Lewy-related Pathology Research Articles

Association Between Lifetime Cigarette Smoking and Lewy Body Accumulation

Cigarette smoking has been associated repeatedly in observational studies with decreased risk of Parkinson's disease (PD), but its relationship to the risk of dementia or Alzheimer's disease (AD) is inconsistent. All of these studies have used clinical diagnoses of disease. We tested the hypothesis that lifetime cigarette use might be associated with reduced risk of neuropathologic changes of Lewy-related pathology (LRP) in multiple brain regions or with reduced risk of consensus neuropathologic changes of AD in a prospective community-based study of brain aging and dementia, the Adult Changes in Thought (ACT) study. We observed that heavy lifetime cigarette smoking (>50 pack years) was associated with significantly reduced relative risk (RR) for LRP, but not AD-type pathologic changes, after correcting for selection bias, and with significantly reduced frequency of LRP in the substantia nigra. These findings are the first of which we are aware to associate reduced LRP in human brain with any exposure, and substantiate observational studies that have associated cigarette smoking with reduced risk of PD. Although cigarette smoking is too toxic to suggest as a treatment, if confirmed, these findings may guide future therapeutic strategies that attempt to suppress LRP in human brain by other means.

Neuropathologic Findings of Dementia with Lewy Bodies (DLB) in a Population-based Vantaa 85+ Study

The consortium on dementia with Lewy bodies has established consensus guidelines for the neuropathologic diagnosis of dementia with Lewy bodies (DLB) including the likelihood that the neuropathologic findings associate with the clinical syndrome. Nevertheless, clinico-pathological correlations remain controversial. We applied the consensus guidelines for determining Lewy-related pathology (LRP) and evaluated the clinical presentation in the prospective, population-based Vantaa 85+ study consisting of individuals at least 85 years of age. LRP was seen in 36% of 304 subjects and categorized as follows: 3% brainstem-predominant, 14% limbic, 15% diffuse neocortical type (4% could not be categorized). The likelihood that the neuropathology predicts the DLB clinical syndrome was low in 6%, intermediate in 13%, and high in 13% of all 304 subjects. In the latter two groups, 77% were demented, 35% had at least one extrapyramidal symptom, and 15% had visual hallucinations. Surprisingly, DLB clinical features associated better with high neurofibrillary stage than with diffuse neocortical LRP. Moreover, the neurofibrillary stage, substantia nigra neuron loss, and grade of Lewy neurites in hippocampal CA2-3 region, each showed a significant association with the extent of LRP. In conclusion, the neuropathologic DLB in this very elderly population was common, but the clinical symptoms tended to associate better with severe neurofibrillary pathology than with extensive LRP.

Visual Hallucinations in Dementia: A Prospective Community-Based Study With Autopsy

Several studies have demonstrated that specific neuropathologic features may be associated with the presence of visual hallucinations in dementia patients, but the clinical usefulness of these studies has been limited because their subjects were selected on the basis of neuropathologic findings rather than clinical presentations. This study seeks to investigate the demographic, clinical, and neuropathologic features of community-based dementia subjects with and without visual hallucations. A prospective examination of the clinical and neuropathologic correlates of visual hallucinations in community-based dementia subjects. One hundred forty-eight subjects with sufficient clinical and neuropathologic data from a community-based incident dementia autopsy case series. Subjects were classified according to the presence or absence of visual hallucinations and subjects with visual hallucinations (N = 27) were younger at intake and more likely to exhibit agitation, delusions, and apathy than subjects without visual hallucinations (N = 121). Subjects with visual hallucinations were also more likely than subjects without visual hallucinations to have Lewy-related pathology (LRP) (78% versus 45%). In addition, a higher frequency of visual hallucinations was observed in subjects with neocortical LRP than subjects with limbic-, amygdala-, or brainstem-predominant LRP. Although Alzheimer disease with concomitant LRP was the most common neuropathologic subtype in the visual hallucinations-positive group (59%), the frequency of subjects with Alzheimer disease pathology did not differ significantly between those with and without visual hallucinations (74% versus 62%). Subjects with visual hallucinations were more likely to have concomitant postural and gait disturbance, additional neuropsychiatric symptoms, and neocortical LRP than subjects without visual hallucinations. Visual hallucinations accompanying dementia have distinct clinical and neuropathologic characteristics that are important for prognosis and clinical management.

