afflicted neurons. Pathologic accumulation of αSyn/LBs proposed by Braak et al. (Neurobiol Aging 24:197–211, 2003), following a predictable sequence of lesions in six stages with ascending progression from medullary and olfactory nuclei to the cortex, has been considered to be linked to clinical dysfunctions. The consensus pathologic guidelines of DLB (Neurology 65:1863–1872, 2005), by semiquantitative scoring to αSyn pathology (LB density and distribution) in specific brain regions, distinguish three phenotypes (brainstem, transitional/limbic, and diffuse neocortical), and also consider concomitant Alzheimer-related pathology. αSyn pathology in the amygdala is often associated with Alzheimer disease. Although some retrospective clinico-pathologic studies have largely confirmed the Braak LB staging system, it shows neither correlation to the clinical severity and duration of parkinsonism nor to nigral αSyn burden and cell loss which significantly correlates with resulting striatal loss of dopamine, dopamine transporter and tyrosine hydroxylase, duration and severity of motor dysfunction. Between 6.3 and 43% of clinically manifested PD cases did not follow this pattern, and in 7–8.3% of those with αSyn-positive inclusions in midbrain and cortex the medullary nuclei were spared. On the other hand, 30–55% of elderly subjects with widespread Lewy pathology revealed no neuropsychiatric symptoms or were not classifiable. Therefore, detection and staging of Lewy pathology without assessment of neuronal loss in specific areas may not have clinical impact and its predictive validity is questionable. For demented patients, modified criteria for categorization of Lewy pathology were proposed. If robust correlations between clinical course and Lewy/αSyn pathology are to be confirmed by future studies, the currently used morphologic staging/classification systems should be revised accordingly.

     

Frontotemporal lobar degeneration and dementia with Lewy bodies: Clinicopathological issues associated with antemortem diagnosis

Currently, the clinical diagnostic criteria of frontotemporal lobar degeneration (FTLD) and dementia with Lewy bodies (DLB) are well known to neurologists and psychiatrists. However, the accuracy of the clinical diagnosis of these diseases in autopsy series is not always adequate. For example, FTLD is a syndrome rather than a clinicopathological disease entity that is comprised of various pathological substrates, including Pick's disease, FTLD with microtubule-associated protein tau gene mutation, FTLD with tau-negative ubiquitin-positive inclusions (FTLD-U), FTLD-U with progranulin gene mutation, corticobasal degeneration, basophilic inclusion body disease, and neuronal intermediate filament inclusion disease. Whether these underlying pathologies can be identified clinically is one of the greatest interests in neuropathological research. The pathophysiological relationship between Lewy pathology and Alzheimer pathology in DLB is explored with interest because it may be associated with the accuracy of clinical diagnoses. For example, although Lewy pathology may progress from the brain stem nuclei to the cerebral cortex in Parkinson's disease, recent studies have demonstrated that the progression pattern in DLB is not always identical to that in Parkinson's disease. It is also considered that the progression pattern of Lewy pathology correlates with the evolution of clinical symptoms and that the progression pattern of Lewy pathology may be altered when Alzheimer pathology coexists. In the present paper, the clinicopathological features of two demented cases are presented, and some pathological issues associated with the clinical diagnosis of FTLD and DLB are discussed.     

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.     

Age-associated prevalence and risk factors of Lewy body pathology in a general population: the Hisayama study

In dementia with Lewy bodies (DLB), the Lewy bodies (LBs) are an essential substrate. Although LB pathology has gained increasing attention as one of the major causes of dementia, little is known about the exact prevalence of LB pathology in the general population. In addition, the pathology of Alzheimer-type dementia (ATD) is frequently associated with DLB. To investigate the prevalence of LB pathology in a community-based population and to evaluate the relationship between LB and ATD pathology, we performed an analysis of 102 consecutive autopsy cases. The survey extended over 2.5 years and autopsy rate was 70.5%. LB pathology was detected using -synuclein immunohistochemistry and was assessed based on consensus guidelines for DLB. ATD pathology was evaluated by both CERAD and NIA-RI criteria. Twenty-nine subjects were clinically demented. LB pathology was present in 23 (22.5%) of 102 cases, and in 12 (41.4%) of the demented subjects. The LB score was not significantly different between DLB cases and non-demented subjects with LB pathology (nd-LB), while the Braak stages were significantly different between the two groups. Prevalence of LB pathology constantly increased with age. DLB cases accompanying severe ATD pathology showed more rapid increase of LB scores than did DLB cases without severe ATD pathology. Moreover, DLB cases with severe ATD pathology had poorer prognoses than those without severe ATD pathology. Our results suggested that aging and severe ATD pathology have a strong effect on the evolution of LB pathology.     

Parkinson's disease and dementia with Lewy bodies: One disease or two?

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) have clinical features in common and are both characterized neuropathologically by the presence of Lewy bodies (LBs). We conducted a clinicopathological correlation pilot study to better understand whether PD and DLB represent two distinct nosological entities or rather exist along the spectrum of a single LB disease. A neuropathologist blinded to clinical diagnoses evaluated brains with largely pure LB pathology to determine LB distribution and frequency. Research clinicians blinded to LB distribution and frequency determined consensus clinical diagnoses. Clinical features separated cases into two groups, one having features most compatible with PD and the other with DLB. The groups were distinguishable mainly by the time course of clinical symptoms. Although the presence of neocortical LBs was more common in the group of patients with clinical features of DLB, neocortical LBs were also present in 1 member of the PD group and even in the clinically normal control subject. Thus, there appear to be two clinical syndromes, distinguished mainly by the time course of symptoms. The mechanisms responsible for the different clinical presentations are not known, and the issue of whether PD and DLB represent two distinct diseases remains unsettled.     

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.     

Does striatal pathology distinguish Parkinson disease with dementia and dementia with Lewy bodies?

The morphological differentiation of Parkinson disease with dementia (PDD) and dementia with Lewy bodies (DLB) is a matter of discussion. The objective of this study was to investigate the regional distribution of beta-amyloid (Abeta) plaques, alpha-synuclein (AS), and pathology in both disorders. The basal ganglia from 17 age-matched patients of PDD and DLB each were immunohistochemically examined with variable degrees of associated Alzheimer pathology using antibodies to Abeta, AS, and tau. DLB brains showed a significantly higher burden of (diffuse) amyloid plaques in the putamen and caudate nucleus and slightly more severe tau pathology than PDD brains despite similar neuritic Braak stages. Phases of Abeta development in DLB brains often, but inconsistently, correlated with both neuritic Braak stages and severity of striatal Abeta load, while these correlations were almost never seen in PDD cases with Alzheimer lesions. They also revealed a higher burden of AS-lesions (both Lewy neurites and Lewy bodies) than PDD cases that commonly had a paucity of all three types of lesion. The globus pallidus was virtually spared in both phenotypes. Differences in AS and Abeta pathologies and much less of tau lesions in the striatum support a morphologic distinction between PDD and DLB, which may be of pathophysiologic importance, but the causes of these differences are unclear.