[18F]FE-PE2I DAT correlates with Parkinson's disease duration, stage, and rigidity/bradykinesia scores: a PET radioligand validation study.

BACKGROUND: Correlations between dopamine transporter (DAT) availability and Parkinson's disease (PD) motor symptoms vary depending on the imaging modality, choice of regions of interest and clinical measures. We aimed to validate the PET radioligand [18F]FE-PE2I as a clinical biomarker in PD, hypothesizing negative correlations between DAT availability in specified nigrostriatal regions with symptom duration, disease stage and motor symptom scores. METHODS: We included 41 PD patients (age 45-79 years; H&Y stage < 3) and 37 healthy control subjects in a cross-sectional study with dynamic [18F]FE-PE2I PET. Binding potential (BPND) was estimated in the caudate nucleus, putamen, ventral striatum, sensorimotor striatum, and substantia nigra using the cerebellum as reference region. RESULTS: We found negative correlations (p < 0.02) between symptom duration and BPND in the putamen and sensorimotor striatum (rs = - .42; rs = - .51), and between H&Y stage and BPND in caudate nucleus, putamen, sensorimotor striatum, and substantia nigra (rs between - .40 and - .54). The first correlations were better described with exponential fitting. MDS-UPDRS-III in 'OFF' state correlated negatively (p < 0.04) with BPND in the sensorimotor striatum (rs = - .47), and excluding tremor score also in the putamen (rs = - .45). CONCLUSION: Results are in agreement with earlier findings in in vivo and post-mortem studies and validate [18F]FE-PE2I as a functional PD biomarker for PD severity. TRIAL REGISTRATION: EudraCT 2011-0020050, Registered April 26 2011; EudraCT 2017-003327-29, Registered October 08 2017; EudraCT 2017-001585-19, Registered August 2 2017. https://eudract.ema.europa.eu/ .

On the physiology of cognitive decline in type 1 diabetes.

OBJECTIVES: Type 1 diabetes mellitus (T1DM) may be associated with cognitive impairment and notably a decline in psychomotor speed, information processing speed and attention. The mechanism for this decline is uncertain. Previous studies by our group and others have demonstrated a decline in EEG-power and event-related potential amplitude in T1DM. The objectives of the present study were to explore whether 1) the association between event-related potential (N100) amplitude and psychomotor speed is different between T1DM and healthy subjects, and 2) the decline in N100 amplitude depends on duration of diabetes. METHODS: Patients with T1DM (N = 204) and healthy control subjects (N = 358) were included in a cross-sectional study. Event-related brain potentials were recorded with auditory reaction tasks. Psychomotor speed was evaluated with the Grooved Pegboard test in a subset of the patients (N = 70) and the healthy control subjects (N = 89). RESULTS: Patients with T1DM had a decrease in the N100 amplitude that correlated with a decline in psychomotor speed, longer duration of diabetes and increasing age. In healthy controls, the N100 amplitude did not decrease with age and the association between psychomotor speed and N100 amplitude was absent. CONCLUSION: The association between psychomotor speed and N100 amplitude is likely to be a specific trait for T1DM since it was not found in healthy controls and was dependent on diabetes duration. Our findings indicate that the pathogenesis of cognitive decline in T1DM may involve a disease-related factor with a long-term influence on the N100 amplitude.

Does Information from the Parkinson KinetiGraph™ (PKG) Influence the Neurologist's Treatment Decisions?-An Observational Study in Routine Clinical Care of People with Parkinson's Disease.

Management of Parkinson's disease traditionally relies solely on clinical assessment. The PKG objectively measures affected persons' movements in daily life. The present study evaluated how often PKG data changed treatment decisions in routine clinical care and to what extent the clinical assessment and the PKG interpretation differed. PKG recordings were performed before routine visits. The neurologist first made a clinical assessment without reviewing the PKG. Signs and symptoms were recorded, and a treatment plan was documented. Afterward, the PKG was evaluated. Then, the neurologist decided whether to change the initial treatment plan or not. PKG review resulted in a change in the initial treatment plan in 21 of 66 participants (31.8%). The clinical assessment and the PKG review differed frequently, mainly regarding individual overall presence of motor problems (67%), profile of bradykinesia/wearing off (79%), dyskinesia (35%) and sleep (55%). PKG improved the dialogue with the participant in 88% of cases. PKG and clinical variables were stable when they were repeated after 3-6 months. In conclusion, PKG information changes treatment decisions in nearly a third of people with Parkinson's disease in routine care. Standard clinical assessment and PKG evaluation are often non-identical. Objective measurements in people living with Parkinson's disease can add therapeutically relevant information.