An atypical autopsy case of Lewy Body disease with clinically diagnosed major depression: A clinical, radiological and pathological study

We report an 84-year-old woman who was clinically diagnosed with late-life major depression (LLMD) and having a diffuse type of dementia with Lewy bodies (DLB) neuropathologically. Clinically, this case showed depressive mood, anxiety, and irritation, but did not show cognitive dysfunction, visual hallucination, fluctuation of alertness and parkinsonism, which define the criteria for diagnosing DLB. Neuropathological examination demonstrated abundant Lewy-related pathology including Lewy bodies and neurites in the hippocampal region and the cerebral cortex, and moderate levels in brain stem nuclei including the substantia nigra, locus ceruleus and dorsal raphe nucleus. These findings suggest the possibility that Lewy-related pathology is associated with the depressive symptoms. Furthermore, it must be noted that some patients diagnosed with LLMD clinically may develop pathology of DLB without the typical or usual clinical symptoms.

Neurofibrillary tau pathology modulated by genetic variation of α‐synuclein

We analyzed whether genetic variation of alpha-synuclein modulates the extent of neuropathological changes in a population-based autopsied sample of 272 elderly Finns. None of the 11 markers was associated with the extent of neocortical beta-amyloid pathology. The intron 4 marker rs2572324 was associated with the extent of neurofibrillary pathology (p = 0.0006, permuted p = 0.004; Braak stages IV-VI vs 0-II). The same variant also showed a trend for association with neocortical Lewy-related pathology. These results suggest for the first time that variation of alpha-synuclein modulates neurofibrillary tau pathology and support the recent observations of an interaction of alpha-synuclein and tau in neurodegeneration.

A critical reappraisal of current staging of Lewy-related pathology in human brain

Sporadic Parkinson disease (sPD) or brainstem-predominant type of Lewy body (LB) disease, and dementia with Lewy bodies (DLB), the two most frequent alpha-synucleinopathies, are progressive multisystem neurodegenerative disorders with widespread occurrence of alpha-synuclein (AS) deposits in the central, peripheral, and autonomic nervous system. For both LB-related disorders, staging/classification systems based on semiquantitative assessment of the distribution and progression pattern of Lewy-related/AS pathology are used that are considered to be linked to clinical dysfunctions. In PD, a six-stage system (Braak) has been suggested to indicate a predictable sequence of lesions with ascending progression from medullary and olfactory nuclei to the cortex, the first two presymptomatic stages being related to incidental LB disease, stages 3 and 4 with motor symptoms, and the last two (cortical) stages may be frequently associated with cognitive impairment. DLB, according to consensus pathologic guidelines, by semiquantitative scoring of AS pathology (LB density and distribution) in specific brain regions, is distinguished into three phenotypes (brainstem, transitional/limbic, and diffuse neocortical), also considering concomitant Alzheimer-related pathology. Retrospective clinico-pathologic studies, although largely confirming the staging system, particularly for younger onset PD with long duration, have shown that between 6.3 and 43% of the cases did not follow the proposed caudo-rostral progression pattern of AS pathology. There was sparing of medullary nuclei in 7-8.3% of clinically manifested PD cases with AS inclusions in midbrain and cortex corresponding to Braak stages 4 and 5, whereas mild parkinsonian symptoms were already observed in stages 2 and 3. There is considerable clinical and pathologic overlap between PD (with or without dementia) and DLB, corresponding to Braak LB stages 5 and 6, both frequently associated with variable Alzheimer-type pathology. Dementia often does not correlate with progressed stages of LB pathology, but may also be related to concomitant Alzheimer lesions or mixed pathologies. There is no relationship between Braak LB stage and the clinical severity of PD, and the predictive validity of this concept is doubtful, since large unselected, retrospective autopsy series in 30-55% of elderly subjects with widespread AS/Lewy-related pathology (Braak stages 5 and 6) reported no definite neuropsychiatric symptoms, suggesting considerable cerebral compensatory mechanisms. Applying the original criteria to large dementia samples, 49% of positive cases were not classifiable. Therefore, modified criteria for the categorization of Lewy-related pathology were proposed for patients with a history of dementia. The causes and molecular basis of the not infrequent deviations from the current staging schemes of AS pathology in PD and DLB, its relation to the onset of classical parkinsonian symptoms and for the lack of definite clinical deficits despite widespread AS pathology in the nervous system remain to be elucidated.

