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Background: Dementia is one of the milestones of advanced Parkinson's disease (PD), with its neuropathological substrate still being a matter of debate, particularly regarding its potential mechanistic implications. Objective(s): The aim of this study was to review the relative importance of Lewy-related alpha-synuclein and Alzheimer's tau and amyloid-beta (Abeta) pathologies in disease progression and dementia in PD. Method(s): We reviewed studies conducted at the Queen Square Brain Bank, Institute of Neurology, University College London, using large PD cohorts. Result(s): Cortical Lewy- and Alzheimer-type pathologies are associated with milestones of poorer prognosis and with non-tremor predominance, which have been, in turn, linked to dementia. The combination of these pathologies is the most robust neuropathological substrate of PD-related dementia, with cortical Abeta burden determining a faster progression to dementia. Conclusion(s): The shared relevance of these pathologies in PD progression and dementia is in line with experimental data suggesting synergism between alpha-synuclein, tau and Abeta and with studies testing these proteins as disease biomarkers, hence favouring the eventual testing of therapeutic strategies targeting these proteins in PD. © 2013 S. Karger AG, Basel.

Background: Dementia is one of the milestones of advanced Parkinson's disease (PD), with its neuropathological substrate still being a matter of debate, particularly regarding its potential mechanistic implications. Objective(s): The aim of this study was to review the relative importance of Lewy-related alpha-synuclein and Alzheimer's tau and amyloid-beta (Abeta) pathologies in disease progression and dementia in PD. Method(s): We reviewed studies conducted at the Queen Square Brain Bank, Institute of Neurology, University College London, using large PD cohorts. Result(s): Cortical Lewy- and Alzheimer-type pathologies are associated with milestones of poorer prognosis and with non-tremor predominance, which have been, in turn, linked to dementia. The combination of these pathologies is the most robust neuropathological substrate of PD-related dementia, with cortical Abeta burden determining a faster progression to dementia. Conclusion(s): The shared relevance of these pathologies in PD progression and dementia is in line with experimental data suggesting synergism between alpha-synuclein, tau and Abeta and with studies testing these proteins as disease biomarkers, hence favouring the eventual testing of therapeutic strategies targeting these proteins in PD. © 2013 S. Karger AG, Basel.

Background: Dementia is one of the milestones of advanced Parkinson's disease (PD), with its neuropathological substrate still being a matter of debate, particularly regarding its potential mechanistic implications. Objective(s): The aim of this study was to review the relative importance of Lewy-related alpha-synuclein and Alzheimer's tau and amyloid-beta (Abeta) pathologies in disease progression and dementia in PD. Method(s): We reviewed studies conducted at the Queen Square Brain Bank, Institute of Neurology, University College London, using large PD cohorts. Result(s): Cortical Lewy- and Alzheimer-type pathologies are associated with milestones of poorer prognosis and with non-tremor predominance, which have been, in turn, linked to dementia. The combination of these pathologies is the most robust neuropathological substrate of PD-related dementia, with cortical Abeta burden determining a faster progression to dementia. Conclusion(s): The shared relevance of these pathologies in PD progression and dementia is in line with experimental data suggesting synergism between alpha-synuclein, tau and Abeta and with studies testing these proteins as disease biomarkers, hence favouring the eventual testing of therapeutic strategies targeting these proteins in PD. © 2013 S. Karger AG, Basel.

Benign tremulous parkinsonism, a tremor dominant syndrome with a relatively slow rate of deterioration, is recognized by clinicians although its pathological basis is not well understood. A systematic review of Queen Square Brain Bank donors was carried out to determine the natural history and pathology of individuals who had tremor dominant parkinsonism with mild non-tremor components and minimal gait disability for at least 8 years. We identified 16 cases of pathologically proved benign tremulous Parkinson's disease (PD); another 5 individuals conformed to the definition but did not have the pathology of PD. Patients with verified benign tremulous PD had less severe neuronal loss in the substantia nigra than controls (chi2: P = .003). Twelve of these had been correctly diagnosed with PD at their first neurological evaluation, whereas the other 4 were originally thought to have another tremor disorder. The only consistent distinguishing feature of the 5 pathologically disproved cases, who may have had either essential tremor with associated rest tremor or dystonic tremor, was a failure to develop unequivocal bradykinesia within a decade of onset of tremor at rest. Our findings support the existence of a distinct subgroup of benign tremulous PD. The slower rate of clinical progression correlates with less severe nigral cell loss at postmortem, although many of these patients transgress the benign tremulous parkinsonism definition by the final third of their disease course and develop the common features of advanced PD. © 2012 Movement Disorders Society.

Benign tremulous parkinsonism, a tremor dominant syndrome with a relatively slow rate of deterioration, is recognized by clinicians although its pathological basis is not well understood. A systematic review of Queen Square Brain Bank donors was carried out to determine the natural history and pathology of individuals who had tremor dominant parkinsonism with mild non-tremor components and minimal gait disability for at least 8 years. We identified 16 cases of pathologically proved benign tremulous Parkinson's disease (PD); another 5 individuals conformed to the definition but did not have the pathology of PD. Patients with verified benign tremulous PD had less severe neuronal loss in the substantia nigra than controls (chi2: P = .003). Twelve of these had been correctly diagnosed with PD at their first neurological evaluation, whereas the other 4 were originally thought to have another tremor disorder. The only consistent distinguishing feature of the 5 pathologically disproved cases, who may have had either essential tremor with associated rest tremor or dystonic tremor, was a failure to develop unequivocal bradykinesia within a decade of onset of tremor at rest. Our findings support the existence of a distinct subgroup of benign tremulous PD. The slower rate of clinical progression correlates with less severe nigral cell loss at postmortem, although many of these patients transgress the benign tremulous parkinsonism definition by the final third of their disease course and develop the common features of advanced PD. © 2012 Movement Disorders Society.

