Cerebrospinal fluid amyloid-  and phenotypic heterogeneity in de novo Parkinson's disease

Alves, Guido; Pedersen, Kenn Freddy; Bloem, Bastiaan R.; Blennow, Kaj; Zetterberg, Henrik; Borm, George F.; Dalaker, Turi O.; Beyer, Mona K.; Aarsland, Dag; Andréasson, Ulf; Lange, Johannes; Tysnes, Ole‐Bjørn; Zivadinov, Robert; Larsen, Jan Petter

doi:10.1136/jnnp-2012-303808

Cited by 56 publications

(41 citation statements)

References 45 publications

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“…Several studies have classified newly diagnosed/ untreated PD patients, or relatively mildly affected [32] into subtypes demonstrating heterogeneity in early PD [2,29,36]. This may work for ''early patients'', however, our findings indicate that categorization may be distorted in the more advanced stages of the disease.…”

Section: Considerations In Regards To Classification Into Pigd and Tdcontrasting

confidence: 59%

Gait and balance in Parkinson’s disease subtypes: objective measures and classification considerations

et al. 2014

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Parkinson's disease (PD) is often divided into tremor dominant (TD) and postural instability gait difficulty (PIGD) subtypes. However, objective measures of gait (e.g., stride length, variability) and balance have not been well studied in these subtypes. To better understand these motor subtypes, we objectively quantified gait and balance and their behavioral correlates. 110 patients with PD underwent a clinical evaluation and were stratified into PIGD and TD subtypes. Participants walked under single and dual task conditions while wearing a single body-fixed sensor, both "OFF" and "ON" medications and at home for 3 days. We also examined performance-based tests of mobility, balance, and fall risk. Stricter criteria were also applied, dividing the subjects into predominant representative subgroups: p-PIGD and p-TD. Both the PIGD (n = 62) and TD (n = 42) groups and the p-PIGD (n = 31) and p-TD (n = 32) subgroups were similar with respect to basic disease characteristics (e.g., disease duration, p > 0.69). Surprisingly gait speed, stride length, and variability did not differ between the PIGD and TD groups (p > 0.05). In contrast, the p-PIGD group had reduced gait speed (under single and dual task conditions), shorter strides, increased stride variability, and decreased stride regularity (regularity: p-PIGD 0.66 ± 0.10; p-TD 0.74 ± 0.08; p = 0.003). The p-PIGD group also scored worse on performance-based tests, compared to the p-TD. Clinical assessments of the disturbances seen in patients with the PIGD subtype are not consistent with objective measures; overlapping between the groups is seen in many objective features of gait and balance. These findings suggest that the proposed alternate classification scheme may be useful.

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Section: Considerations In Regards To Classification Into Pigd and Tdcontrasting

confidence: 59%

Gait and balance in Parkinson’s disease subtypes: objective measures and classification considerations

et al. 2014

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“…Our findings broadly concur with previous cross-sectional reports showing a relationship with amyloid (from CSF and PET imaging) and motor disturbance especially in the PIGD phenotype in early and advanced PD. 10,11,30 However, importantly, our findings highlight limitations of previous work and argue for a more selective investigation of gait impairment.…”

Section: Postural Controlmentioning

confidence: 37%

“…Crosssectional studies in early and advanced PD show an association between CSF biomarkers and postural instability and gait (PIGD) phenotype. 10,11 However, lack of quantitative gait analysisFrom the Institute of Neuroscience …”

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confidence: 99%

“…CSF biomarkers were selected for analysis on the basis of previous reports. 10,11 Dopa-resistant gait impairments were identified as follows: first, change per year for all (16) gait characteristics derived from single and dual task testing was assessed with a linear mixed-effects model (lme4 package, R statistical software version 3.2.2, Vienna, Austria). 28,29 Participants and time (from baseline assessment to subsequent testing sessions) were included as random effects and age at baseline and sex as fixed effects.…”

