Lewy Body Dementias: A Coin with Two Sides? (original) (raw)
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Neuropathology and Applied Neurobiology, 2020
Novel clinicopathological characteristics differentiate dementia with Lewy bodies from Parkinson's disease dementia Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) known as Lewy body dementias have overlapping clinical and neuropathological features. Neuropathology in both includes combination of Lewy body and Alzheimer's disease (AD) pathology. Cerebral amyloid angiopathy (CAA), often seen in AD, is increasingly recognized for its association with dementia. Aims: This study investigated clinical and neuropathological differences between DLB and PDD. Methods: 52 PDD and 16 DLB cases from the Queen Square Brain Bank (QSBB) for Neurological disorders were included. Comprehensive clinical data of motor and cognitive features were obtained from medical records. Neuropathological assessment included examination of CAA, Lewy body and AD pathology. Results: CAA was more common in DLB than in PDD (P = 0.003). The severity of CAA was greater in DLB than in PDD (P = 0.009), with significantly higher CAA scores in the parietal lobe (P = 0.043), and the occipital lobe (P = 0.008), in DLB than in PDD. The highest CAA scores were observed in cases with APOE e4/4 and e2/4. Survival analysis showed worse prognosis in DLB, as DLB reached each clinical milestone sooner than PDD. Absence of dyskinesia in DLB is linked to the significantly lower lifetime cumulative dose of levodopa in comparison with PDD. Conclusions: This is the first study which identified prominent concurrent CAA pathology as a pathological substrate of DLB. More prominent CAA and rapid disease progression as measured by clinical milestones distinguish DLB from PDD.
Clinical Neurology and Neurosurgery, 1995
One of the characteristic histological features of Parkinson's disease (PD), with or without dementia, is the presence of Lewy bodies (LBs) in the brainstem and neocortical and limbic structures. They are often accompanied by Alzheimer type pathology (ATP). In the present retrospective study the clinical features and post-mortem findings of 18 consecutive and unselected PD patients were compared, with special reference to the frequent but not exclusive association of LBs with ATP in Lewy body disease (LBD). LBD is the term applied to a particular pattern of neuronal degeneration associated with LBs. In this study of idiopathic PD patients ATP seems to be the major determinant of the cognitive decline in most patients. Cortical Lewy Bodies (CLBs) were present in all patients reviewed, whether or not dementia was present. It was not possible to distinguish a specific pattern in the cognitive or psychopathological symptoms of dementia that would differentiate LBD from Alzheimer's disease (AD). Although in most cases hippocampal CA2-3 ubiquitin immunoreactive neurites were observed, here again there was no correlation with the presence of dementia.
Pathologic Correlates of Dementia in Individuals with Lewy Body Disease
Brain Pathology, 2010
Cognitive impairment and dementia are more common in patients with Parkinson disease (PD) than age-matched controls, and appear to become more frequent as PD progresses. However, estimates of dementia in patients with PD have varied widely, likely due in part to differences in case definition, case ascertainment, and methodology. First, we review investigations of usual pathologic correlates of dementia in patients with brainstem (b) Lewy Body Disease (LBD) and report our findings from the initial 266 brain autopsies from a population-based study of brain aging and incident dementia. Our results showed that 2.6% of subjects were diagnosed with PD during life but that 20% had bLBD at autopsy. Seventy percent of individuals with bLBD had high-level of one or more cerebral pathologic changes significantly associated with dementia: Alzheimer's disease (AD), cerebral (c) LBD, or microvascular brain injury (μVBI); these were commonly co-morbid. Next we consider proposed contributors to cognitive impairment and dementia in the approximately 30% of patients with only bLBD, including regionally selective dendritic degeneration of neostriatal medium spiny neurons. Diseases contributing to cognitive impairment and dementia in patients with bLBD are heterogeneous, providing diagnostic challenges as well as multiple opportunities for successful intervention in patients with PD.
Journal of Neurochemistry, 2019
Lewy body diseases share clinical, pathological, genetic and biochemical signatures, and are regarded as a highly heterogeneous group of neurodegenerative disorders. Inclusive of Parkinson's disease (PD), Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB), controversy still exists as to whether they should be considered as separate disease entities or as part of the same disease continuum. Here we discuss emerging knowledge relating to both clinical, and neuropathological differences and consider current biomarker strategies as we try to improve our diagnostic capabilities and design of disease modifying therapeutics for this group of debilitating neurodegenerative disorders. image This article is part of the Special Issue “Synuclein”.
