CSF Aβ1-42 predicts cognitive impairment in de novo PD patients

Transcription

1 CSF Aβ1-42 predicts cognitive impairment in de novo PD patients Mark Terrelonge MPH *1, Karen Marder MD MPH 1, Daniel Weintraub MD 2, Roy Alcalay MD MS 1 1 Columbia University Department of Neurology 2 University of Pennsylvania Department of Psychiatry Abstract Number 1219 *Nothing to disclose

2 Introduction Low CSF beta-amyloid is associated with higher rate of conversion from mild cognitive impairment to Alzheimer s disease (Shaw, 2009) Low CSF beta-amyloid predicts faster cognitive decline in more temporally advanced PD (Compta, 2013; Parnetti, 2013;Hall 2014) Data in early PD is available from one study (Alves, 2010; Alves,2014) Is there evidence of CSF correlate to early cognitive decline in PD?

3 Methods: PPMI Parkinson s Progression Markers Initiative 4 International, multi-center prospective study following 423 PD cases and 196 controls Baseline CSF profile Biannual Neurological and Cognitive Evaluations PD Cohort Inclusion Enrolled within 2 years of diagnosis Not expected to need PD medications within 6 months Exclusion Clinical diagnosis of dementia MRI evidence of another clinically significant neurologic disorder

4 Methods Data was acquired in January participants from the PPMI PD cohort (mean duration: 7.6 months) Baseline CSF proteins: β-amyloid 1-42 (Aβ 1-42) α-synuclein Total tau Phosphorylated tau 181 (P-tau 181 ) Cognitive impairment(ci): 2 out of 6 scores 1.5 SD below standardized mean of healthy controls Baseline CSF profile correlated with CI status at 2 years Beta-Amyloid Protein Logistic models adjusted for age, gender, education, Movement Disorder Society United Parkinson s Disease Rating Scale Part 3 motor score, and cognitive impairment at baseline.

5 Baseline characteristics Results No Cognitive Impairment at 2 years (N=223) Cognitive Impairment at 2 years (N=50) Those with CI at 2 years had significantly lower baseline CSF Aβ 1-42 than those without CI. No relationship between CSF α-synuclein, total tau, or P-tau 181 P-value CSF Aβ1-42 levels pg/ml <0.01 CSF Alpha-synuclein pg/ml CSF Total tau pg/ml CSF Phosphorylated tau -181 pg/ml Gender (% male) 64.6% 70.0% 0.47 Age (years) Education (years) MDS-UPDRS Part 3 Motor Score Geriatric Depression Scale Score Presence of Cognitive Impairment 11.7% 34.0% <0.01 at Baseline

6 Results Univariable analysis Multivariable analysis 1 CSF Markers OR 95% CI P value OR 95% CI P value Aβ pg/mL 1.05 (1.02,1.09) < (1.01, 1.09) 0.01 α-synuclein 10 pg/ml 1.00 (1.00, 1.01) (1.00, 1.01) 0.11 total tau 10pg/mL 0.96 (0.81,1.15) (0.84, 1.24) 0.81 p-tau pg/mL 1.17 (0.83,1.66) (0.81, 1.67) 0.41 Logistic regression model of all 273 patients Adjusted for age, gender, education, motor severity, and baseline CI status Lower baseline β-amyloid 1-42 levels were associated with higher odds of CI at two years.

7 Discussion CSF β-amyloid 1-42 level at disease onset is an independent predictor of CI in early PD Limitations: Inability to define MCI by Movement Disorder Society Task Force criteria (Litvan, 2012) CI may not be stable diagnosis (Han, 2012) Strengths: Large multicenter, international longitudinal study Consistent with prior studies on early PD CSF β-amyloid 1-42 (Alves, 2010)

8 Thanks PPMI & Michael J Fox Foundation Stanford Med Scholars Columbia Mailman Biostatistics Department Dr. Karen Marder and Dr. Dan Weintraub Dr. Roy Alcalay

9 References 1. Shaw et al. Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects. Ann Neurol Parnetti et al. Cerebrospinal fluid biomarkers in Parkinson disease. Nat Rev Neurol Alves et al. Abeta42 predicts early-onset dementia in Parkinson disease. Neurology Parkinson Progression Marker I. The Parkinson Progression Marker Initiative (PPMI). Prog Neurobiol Alves et al. CSF amyloid-beta and tau proteins, and cognitive performance, in early and untreated Parkinson's disease: the Norwegian ParkWest study. J Neurol Neurosurg Psychiatry Compta et al. Combined dementia-risk biomarkers in Parkinson's disease: a prospective longitudinal study. Parkinsonism Relat Disord Litvan et al. Diagnostic criteria for mild cognitive impairment in Parkinson's disease: Movement Disorder Society Task Force guidelines. Movement Disorders Han et al. Predictive validity and diagnostic stability of mild cognitive impairment subtypes. Alzheimers Dement 2012

10 Supplemental Slide: Neuro-psych Battery Hopkins Verbal Learning Test-Revised [HVLT-R] Recall HVLT-R Recognition Judgment of Line Orientation Letter Number Sequencing Semantic Fluency Symbol Digit Modalities Test

11 Supplemental Slide: Baseline Characteristics Baseline characteristics No Cognitive Impairment at 2 years (N=223) Cognitive Impairment at 2 years (N=50) P- value Gender (% male) 64.6% 70.0% 0.47 Age (years) Age at Disease Onset (years) Disease Duration (months) Education (years) Movement Disorders Society- United Parkinson s Disease Rating Scale Motor Score Geriatric Depression Scale Score Presence of Cognitive 11.7% 34.0% <0.01 Impairment at Baseline Self-reported Cognitive 28.25% 30.0% 0.80 changes at baseline on the Movement Disorders Society United Parkinson s Disease Rating Scale CSF Aβ1-42 levels pg/ml <0.01 CSF Alpha-synuclein pg/ml CSF Total tau pg/ml CSF Phosphorylated tau pg/ml CSF Alpha-synuclein/ Total tau CSF Total tau/ Aβ CSF Phosphorylated tau / Aβ1-42 CSF Phosphorylated tau- 181/ Total tau

12 Supplemental Slide: ATI Abeta/tau index= ATI ATI= Abeta 1-42/[ (Total Tau)] ATI < 1 ATI > 1 CI= Yes CI= No Chi-Squared= 0.03 Not significant as predictor of CI in multivariable models Decreases significant of Abeta-42 in multivariable model