Cognitive Impairment in Parkinson’s Disease and Dementia with Lewy Bodies: A Spectrum of Disease

Gross, Rachel G.; Siderowf, Andrew; Hurtig, Howard I.

doi:10.1159/000109756

Cited by 43 publications

(13 citation statements)

References 70 publications

(102 reference statements)

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“…Cognitive impairment is a major consequence of LB disorders (Gross et al, 2008;Hanson and Lippa, 2009). To test the effect of abnormal α-syn accumulation on cognitive function, we performed associative memory tests by analyzing fear conditioning behavior.…”

Section: Resultsmentioning

confidence: 99%

-Syn Suppression Reverses Synaptic and Memory Defects in a Mouse Model of Dementia with Lewy Bodies

Lim

Kehm

Lee

et al. 2011

Journal of Neuroscience

108

117

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Abnormally accumulated α-syn is a pathological hallmark of Lewy body related disorders such as Parkinson’s disease (PD) and Dementia with Lewy body disease (DLB). However, it is not well understood whether and how abnormal accumulation of α-syn leads to cognitive impairment or dementia in PD and DLB. Furthermore, it is not known whether targeted removal of α-syn pathology can reverse cognitive decline. Here we find that the distribution of α-syn pathology in an inducible α-syn transgenic mouse model recapitulates that in human DLB. Abnormal accumulation of α-syn in the limbic system, particularly in the hippocampus, correlated with memory impairment and lead to structural synaptic deficits. Furthermore, when α-syn expression was suppressed, we observed partial clearing of pre-existing α-syn pathology and reversal of structural synaptic defects, resulting in an improvement in memory function.

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Section: Resultsmentioning

confidence: 99%

-Syn Suppression Reverses Synaptic and Memory Defects in a Mouse Model of Dementia with Lewy Bodies

Lim

Kehm

Lee

et al. 2011

Journal of Neuroscience

108

117

View full text Add to dashboard Cite

show abstract

“…It has been difficult yet highly desirable to sub-type disorders within the broad spectrum of PD early on to foretell differences and provide specific neuroprotective treatments. By now we know that how the disease progresses and how it affects the individual largely depends on where the disease begins [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48]. Thus early formations of LB in the neocortex lead to dementia with marked cognitive/memory impairments [49].…”

Section: Metricsmentioning

confidence: 99%

Spatial-Orientation Priming Impedes Rather than Facilitates the Spontaneous Control of Hand-Retraction Speeds in Patients with Parkinson’s Disease

et al. 2013

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BackgroundOften in Parkinson’s disease (PD) motor-related problems overshadow latent non-motor deficits as it is difficult to dissociate one from the other with commonly used observational inventories. Here we ask if the variability patterns of hand speed and acceleration would be revealing of deficits in spatial-orientation related decisions as patients performed a familiar reach-to-grasp task. To this end we use spatial-orientation priming which normally facilitates motor-program selection and asked whether in PD spatial-orientation priming helps or hinders performance.MethodsTo dissociate spatial-orientation- and motor-related deficits participants performed two versions of the task. The biomechanical version (DEFAULT) required the same postural- and hand-paths as the orientation-priming version (primed-UP). Any differences in the patients here could not be due to motor issues as the tasks were biomechanically identical. The other priming version (primed-DOWN) however required additional spatial and postural processing. We assessed in all three cases both the forward segment deliberately aimed towards the spatial-target and the retracting segment, spontaneously bringing the hand to rest without an instructed goal.Results and ConclusionsWe found that forward and retracting segments belonged in two different statistical classes according to the fluctuations of speed and acceleration maxima. Further inspection revealed conservation of the forward (voluntary) control of speed but in PD a discontinuity of this control emerged during the uninstructed retractions which was absent in NC. Two PD groups self-emerged: one group in which priming always affected the retractions and the other in which only the more challenging primed-DOWN condition was affected. These PD-groups self-formed according to the speed variability patterns, which systematically changed along a gradient that depended on the priming, thus dissociating motor from spatial-orientation issues. Priming did not facilitate the motor task in PD but it did reveal a breakdown in the spatial-orientation decision that was independent of the motor-postural path.

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“…PD patients frequently develop cognitive impairments after the onset of motor symptoms, but in some PD patients, cognitive impairments and dementia may precede movement abnormalities. Depending on the timing of the motor or cognitive impairments, patients may be assigned with a clinical diagnosis of Parkinson’s disease with dementia (PDD), or dementia with Lewy bodies (DLB) (Goldmann et al, 2008;Lippa et al, 2007). Despite clinical differences between PDD and DLB, growing evidence supports the view that they may represent a spectrum of the same disease, which is linked to pathological accumulations of alpha-synuclein (α–syn) primarily in neurons as Lewy bodies (LBs) or in their processes as Lewy neurites (LNs) (Aarsland et al, 2009;Goldmann et al, 2008;Lippa et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Forebrain overexpression of α-synuclein leads to early postnatal hippocampal neuron loss and synaptic disruption

Lim

Kehm

et al. 2010

Experimental Neurology

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Transgenic (Tg) mouse models of Parkinson's disease (PD) generated to date have primarily been designed to overexpress human alpha-synuclein (α-syn) to recapitulate PD-like motor impairments as well as PD-like nigro-striatal degeneration and α-syn pathology. However, cognitive impairments and cortical α-syn pathology also are common in PD patients. To model these features of PD, we created forebrain-specific conditional Tg mice that overexpress human wild type (WT) or A53T mutant α-syn. Here we show that both WT and A53T mutant α-syn lead to massive degeneration of postmitotic neurons in the hippocampal dentate gyrus (DG) during postnatal development, with hippocampal synapse loss as evidenced by reduced levels of pre-and postsynaptic markers. However, when mutant and WT α-syn expression was repressed until the Tg mice were mature postnatally and then induced for several months, no hippocampal neuron loss was observed. These data imply that developing neurons are more vulnerable to degenerate than mature neurons as a consequence of forebrain WT and mutant α-syn overexpression.

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Cognitive Impairment in Parkinson’s Disease and Dementia with Lewy Bodies: A Spectrum of Disease

Cited by 43 publications

References 70 publications

-Syn Suppression Reverses Synaptic and Memory Defects in a Mouse Model of Dementia with Lewy Bodies

-Syn Suppression Reverses Synaptic and Memory Defects in a Mouse Model of Dementia with Lewy Bodies

Spatial-Orientation Priming Impedes Rather than Facilitates the Spontaneous Control of Hand-Retraction Speeds in Patients with Parkinson’s Disease

Forebrain overexpression of α-synuclein leads to early postnatal hippocampal neuron loss and synaptic disruption

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