Gait speed in Parkinson disease correlates with cholinergic degeneration. Neurology
ABSTRACT We investigated dopaminergic and cholinergic correlates of gait speed in Parkinson disease (PD) and non-PD control subjects to test the hypothesis that gait dysfunction in PD may result from multisystem degeneration.
This was a cross-sectional study. Subjects with PD but without dementia (n = 125, age 65.6 ± 7.3 years) and elderly subjects without PD (n = 32, age 66.0 ± 10.6 years) underwent [(11)C]dihydrotetrabenazine dopaminergic and [(11)C]methyl-4-piperidinyl propionate acetylcholinesterase PET imaging, and cognitive and clinical testing, including an 8.5-m walk in the dopaminergic "off" state. The fifth percentile of cortical cholinergic activity in the elderly without PD was used to define normal-range activity in the subjects with PD.
Normal-range cortical cholinergic activity was present in 87 subjects with PD (69.6%). Analysis of covariance using gait speed as the dependent variable demonstrated a significant model (F = 6.70, p < 0.0001) with a significant group effect (F = 3.36, p = 0.037) and significant slower gait speed in the low cholinergic PD subgroup (0.97 ± 0.22 m/s) with no significant difference between the normal-range cholinergic PD subgroup (1.12 ± 0.20 m/s) and control subjects (1.17 ± 0.18 m/s). Covariate effects were significant for cognition (F = 6.58, p = 0.011), but not for striatal dopaminergic innervation, sex, or age.
Comorbid cortical cholinergic denervation is a more robust marker of slowing of gait in PD than nigrostriatal denervation alone. Gait speed is not significantly slower than normal in subjects with PD with relatively isolated nigrostriatal denervation.
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- "If these cortices were to lack cholinergic input such compensatory recruitment would remain largely ineffective. The recent finding that slow gait speed in PD patients is correlated with comorbid cholinergic cell loss, but is not affected in patients with relatively isolated dopamine loss (Bohnen et al., 2013) is also consistent with the hypothesis that cholinergic cell loss unmasks the low-vigor gait resulting from striatal dopamine loss (Mazzoni et al., 2007; Niv et al., 2007). Partial striatal dopamine loss alone did not result in impairments in MCMCT performance, suggesting that compensatory attentional mechanisms contributed to the prevention of falls in these animals. "
ABSTRACT: Falls are a major source of hospitalization, long-term institutionalization, and death in older adults and patients with Parkinson's Disease (PD). Limited attentional resources are a major risk factor for falls. In this review, we specify cognitive-behavioral mechanisms that produce falls and map these mechanisms onto a model of multi-system degeneration. Results from PET studies in PD fallers and findings from a recently developed animal model support the hypothesis that falls result from interactions between loss of basal forebrain cholinergic projections to the cortex and striatal dopamine loss. Striatal dopamine loss produces inefficient, low-vigor gait, posture control, and movement. Cortical cholinergic deafferentation impairs a wide range of attentional processes, including monitoring of gait, posture and complex movements. Cholinergic cell loss reveals the full impact of striatal dopamine loss on motor performance, reflecting loss of compensatory attentional supervision of movement. Dysregulation of dorsomedial striatal circuitry is an essential, albeit not exclusive, mediator of falls in this dual-system model. Because cholinergic neuromodulatory activity influences cortical circuitry primarily via stimulation of α4β2* nicotinic acetylcholine receptors, and because agonists at these receptors are known to benefit attentional processes in animals and humans, treating PD fallers with such agonists, as an adjunct to dopaminergic treatment, is predicted to reduce falls. Falls are an informative behavioral endpoint to study attentional-motor integration by striatal circuitry.Experimental Neurology 05/2014; 257. DOI:10.1016/j.expneurol.2014.04.032 · 4.62 Impact Factor
Article: Parkinson Disease Subtypes[Show abstract] [Hide abstract]
ABSTRACT: IMPORTANCE It is increasingly evident that Parkinson disease (PD) is not a single entity but rather a heterogeneous neurodegenerative disorder. OBJECTIVE To evaluate available evidence, based on findings from clinical, imaging, genetic and pathologic studies, supporting the differentiation of PD into subtypes. EVIDENCE REVIEW We performed a systematic review of articles cited in PubMed between 1980 and 2013 using the following search terms: Parkinson disease, parkinsonism, tremor, postural instability and gait difficulty, and Parkinson diseasesubtypes. The final reference list was generated on the basis of originality and relevance to the broad scope of this review. FINDINGS Several subtypes, such as tremor-dominant PD and postural instability gait difficulty form of PD, have been found to cluster together. Other subtypes also have been identified, but validation by subtype-specific biomarkers is still lacking. CONCLUSIONS AND RELEVANCE Several PD subtypes have been identified, but the pathogenic mechanisms underlying the observed clinicopathologic heterogeneity in PD are still not well understood. Further research into subtype-specific diagnostic and prognostic biomarkers may provide insights into mechanisms of neurodegeneration and improve epidemiologic and therapeutic clinical trial designs.02/2014; 71(4). DOI:10.1001/jamaneurol.2013.6233
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ABSTRACT: Idiopathic Parkinson disease (PD) is an α-synucleinopathy, one of several proteinopathies characterized by intracellular and extracellular accumulation of abnormal filament proteins.(1) Relentless progression of neuropathologic changes, consisting of α-synuclein-positive Lewy bodies and Lewy neurites, and widespread neuronal loss closely correlate with clinical worsening of motor and nonmotor PD symptoms. Typically, unilateral onset of tremor, rigidity, or bradykinesia, the cardinal motor features, is followed by contralateral spread of disease signs. The presence of midline problems, such as gait disorder and balance impairment, generally represents a more advanced phase of the disease, used as the central criteria in Hoehn & Yahr staging.Neurology 03/2014; 82(17). DOI:10.1212/WNL.0000000000000370 · 8.30 Impact Factor