The progression of pathology in longitudinally followed patients with Parkinson’s disease (original) (raw)
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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.
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.
Parkinson Disease Neuropathology
Archives of Neurology, 2002
To investigate the neuropathologic substrate for dementia occurring late in Parkinson disease (PD). Design: We identified 13 patients with a clinical diagnosis of PD who experienced dementia at least 4 years after parkinsonism onset (mean, 10.5 years) and subsequently underwent postmortem examination. Despite levodopa therapy, 9 patients later became severely impaired and nonambulatory, requiring total or near-total care; this included 4 patients treated with 1200 mg/d or more of levodopa (with carbidopa), which was consistent with loss of the levodopa response. These 13 patients were compared with 9 patients clinically diagnosed as having PD, but without dementia, who had undergone autopsies. Results: Twelve of 13 PD patients with dementia had findings of diffuse or transitional Lewy body disease as the primary pathologic substrate for dementia; 1 had progressive supranuclear palsy. This pathology also apparently accounted for the levodopa refractory state. Among the 12 PD patients with dementia, mean and median Lewy body counts were increased nearly 10-fold in neocortex
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.
Lewy- and Alzheimer-type pathologies in Parkinson's disease dementia: which is more important?
Brain, 2011
The relative importance of Lewy-and Alzheimer-type pathologies to dementia in Parkinson's disease remains unclear. We have examined the combined associations of a-synuclein, tau and amyloid-b accumulation in 56 pathologically confirmed Parkinson's disease cases, 29 of whom had developed dementia. Cortical and subcortical amyloid-b scores were obtained, while tau and a-synuclein pathologies were rated according to the respective Braak stages. Additionally, cortical Lewy body and Lewy neurite scores were determined and Lewy body densities were generated using morphometry. Non-parametric statistics, together with regression models, receiver-operating characteristic curves and survival analyses were applied. Cortical and striatal amyloid-b scores, Braak tau stages, cortical Lewy body, Lewy neurite scores and Lewy body densities, but not Braak a-synuclein stages, were all significantly greater in the Parkinson's disease-dementia group (P 5 0.05), with all the pathologies showing a significant positive correlation to each other (P 5 0.05). A combination of pathologies [area under the receiver-operating characteristic curve = 0.95 (0.88-1.00); P 5 0.0001] was a better predictor of dementia than the severity of any single pathology. Additionally, cortical amyloid-b scores (r = À0.62; P = 0.043) and Braak tau stages (r = À 0.52; P = 0.028), but not Lewy body scores (r = À 0.25; P = 0.41) or Braak a-synuclein stages (r = À 0.44; P = 0.13), significantly correlated with mini-mental state examination scores in the subset of cases with this information available within the last year of life (n = 15). High cortical amyloid-b score (P = 0.017) along with an older age at onset (P = 0.001) were associated with a shorter time-to-dementia period. A combination of Lewy-and Alzheimer-type pathologies is a robust pathological correlate of dementia in Parkinson's disease, with quantitative and semi-quantitative assessment of Lewy pathology being more informative than Braak a-synuclein stages. Cortical amyloid-b and age at disease onset seem to determine the rate to dementia.
Neuropathological correlates of parkinsonian disorders in a large Dutch autopsy series
Acta Neuropathologica Communications, 2020
The clinical diagnosis in patients with parkinsonian disorders can be challenging, and a definite diagnosis requires neuropathological confirmation. The aim of this study was to examine whether a clinical diagnosis of Parkinson’s disease (PD) and atypical parkinsonian disorders predict the presence of Lewy pathology (LP) and concomitant neuropathological lesions.We included 293 donors with a history of parkinsonism without dementia at disease onset, collected by the Netherlands Brain Bank (NBB) from 1989 to 2015. We retrospectively categorized donors according the International Parkinson and Movement Disorder Society clinical diagnostic criteria for PD (MDS-PD criteria) as ‘not PD’, ‘probable PD’ or ‘established PD’. We compared the final clinical diagnosis to presence of neuropathological lesions as defined by BrainNet Europe and National Institute on Aging – Alzheimer's Association guidelines.LP was present in 150 out of 176 donors (85%) with a clinical diagnosis of PD, in 8 out of 101 donors (8%) with atypical parkinsonian disorders and in 4 out of 16 donors (25%) without a definite clinical diagnosis. Independent from age at death, stages of amyloid-β, but not neurofibrillary tau or neuritic plaques, were higher in donors with LP compared to other types of pathology (p = 0.009). The MDS-PD criteria at a certainty level of ‘probable PD’ predicted presence of LP with a diagnostic accuracy of 89.3%. Among donors with LP, ‘established PD’ donors showed similar Braak α-synuclein stages and stages of amyloid-β, neurofibrillary tau and neuritic plaques compared to ‘not PD’ or ‘probable PD’ donors.In conclusion, both a clinical diagnosis of PD as well as MDS-PD criteria accurately predicted presence of LP in NBB donors. LP was associated with more widespread amyloid-β pathology, suggesting a link between amyloid-β accumulation and LP formation.
