Impaired synaptic function is linked to cognition in Parkinson's disease.

OBJECTIVE: Cognitive impairment is frequent in Parkinson's disease, but the underlying mechanisms are insufficiently understood. Because cortical metabolism is reduced in Parkinson's disease and closely associated with cognitive impairment, and CSF amyloid-ß species are reduced and correlate with neuropsychological performance in Parkinson's disease, and amyloid-ß release to interstitial fluid may be related to synaptic activity; we hypothesize that synapse dysfunction links cortical hypometabolism, reduced CSF amyloid-ß, and presynaptic deposits of α-synuclein. We expect a correlation between hypometabolism, CSF amyloid-ß, and the synapse related-markers CSF neurogranin and α-synuclein. METHODS: Thirty patients with mild-to-moderate Parkinson's disease and 26 healthy controls underwent a clinical assessment, lumbar puncture, MRI, 18F-fludeoxyglucose-PET, and a neuropsychological test battery (repeated for the patients after 2 years). RESULTS: All subjects had CSF amyloid-ß 1-42 within normal range. In Parkinson's disease, we found strong significant correlations between cortical glucose metabolism, CSF Aß, α-synuclein, and neurogranin. All PET CSF biomarker-based cortical clusters correlated strongly with cognitive parameters. CSF neurogranin levels were significantly lower in mild-to-moderate Parkinson's disease compared to controls, correlated with amyloid-ß and α-synuclein, and with motor stage. There was little change in cognition after 2 years, but the cognitive tests that were significantly different, were also significantly associated with cortical metabolism. No such correlations were found in the control group. INTERPRETATION: CSF Aß, α-synuclein, and neurogranin concentrations are related to cortical metabolism and cognitive decline. Synaptic dysfunction due to Aß and α-synuclein dysmetabolism may be central in the evolution of cognitive impairment in Parkinson's disease.

Detecting At-Risk Alzheimer's Disease Cases.

While APOEɛ4 is the major genetic risk factor for Alzheimer's disease (AD), amyloid dysmetabolism is an initial or early event predicting clinical disease and is an important focus for secondary intervention trials. To improve identification of cases with increased AD risk, we evaluated recruitment procedures using pathological CSF concentrations of Aß42 (pAß) and APOEɛ4 as risk markers in a multi-center study in Norway. In total, 490 subjects aged 40-80 y were included after response to advertisements and media coverage or memory clinics referrals. Controls (n = 164) were classified as normal controls without first-degree relatives with dementia (NC), normal controls with first-degree relatives with dementia (NCFD), or controls scoring below norms on cognitive screening. Patients (n = 301) were classified as subjective cognitive decline or mild cognitive impairment. Subjects underwent a clinical and cognitive examination and MRI according to standardized protocols. Core biomarkers in CSF from 411 and APOE genotype from 445 subjects were obtained. Cases (both self-referrals (n = 180) and memory clinics referrals (n = 87)) had increased fractions of pAß and APOEɛ4 frequency compared to NC. Also, NCFD had higher APOEɛ4 frequencies without increased fraction of pAß compared to NC, and cases recruited from memory clinics had higher fractions of pAß and APOEɛ4 frequency than self-referred. This study shows that memory clinic referrals are pAß enriched, whereas self-referred and NCFD cases more frequently are pAß negative but at risk (APOEɛ4 positive), suitable for primary intervention.

Neuropsychological Profiles in Mild Cognitive Impairment due to Alzheimer's and Parkinson's Diseases.

BACKGROUND: Neuropsychological comparisons between patients with mild cognitive impairment due to Parkinson's disease (MCI-PD) and Alzheimer's disease (MCI-AD) is mostly based on indirect comparison of patients with these disorders and normal controls (NC). OBJECTIVE: The focus of this study was to make a direct comparison between patients with these diseases. METHODS: The study compared 13 patients with MCI-PD and 19 patients with MCI-AD with similar age, education and gender. The participants were recruited and assessed at the same university clinic with equal methods. RESULTS: The main finding was that on group level, MCI-AD scored significantly poorer on learning and memory tests than MCI-PD, whereas MCI-PD were impaired on 1 of 3 measures of executive functioning. CONCLUSION: MCI-AD performed poorer learning and memory tests, whereas MCI-PD only scored below the employed cut-off on one single executive test. In general, MCI-PD was noticeably less cognitively impaired than MCI-AD.