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confidence: 99%

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Decrease in Aβ42 predicts dopa-resistant gait progression in early Parkinson disease

et al. 2017

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Objective: This prospective observational study investigates the role of CSF biomarkers in predicting progression of dopa-resistant gait impairments in Parkinson disease (PD) in the first 36 months from diagnosis.Methods: Quantitative gait analysis was carried out longitudinally using an instrumented walkway (GAITRite) in 108 people with PD and 130 age-matched controls. A subgroup of 44 people with PD underwent lumbar puncture from which a battery of CSF biomarkers was measured: b-amyloid 1-42 and 1-40 (Ab42 and Ab40), total and phosphorylated tau protein (t-tau/p-tau 181 ), and a-synuclein (aSyn). Linear mixed models examined the association between CSF and doparesistant gait characteristics (defined as substantial progression despite optimal medication).Results: Low baseline CSF Ab42, and to a lesser extend Ab40, predicted decline in gait characteristics in the first 3 years following diagnosis, independently explaining up to 12% of progression of step time variability (single task) and step length variability (dual-task). Interestingly, these findings were independent of age and cognition.Conclusions: These findings implicate underlying amyloid pathology in neural networks involved in locomotor control. Results suggest that disturbed Ab metabolism may be a biomarker for doparesistant gait impairments in early PD. Our findings raise interesting questions regarding therapeutic interventions such as compounds or molecules aimed at reducing amyloid burden to mitigate gait disturbance in early PD and potentially falls risk. Finally, progression of discrete gait characteristics suggests they may have potential as clinical biomarkers of pathology and disease progression. Parkinson disease (PD) is a common neurodegenerative disorder, second to Alzheimer disease. 1Gait impairments are significant in very early disease, and even at this stage dominate as risk factors for falls.2 While some aspects of gait are well-controlled by dopaminergic therapies in the early stages, resistance to levodopa makes clinical management challenging.Recent work highlights the significant contribution of cholinergic disturbance to gait, 3,4 and recent trials targeting the cholinergic system have met with moderate success.5 CSF proteins (e. g., b-amyloid [Ab] 40 and Ab42; total and p-tau 181 ), traditionally biomarkers of dementia and dementia risk, 6-9 have also been implicated in motor impairment, highlighting a role for pathologic protein accumulation other than Lewy body and PD-specific a-synuclein (aSyn). Crosssectional studies in early and advanced PD show an association between CSF biomarkers and postural instability and gait (PIGD) phenotype. 10,11 However, lack of quantitative gait analysisFrom the Institute of Neuroscience

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“…CSF amyloid beta peptides are altered from the early phases of PD, 68,69 especially in patients with dementia. 70 Regarding α-syn, the majority of recent studies have shown decreased CSF levels in PD patients, as compared to controls, although this marker apparently cannot distinguish among different synucleopathies.…”

Section: Csf Biomarkersmentioning

confidence: 99%

Biomarkers of Parkinson's disease: recent insights, current challenges, and future prospects

Picillo¹,

Moccia²,

Spina³

et al. 2016

JPRLS

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Cerebrospinal fluid amyloid- and phenotypic heterogeneity in de novo Parkinson's disease

Cited by 56 publications

References 45 publications

Gait and balance in Parkinson’s disease subtypes: objective measures and classification considerations

Gait and balance in Parkinson’s disease subtypes: objective measures and classification considerations

Decrease in Aβ42 predicts dopa-resistant gait progression in early Parkinson disease

Biomarkers of Parkinson's disease: recent insights, current challenges, and future prospects

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Cerebrospinal fluid amyloid- and phenotypic heterogeneity in de novo Parkinson's disease

Cited by 56 publications

References 45 publications

Gait and balance in Parkinson’s disease subtypes: objective measures and classification considerations

Gait and balance in Parkinson’s disease subtypes: objective measures and classification considerations

Decrease in Aβ42 predicts dopa-resistant gait progression in early Parkinson disease

Biomarkers of Parkinson&#39;s disease: recent insights, current challenges, and future prospects

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Biomarkers of Parkinson's disease: recent insights, current challenges, and future prospects