The Sydney multicenter study of Parkinson's disease: The inevitability of dementia at 20 years
Movement Disorders, 2008
After 20 years follow-up of newly diagnosed patients with Parkinson's disease (PD), 100 of 136 (74%) have died. The mortality rate fell in the first 3 years of treatment, then rose compared to the general population, the standardized mortality ratio from 15 to 20 years reaching 3.1. Drug induced dyskinesia and end of dose failure were experienced by most patients, but the main current problems relate to the non-levodopa responsive features of the disease. Dementia is present in 83% of 20-year survivors. Dementia correlates with increasing age and probably reflects an interplay of multiple pathologies. Seventeen people with dementia had postmortems. Eight had diffuse Lewy bodies as the only cause of dementia, while others had mixed neuropathology. Only one person lives independently and 48% are in nursing homes. Excessive daytime sleepiness is noted in 70%, falls have occurred in 87%, freezing in 81%, fractures in 35%, symptomatic postural hypotension in 48%, urinary incontinence in 71%, moderate dysarthria in 81%, choking in 48%, and hallucinations in 74%. The challenge is to understand the cellular mechanisms underlying the diverse features of advanced PD that go far beyond a lack of dopamine.
Evidence that incidental Lewy body disease is pre-symptomatic Parkinson’s disease
Acta Neuropathologica, 2008
Lewy bodies, the histologic hallmark of Parkinson's disease (PD), are detected in the brains of about 10% of clinically normal people over the age of 60 years. When Lewy bodies are found in normal individuals, the process is sometimes referred to as incidental Lewy body disease (iLBD). The distribution of Lewy bodies in iLBD is similar to the distribution in PD, but neuronal populations vulnerable to Lewy bodies do not show signiWcant neuronal loss in iLBD. It remains unknown if Lewy bodies in this setting represent pre-symptomatic PD or an age-related change unrelated to PD. To address this question we identiWed cases of iLBD and used a marker for dopaminergic and noradrenergic neurons, tyrosine hydroxylase (TH), to determine if there were changes similar to those found in PD. TH immunoreactivity in the striatum and the epicardial nerve Wbers was decreased in iLBD compared to normal controls, but not to the same extent as in PD. The Wndings suggest that iLBD is preclinical PD and that the lack of symptoms is due to subthreshold pathology.
Dementia & Neuropsychologia, 2022
Conflict of interest: JS: Participation as speaker in symposia sponsored by Roche laboratory; LPS: Participation in advisory boards for Biogen. Participation as speaker in symposia sponsored by Aché, Apsen, and Biogen laboratories; MLFB: Participation in advisory boards for Biogen. Development of material for continuous medical education and participation as speaker in symposia sponsored by EMS and Torrent laboratories; PC: Participation as principal investigator in clinical trials for Novo Nordisk and Roche laboratories. Participation in advisory boards for Aché, Biogen, EMS, Nutricia, and Roche laboratories. Development of material for continuous medical education and participation as speaker in symposia sponsored by Aché, Nutricia, Libbs, Roche, Sandoz, Torrent, and Zodiac laboratories; PHFB: Participation in advisory boards for Biogen and Novo Nordisk laboratories. Supervision of training activities for Biogen, Janssen-Cilag, and Novo Nordisk laboratories and for Quintiles. Participation as speaker in symposia sponsored by Apsen, Nutricia, Roche, and Sandoz laboratories; LCS: Participation in advisory board for Biogen. Participation as speaker in symposia sponsored by Biogen; RN: Participation in advisory board for Biogen; JBP, VT, HBF, MS, MTB, BJAPB, FACV, MLFG, SMDB, RMC, NAFF: There is no conflict of interest to declare.
Etiologies of Parkinsonism in a Century-Long Autopsy-Based Cohort
Brain Pathology, 2013
We investigated the distribution of different etiologies underlying Parkinsonism in a hospital-based autopsy collection, studied the demographic data and evaluated diagnostic accuracy using histopathological examination as the gold standard. Out of a total of 9359 consecutive autopsy cases collected between 1914 and 2010, we identified 261 individuals who carried a clinical diagnosis of a Parkinsonian syndrome at death. A detailed neuropathological examination revealed idiopathic Parkinson's disease (PD) in 62.2%, progressive supranuclear palsy (PSP) in 4.2%, multiple system atrophy (MSA) in 2.3%, corticobasal degeneration (CBD) in 1.2%, postencephalitic Parkinsonism (PEP) in 2.7%, vascular Parkinsonism (VaP) in 8.8% and Alzheimer-type pathology (ATP) of the substantia nigra in 8%. The diagnostic accuracy of PD in our cohort was lower (71.2%) than those reported in previous studies, although it tended to increase during the last decades up to 85.7%. Of particular interest, we found that PD, while being the most frequent cause of Parkinsonism, was greatly overdiagnosed, with VaP and ATP being the most frequent confounding conditions.