Hippocampal subfield atrophy in relation to cerebrospinal fluid biomarkers and cognition in early Parkinson's disease: a cross-sectional study.

Cognition is often affected early in Parkinson's disease (PD). Lewy body and amyloid ß (Aß) pathology and cortical atrophy may be involved. The aim of this study was to examine whether medial temporal lobe structural changes may be linked to cerebrospinal fluid (CSF) biomarker levels and cognition in early PD. PD patients had smaller volumes of total hippocampus, presubiculum, subiculum, CA2-3, CA4-DG, and hippocampal tail compared with normal controls (NCs). In the PD group, lower CSF Aß38 and 42 were significant predictors for thinner perirhinal cortex. Lower Aß42 and smaller presubiculum and subiculum predicted poorer verbal learning and delayed verbal recall. Smaller total hippocampus, presubiculum and subiculum predicted poorer visuospatial copying. Lower Aß38 and 40 and thinner perirhinal cortex predicted poorer delayed visual reproduction. In conclusion, smaller volumes of hippocampal subfields and subhippocampal cortex thickness linked to lower CSF Aß levels may contribute to cognitive impairment in early PD. Thirty-three early PD patients (13 without, 5 with subjective, and 15 with mild cognitive impairment) and NC had 3 T magnetic resonance imaging (MRI) scans. The MRI scans were post processed for volumes of hippocampal subfields and entorhinal and perirhinal cortical thickness. Lumbar puncture for CSF biomarkers Aß38, 40, 42, total tau, phosphorylated tau (Innogenetics), and total α-synuclein (Meso Scale Diagnostics) were performed. Multiple regression analyses were used for between-group comparisons of the MRI measurements in the NC and PD groups and for assessment of CSF biomarkers and neuropsychological tests in relation to morphometry in the PD group.

Amyloid-ß and α-synuclein cerebrospinal fluid biomarkers and cognition in early Parkinson's disease.

INTRODUCTION: Cognitive impairment in early Parkinson's disease (PD) is common and distinct from early Alzheimer's disease. Predictors and mechanisms are only partially known, but α-synuclein, amyloid-ß and tau dysmetabolism may be involved. Our aim was to study associations between cerebrospinal fluid biomarkers (CSF) and cognition in non-dementia PD compared to normal controls (NC) and non-PD patients with mild cognitive impairment (MCI non-PD). METHODS: Patients were classified as having normal, subjective or mild cognitive impairment after cognitive screening. CSF levels of total α-synuclein (t-α-syn), amyloid-ß (Aß) 38, 40 and 42, total tau (T-tau) and phosphorylated tau (P-tau) were measured in 34 NC, 31 early, non-dementia PD and 28 MCI non-PD patients. A well validated neuropsychological test battery was administered. RESULTS: In the PD group, 13 had normal cognition, 4 had subjective and 14 mild cognitive impairment. PD patients had significantly lower CSF biomarker levels of t-α-syn, Aß38, 40 and 42, T-tau and P-tau compared to NC. Compared to MCI non-PD, t-α-syn, Aß38 and 40, T-tau and P-tau were also lower, while Aß42 was significantly higher in the PD group. Aß38 and 40 correlated strongly with t-α-syn levels in PD. Lower Aß42 was associated with decreased verbal learning, delayed verbal recall and response inhibition in PD. CONCLUSION: While Aß38, 40 and t-α-syn levels are strongly correlated, only lower Aß42 was associated with reduced cognitive functions in early PD, mainly connected to medial temporal lobe-based cognitive functions.