Patients with Parkinson's disease who develop disabling levodopa-induced motor fluctuations have a stronger therapeutic response than those who experience a more modest but stable response. A difference in the histopathological lesion between the two groups might be responsible. Case records from 97 patients with pathologically proven Parkinson's disease were reviewed to determine the pattern of levodopa response. Pathological findings for fluctuating and non-fluctuating cases were compared. Patients with motor fluctuations had a younger age of onset and longer disease course (P < 0.001), although mean age at death was almost the same. Four milestones of advanced disease (frequent falls, visual hallucinations, cognitive disability and need for residential care) occurred at a similar time from death in each group; this interval was not proportionate to the disease duration. There were no significant differences in the severity or distribution of Lewy body or other pathologies. Irrespective of the pattern of levodopa response, patients reach a common pathological endpoint at a similar age, and the duration and manifestations of end-stage disease are alike. A non-linear or exponential time relationship may govern the late clinical and pathological progression of Parkinson's disease. © The Author (2007). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.

We have carried out a systematic review of the case files of 242 donors with pathologically verified Parkinson's disease at the Queen Square Brain Bank for Neurological Disorders in an attempt to corroborate the data-driven subtype classification proposed by Lewis and colleagues (Heterogeneity of Parkinson's disease in the early clinical stages using a data driven approach. J Neurol Neurosurg Psychiatry 2005; 76: 343-8). Cases were segregated into earlier disease onset (25), tremor dominant (31), non-tremor dominant (36) and rapid disease progression without dementia (8) subgroups. We found a strong association between a non-tremor dominant disease pattern and cognitive disability. The earlier disease onset group had the longest duration to death, and greatest delay to the onset of falls and cognitive decline. Patients with a tremor dominant disease pattern did not live significantly longer than non-tremor dominant patients and showed no difference in mean time to onset of falls and hallucinations. Rapid disease progression was associated with older age, early depression and early midline motor symptoms, and in 70 of the cases, tremulous onset. The non-tremor dominant subgroup had a significantly higher mean pathological grading of cortical Lewy bodies than all other groupings (P < 0.05) and more cortical amyloid-beta plaque load and cerebral amyloid angiopathy than early disease onset and tremor dominant groups (P = 0.047). An analysis of cases with pathologically defined neocortical Lewy body disease confirmed the link between bradykinetic onset, cognitive decline and Lewy body deposition in the neocortex. Although neuropathological examination failed to distinguish the other subtypes, the classification scheme was supported by an analysis of clinical data that were independent of the basic subgroup definitions.

Patients with Parkinson's disease who develop disabling levodopa-induced motor fluctuations have a stronger therapeutic response than those who experience a more modest but stable response. A difference in the histopathological lesion between the two groups might be responsible. Case records from 97 patients with pathologically proven Parkinson's disease were reviewed to determine the pattern of levodopa response. Pathological findings for fluctuating and non-fluctuating cases were compared. Patients with motor fluctuations had a younger age of onset and longer disease course (P < 0.001), although mean age at death was almost the same. Four milestones of advanced disease (frequent falls, visual hallucinations, cognitive disability and need for residential care) occurred at a similar time from death in each group; this interval was not proportionate to the disease duration. There were no significant differences in the severity or distribution of Lewy body or other pathologies. Irrespective of the pattern of levodopa response, patients reach a common pathological endpoint at a similar age, and the duration and manifestations of end-stage disease are alike. A non-linear or exponential time relationship may govern the late clinical and pathological progression of Parkinson's disease. © The Author (2007). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.

We have carried out a systematic review of the case files of 242 donors with pathologically verified Parkinson's disease at the Queen Square Brain Bank for Neurological Disorders in an attempt to corroborate the data-driven subtype classification proposed by Lewis and colleagues (Heterogeneity of Parkinson's disease in the early clinical stages using a data driven approach. J Neurol Neurosurg Psychiatry 2005; 76: 343-8). Cases were segregated into earlier disease onset (25), tremor dominant (31), non-tremor dominant (36) and rapid disease progression without dementia (8) subgroups. We found a strong association between a non-tremor dominant disease pattern and cognitive disability. The earlier disease onset group had the longest duration to death, and greatest delay to the onset of falls and cognitive decline. Patients with a tremor dominant disease pattern did not live significantly longer than non-tremor dominant patients and showed no difference in mean time to onset of falls and hallucinations. Rapid disease progression was associated with older age, early depression and early midline motor symptoms, and in 70 of the cases, tremulous onset. The non-tremor dominant subgroup had a significantly higher mean pathological grading of cortical Lewy bodies than all other groupings (P < 0.05) and more cortical amyloid-beta plaque load and cerebral amyloid angiopathy than early disease onset and tremor dominant groups (P = 0.047). An analysis of cases with pathologically defined neocortical Lewy body disease confirmed the link between bradykinetic onset, cognitive decline and Lewy body deposition in the neocortex. Although neuropathological examination failed to distinguish the other subtypes, the classification scheme was supported by an analysis of clinical data that were independent of the basic subgroup definitions.