The significance of medial temporal lobe atrophy

Medial temporal lobe atrophy (MTA) is a sensitive radiologic marker for Alzheimer disease (AD) and associated with cognitive impairment. The value of MTA in the oldest old (>85 years old) is largely unknown. A total of 132 formalin-fixed brains from the Vantaa 85+ community-based study were subjected to postmortem MRI. Visual ratings of MTA were determined in a blinded fashion and compared with neuropathologic findings and clinical assessment (dementia according to Diagnostic and Statistical Manual of Mental Disorders-III-R). A strong relationship was found between MTA scores and Alzheimer pathology (p < 0.001). The previously proposed cutoff MTA score >2 correctly excluded subjects with no or borderline Alzheimer-type pathology (45/48), but was not very sensitive for AD (modified National Institute on Aging-Reagan Institute criteria). MTA scores >2 were also found in subjects with other primary neurodegenerative hippocampal pathology including hippocampal sclerosis, Lewy-related pathology, and argyrophilic grain disease, either alone or in combination with Alzheimer-type pathology. High MTA scores were associated with clinical dementia-in this subgroup, sensitivity was 63% and specificity 69% for AD. Medial temporal lobe atrophy (MTA) on postmortem MRI is sensitive to primary degenerative hippocampal pathology in the very old, but not specific for Alzheimer-type pathology. MTA scores of 2 or less are not frequently associated with dementia.

Clinicopathological concordance and discordance in three monozygotic twin pairs with familial Alzheimer’s disease

Aim:Neuropathological examination of both individuals in a monozygotic (MZ) twin pair with Alzheimer’s disease (AD) is rare, especially in the molecular genetic era. We had the opportunity to assess the...

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 alpha-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 a-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.

Dementia with Lewy Bodies

Synucleinopathies, with and without dementia, encompass a wide range of diseases including Parkinson's disease, multiple system atrophy, rapid eye movement (REM) sleep behavior disorder, and dementia with Lewy bodies (DLB). DLB is a neurodegenerative disorder resulting in slowly progressive and unrelenting dementia until death. Prevalence studies suggest that it is the second most common dementing illness in the elderly. The neuropathologic findings of DLB show a wide anatomic range. Lewy bodies and Lewy-related pathology are found from the brain stem to the cortex and, in many cases, associated with concurrent Alzheimer's disease pathology. A recent international consortium on DLB has resulted in revised criteria for the clinical and pathological diagnosis of DLB incorporating new information about the core clinical features and improved methods for their assessment. The presentation of DLB is typically one of cortical and subcortical cognitive impairments, with worse visuospatial and executive dysfunction than Alzheimer's disease. There may be relative sparing of memory especially in the early stages. Core clinical features of DLB include fluctuating attention, recurrent visual hallucinations, and parkinsonism. Suggestive features include REM sleep behavior disorder, severe neuroleptic sensitivity, and low dopamine transporter uptake in the basal ganglia on functional neuroimaging. Additional supportive features that commonly occur in DLB, but with lower specificity, include repeated falls and syncope, transient, unexplained loss of consciousness, severe autonomic dysfunction, hallucinations in other modalities, systematized delusions, depression, relative preservation of medial temporal lobe structures on structural neuroimaging, reduced occipital activity on functional neuroimaging, prominent slow wave activity on electroencephalogram, and low uptake myocardial scintigraphy. Management of DLB includes pharmacological and nonpharmacological interventions for its cognitive, neuropsychiatric, motor, and sleep disturbances.

Clinical and neuropathological correlates of dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) is characterized pathologically by widespread Lewy body (LB) neuronal inclusions in the brain, but the contribution of LBs to the clinical syndrome of dementia and parkinsonism is unclear. In a clinical-pathological study of 25 cases with DLB, we examined the regional neuroanatomical distribution of Lewy-related pathology using alpha-synuclein immunostaining to evaluate the relationship between LBs, neuronal loss, Alzheimer-type changes, and the clinical phenotype. Compared to traditional ubiquitin immunostaining, alpha-synuclein immunohistochemistry was more specific and slightly more sensitive, staining about 5% more intracytoplasmic structures. There was a consistent pattern of vulnerability to LB formation across subcortical, paralimbic, limbic, and neocortical structures, which was independent of concomitant Alzheimer-type changes. There were no significant differences in regional LB densities among patients with or without cognitive fluctuations, visual hallucinations, delusions, recurrent falls or parkinsonism. Duration of disease correlated weakly with LB density. There was no neuronal loss in superior temporal sulcus or entorhinal cortex in pure DLB cases compared to nondemented controls. Thus, DLB is characterized by a specific neuroanatomical vulnerability to LB pathology, distinct from AD pathology, with a complicated relationship to clinical symptoms.