Simplified quantification of [18F]FE-PE2I PET in Parkinson's disease: Discriminative power, test-retest reliability and longitudinal validity during early peak and late pseudo-equilibrium.

Quantification of dopamine transporter (DAT) availability with [18F]FE-PE2I PET enables the detection of presynaptic dopamine deficiency and provides a potential progression marker for Parkinson`s disease (PD). Simplified quantification is feasible, but the time window of short acquisition protocols may have a substantial impact on the reliability of striatal binding estimates. Dynamic [18F]FE-PE2I PET data of cross-sectional (33 PD patients, 24 controls), test-retest (9 patients), and longitudinal (12 patients) cohorts were used to assess the variability and reliability of specific binding ratios (SBR) measured during early peak and late pseudo-equilibrium. Receiver operating characteristics area under the curve (PD vs. controls) was high for early (0.996) and late (0.991) SBR. Early SBR provided more favourable effect size, absolute variability, and standard error of measurement than late SBR (caudate: 1.29 vs. 1.23; 6.9% vs. 9.8%; 0.09 vs. 0.20; putamen: 1.75 vs. 1.67; 7.7% vs. 14.0%; 0.08 vs. 0.17). The annual percentage change was comparable for both time windows (-7.2%-8.5%), but decline was significant only for early SBR. Whereas early and late [18F]FE-PE2I PET acquisitions have similar discriminative power to separate PD patients and controls, the early peak equilibrium acquisition can be recommended if [18F]FE-PE2I is used to measure longitudinal changes of DAT availability.

Mechanism of visual network dysfunction in relapsing-remitting multiple sclerosis and its relation to cognition.

OBJECTIVE: To investigate if changes in brain network function and connectivity contribute to the abnormalities in visual event related potentials (ERP) in relapsing-remitting multiple sclerosis (RRMS), and explore their relation to a decrease in cognitive performance. METHODS: We evaluated 72 patients with RRMS and 89 healthy control subjects in a cross-sectional study. Visual ERP were generated using illusory and non-illusory stimuli and recorded using 21 EEG scalp electrodes. The measured activity was modelled using Dynamic Causal Modelling. The model network consisted of 4 symmetric nodes including the primary visual cortex (V1/V2) and the Lateral Occipital Complex. Patients and controls were tested with a neuropsychological test battery consisting of 18 cognitive tests covering six cognitive domains. RESULTS: We found reduced cortical connectivity in bottom-up and interhemispheric connections to the right lateral occipital complex in patients (p < 0.001). Furthermore, interhemispherical connections were related to cognitive dysfunction in several domains (attention, executive function, visual perception and organization, processing speed and global cognition) for patients (p < 0.05). No relation was seen between cortical network connectivity and cognitive function in the healthy control subjects. CONCLUSION: Changes in the functional connectivity to higher cortical regions provide a neurobiological explanation for the changes of the visual ERP in RRMS. SIGNIFICANCE: This study suggests that changes in connectivity to higher cortical regions partly explain visual network dysfunction in RRMS where a lower interhemispheric connectivity may contribute to impaired cognitive function.

Reliability of dopamine transporter PET measurements with [18F]FE-PE2I in patients with Parkinson's disease.

BACKGROUND: Reliable quantification of dopamine transporter (DAT), a biomarker for Parkinson's disease (PD), is essential for diagnostic purposes as well as for evaluation of potential disease-modifying treatment. Due to degeneration of dopaminergic neurons and thus lower expected radioligand binding to DAT, higher measurement variability in PD patients might be expected than earlier reproducibility results in healthy controls. Therefore, we aimed to examine the test-retest properties of [18F]FE-PE2I-PET in PD patients. METHODS: Nine patients with PD (Hoehn and Yahr stage < 3) were included (men/women 6/3; mean age 65.2 ± 6.8 years). Each patient underwent two [18F]FE-PE2I-PET measurements within 7-28 days. The outcome measure was non-displaceable binding potential generated using wavelet-aided parametric imaging with cerebellum as reference region. We assessed test-retest performance using estimates of reliability and repeatability. Regions for primary analysis were caudate, putamen, ventral striatum, and substantia nigra. Exploratory analysis was performed for functional subdivisions of the striatum. We also compared the more vs. less affected side. RESULTS: [18F]FE-PE2I showed absolute variability estimates of 5.3-7.6% in striatal regions and 11% in substantia nigra and ICCs of 0.74-0.97 (median 0.91). The absolute variability for functional striatal subdivisions was 6.0-9.6% and ICCs of 0.76-0.91 (median 0.91). The less affected substantia nigra exhibited greater consistency than the more affected side. According to power calculations based on the current sample size, DAT changes of 5-11% in the striatum and 28% in the substantia nigra can be detected with a power of 0.8 (p < 0.0125). CONCLUSION: DAT-PET measurements with [18F]FE-PE2I in PD patients showed good repeatability and reliability. The slightly lower reliability in the substantia nigra in patients may be explained by lower DAT density and smaller anatomical size. Power calculations suggest that [18F]FE-PE2I PET is a suitable marker for longitudinal DAT decline in PD. TRIAL REGISTRATION: EudraCT 2017-003327-29.