Parkinson's Disease Dementia and Lewy Body Disease
2019
Dementia with Lewy Bodies (DLB) and Parkinson's disease dementia (PD-D) are Lewy body (LB)-related neurodegen-erative dementias sharing many clinical and neuropatholo-gical features. Both conditions affect cognition, behavior, movement, and autonomic functions. When the clinical picture is fully developed, DLB and PD-D are practically indistinguishable. Regarding molecular pathology, both are synucleinopathies, characterized by the accumulation of misfolded α-synuclein protein in the form of LBs and Lewy neurites. DLB and PD-D are believed to represent two entities on the same disease spectrum. The main difference between these two conditions is the temporal sequence of symptoms. Motor symptoms precede dementia in PD-D, whereas it coincides with or follows dementia in DLB within 1 year. Dementia with Lewy Bodies DLB is the second most common neurodegenerative dementia following Alzheimer's disease (AD). In contrast to AD, motor and behavioral symptoms appear early in the course of the disease in DLB and may be the major burden of the disease. Epidemiology and Risk Factors DLB accounts for 5% of all dementia cases over the age of 75. 1 In a systematic review, the prevalence of DLB was found to be between 0.02 and 33.3 per 1,000. 1 The incidence rate of DLB is 3.5 per 100,000 person-years overall, 2 and the incidence increases with age. 3 Risk factors associated with DLB are old age, mutations in the glucocerebrosidase (GBA) and α-synuclein genes, and carrying the H1 haplotype of the microtubule-associated protein tau (MAPT). 4-6 There are also new candidate risk genes associated with DLB such as BCL7C and GABRB3. 7 Compared with AD, the findings on apolipoprotein E4 (APOE) polymorphisms in DLB are inconclusive. Vascular risk factors are less associated with DLB compared with AD. Clinical Features The cardinal clinical features of DLB consist of motor, cog-nitive, behavioral, and autonomic symptoms. The cognitive profile is characterized by particularly severe deficits in attention as well as executive and visuospatial functions. In early phases of the disease, memory may be relatively Keywords ► dementia with Lewy bodies ► Parkinson's disease dementia ► synucleinopathy ► imaging Abstract Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PD-D) are Lewy body-related neurodegenerative disorders sharing common clinical and neuropathological findings. The clinical features of both conditions include cognitive impairment, behavioral symptoms, autonomic dysfunction, sleep disorders, and parkinsonism. The cognitive profile of both disorders is characterized by particularly severe deficits in executive and visuospatial functions as well as attention. Clinical differentiation between DLB and PD-D is based on an arbitrary distinction between the time of onset of parkinsonism and cognitive symptoms; extrapyramidal symptoms precede dementia in PD-D, whereas it coincides with or follows dementia within 1 year in DLB. When the clinical picture is fully developed, DLB and PD-D are practically indistinguishable. Although the diagnosis is basically clinical, structural and functional neuroimaging as well as cerebrospinal fluid biomarkers may help the clinician in the diagnosis. Placebo-controlled randomized trials of the cholinesterase inhibitors have shown modest but significant benefits in cognition, global function, and neuropsychiatric symptoms in both disorders. Behavioral symptoms such as hallucinations and delusions should be treated with caution with antipsychotics, as they have the potential to worsen motor and cognitive symptoms.
Diagnosis and management of dementia with Lewy bodies: Third report of the DLB Consortium
Neurology, 2006
The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in ϳ50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors. NEUROLOGY 2005;65:1863-1872 Clinical diagnostic criteria for DLB. Since the publication of Consensus criteria for clinical and pathologic diagnosis of dementia with Lewy bodies (DLB), 1,2 new information indicates that clinical criteria for probable DLB have acceptable specificity, but suboptimal sensitivity. Reasons identified in-clude difficulties in recognition of the core feature fluctuation 5,6 and a low rate of all core features (fluctuation, visual hallucinations, parkinsonism) in the presence of neocortical, neurofibrillary tangle (NFT) pathology. 7-9 The criteria have therefore been modified (table 1) to incorporate additional items indicative of LB pathology. Distinction is made between clinical features or investigations that are suggestive of DLB, i.e., have been demonstrated to be significantly more frequent than in
Parkinson's disease dementia – A diminished role for the Lewy body
Parkinsonism & Related Disorders, 2009
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.
Dementia with Lewy bodies: findings from an international multicentre study
International Journal of Geriatric Psychiatry, 2000
Objectives[ To describe the baseline demographic\ neuropsychiatric and neurological data of a large selected clinical sample of patients with dementia with Lewy Bodies "DLB# from an international multicentre trial with rivastigmine[ To examine the usefulness of the Consensus Criteria for the diagnosis of DLB in di}erent countries[ Methods[ Seventeen centres from Spain\ the UK and Italy recruited patients diagnosed clinically as probable DLB according to recent Consensus Criteria "McKeith et al[\ 0885#[ A standard clinical protocol including inclu! sion:exclusion criteria\ collection of demographic and medical data\ cognitive "Mini Mental State Examination] MMSE#\ motor "Uni_ed Parkinson|s Disease Rating Scale] UPDRS# and neuropsychiatric "Neuropsychiatric Inven! tory] NPI# examinations\ was applied after obtaining informed consent[ Data were summarised and compared across countries with uni! and multivariate analyses[ Results[ One hundred and twenty patients were recruited] 45[6) males\ mean "SD# age 62[8 "5[3# years\ range 46Ð 76 years[ Sixty percent ful_lled all three core diagnostic features of DLB\ and 39) only two "{parkinsonism| 81[3)\ {cognitive~uctuations| 78[0)\ {visual hallucinations| 66[2)#[ {Systematised delusions| "35)# and {repeated falls| "31)# were the most frequent supportive diagnostic features[ There were no di}erences across countries in demo! graphic\ diagnostic or clinical features[ Patients showed a wide range of psychopathology which was weakly correlated with cognitive impairment[ Some mild extrapyramidal signs "EPS# were observed in most patients[ Conclusions[ The Consensus Criteria for DLB can be consistently applied across many di}erent sites for multicentre studies[ {Parkinsonism| and {cognitive~uctuations| as core features and {systematised delusions| and {repeated falls| as supportive features are the most frequent diagnostic clues[ Neuropsychiatric disturbances\ in particular apathy\ delusions\ hallucinations and anxiety\ and mild symmetric EPS are frequent in DLB and are only related weakly to cognitive impairment[