Event related potential and response time give evidence for a physiological reserve in cognitive functioning in relapsing-remitting multiple sclerosis.

Cognitive dysfunction is common in multiple sclerosis (MS). Different factors may moderate the degree of cognitive deficit. The aim of the present study was to distinguish different mechanisms for cognitive reserve in relapsing-remitting MS (RRMS). The effects of clinical variables (physical disability, depression), premorbid intelligence (years of education, vocabulary knowledge), visual event-related potential measures (P300) and response time (RT) were studied in RRMS patients (n=71) and healthy subjects (n=89). Patients with high P300 amplitude and short RT had better cognitive performance. This effect was significantly weaker in controls. High P300 and short RT may be physiological markers of a cognitive reserve in RRMS. In contrast, the association between cognitive scores and premorbid intelligence was similar in patients and in control subjects. The effects of physiological reserve and clinical variables were studied in a hierarchical linear regression model of cognitive performance in RRMS. P300 amplitude and RT explained a considerable amount of variance in global cognitive performance (34%, p<0.001). The effects of P300 and RT were not moderated by premorbid intelligence. Physical disability and depression added significantly to explained variance, and the final model accounted for 44% (p<0.001) of the variation. We conclude that physiological reserve is the strongest moderator of cognitive impairment in RRMS.

P300 amplitude and response speed relate to preserved cognitive function in relapsing-remitting multiple sclerosis.

OBJECTIVE: To explore if cognitive impairment in relapsing-remitting multiple sclerosis (RRMS) is associated with abnormal neural function and if there is evidence of neural compensatory mechanisms. METHODS: Seventy-two RRMS patients and 89 healthy control subjects were included in a cross-sectional study. Event-related brain potential (P300) and response time (RT) were recorded with visual and auditory choice reaction tasks. Cognitive function was evaluated with an 18 item test battery. RESULTS: Patients had a decrease in cognitive function (p<0.001 for global score) and increased visual P300 amplitude frontally. P300 amplitude was normal in other brain areas and RT was normal. P300 latency was normal except for an increase in auditory latency occipitally. Cognitive performance correlated positively with parietal P300 amplitude in patients but not in controls. Cognition had stronger correlation (negative) with RT in patients than in controls. CONCLUSIONS: Patients with low P300 amplitude and long RT were more often cognitively impaired. This indicates that general factors such as signal amplitude and speed are limiting for cognitive function in RRMS patients. The increase in frontal P300 amplitude may be a compensatory effect. SIGNIFICANCE: Our findings suggest that high amplitude and fast speed may be protective against cognitive impairment.

Cognitive impairment has a strong relation to nonsomatic symptoms of depression in relapsing-remitting multiple sclerosis.

It is unclear how cognitive impairment in multiple sclerosis (MS) is influenced by physical disability, fatigue, and depression. Our aim was to identify the strongest clinical predictors for cognitive impairment in relapsing-remitting MS (RRMS) patients. The clinical risk factors included in the analysis were physical disability (EDSS), fatigue (FSS), the somatic and nonsomatic components of depression (BDI), disease progression rate [Multiple Sclerosis Severity Score (MSSS)], and psychotropic medication. Cognitive impairment had a prevalence of 30.5% in patients affecting preferentially attention, executive functions, processing speed and visual perception/organization. MSSS was not associated with cognitive impairment, depression, or fatigue. In regression models, cognitive performance was best predicted by the nonsomatic symptoms of depression alone or in combination with physical disability. Exclusion of patients with any psychotropic medication did not influence the results. Our results underscore the importance of evaluating depressive symptoms when suspecting cognitive impairment in patients with RRMS.