George Petrides

Cerebral glucose metabolism and cognition in newly diagnosed Parkinson’s disease: ICICLE-PD study

Objective To assess reductions of cerebral glucose metabolism in Parkinsons disease (PD) with 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET), and their associations with cognitive decline. Methods FDG-PET was performed on a cohort of 79 patients with newly diagnosed PD (mean disease duration 8 months) and 20 unrelated controls. PD participants were scanned while on their usual dopaminergic medication. Cognitive testing was performed at baseline, and after 18 months using the Cognitive Drug Research (CDR) and Cambridge Neuropsychological Test Automated Battery (CANTAB) computerised batteries, the Mini-Mental State Examination (MMSE), and the Montreal Cognitive Assessment (MoCA). We used statistical parametric mapping (SPM V.12) software to compare groups and investigate voxelwise correlations between FDG metabolism and cognitive score at baseline. Linear regression was used to evaluate how levels of cortical FDG metabolism were predictive of subsequent cognitive decline rated with the MMSE and MoCA. Results PD participants showed reduced glucose metabolism in the occipital and inferior parietal lobes relative to controls. Low performance on memory-based tasks was associated with reduced FDG metabolism in posterior parietal and temporal regions, while attentional performance was associated with more frontal deficits. Baseline parietal to cerebellum FDG metabolism ratios predicted MMSE (β=0.38, p=0.001) and MoCA (β=0.3, p=0.002) at 18 months controlling for baseline score. Conclusions Reductions in cortical FDG metabolism were present in newly diagnosed PD, and correlated with performance on neuropsychological tests. A reduced baseline parietal metabolism is associated with risk of cognitive decline and may represent a potential biomarker for this state and the development of PD dementia.

Associations between COPD related manifestations: a cross-sectional study

BackgroundCardiovascular disease, osteoporosis and emphysema are associated with COPD. Associations between these factors and whether they predict all-cause mortality in COPD patients are not well understood. Therefore, we examined associations between markers of cardiovascular disease (coronary artery calcification [CAC], thoracic aortic calcification [TAC] and arterial stiffness), bone density (bone attenuation of the thoracic vertebrae), emphysema (PI-950 and 15th percentile) and all-cause mortality in a COPD cohort.MethodsWe assessed CAC, TAC, bone attenuation of the thoracic vertebrae, PI-950 and 15th percentile on low-dose chest computed tomography in COPD subjects. We measured arterial stiffness as carotid-radial pulse wave velocity (PWV), and identified deaths from the national register.ResultsWe studied 119 COPD subjects; aged 67.8 ±7.3, 66% were males and mean FEV1% predicted was 46.0 ±17.5. Subjects were classified into three pre-specificed groups: CAC = 0 (n = 14), 0 < CAC ≤ 400 (n = 41) and CAC > 400 (n = 64). Subjects with higher CAC were more likely to be older (p < 0.001) and male (p = 0.03), and more likely to have higher systolic blood pressure (p = 0.001) and a history of hypertension (p = 0.002) or ischemic heart disease (p = 0.003). Higher CAC was associated with higher PWV (OR 1.62, p = 0.04) and lower bone attenuation (OR 0.32, p = 0.02), but not with 15th percentile, after adjustment for age, sex and pack-years of smoking. In a Cox proportional hazards model, CAC, TAC and 15th percentile predicted all-cause mortality (HR 2.01, 2.09 and 0.66, respectively).ConclusionsIncreased CAC was associated with increased arterial stiffness and lower bone density in a COPD cohort. In addition, CAC, TAC and extent of emphysema predicted all-cause mortality.Trial registrationLothian NHS Board, Lothian Research Ethics Committee, LREC/2003/8/28.

Reduced cardiac volumes in chronic fatigue syndrome associate with plasma volume but not length of disease: a cohort study

Objectives To explore potential mechanisms that underpin the cardiac abnormalities seen in chronic fatigue syndrome (CFS) using non-invasive cardiac impedance, red cell mass and plasma volume measurements. Methods Cardiac MR (MR) examinations were performed using 3 T Philips Intera Achieva scanner (Best, NL) in participants with CFS (Fukuda; n=47) and matched case-by-case controls. Total volume (TV), red cell volume (RCV) and plasma volume (PV) measurements were performed (41 CFS and 10 controls) using the indicator dilution technique using simultaneous 51-chromium labelling of red blood cells and 125-iodine labelling of serum albumin. Results The CFS group length of history (mean±SD) was 14±10 years. Patients with CFS had significantly reduced end-systolic and end-diastolic volumes together with reduced end-diastolic wall masses (all p<0.0001). Mean±SD RCV was 1565±443 mL with 26/41 (63%) having values below 95% of expected. PV was 2659±529 mL with 13/41 (32%) <95% expected. There were strong positive correlations between TV, RCV and PV and cardiac end-diastolic wall mass (all p<0.0001; r2=0.5). Increasing fatigue severity correlated negatively with lower PV (p=0.04; r2=0.2). There were no relationships between any MR or volume measurements and length of history, suggesting that deconditioning was unlikely to be the cause of these abnormalities. Conclusions This study confirms an association between reduced cardiac volumes and blood volume in CFS. Lack of relationship between length of disease, cardiac and plasma volumes suggests findings are not secondary to deconditioning. The relationship between plasma volume and severity of fatigue symptoms suggests a potential therapeutic target in CFS.

Neuropsychiatric symptoms and cognitive profile in mild cognitive impairment with Lewy bodies

BACKGROUND The accurate clinical characterisation of mild cognitive impairment (MCI) is becoming increasingly important. The aim of this study was to compare the neuropsychiatric symptoms and cognitive profile of MCI with Lewy bodies (MCI-LB) with Alzheimers disease MCI (MCI-AD). METHODS Participants were ⩾60 years old with MCI. Each had a thorough clinical and neuropsychological assessment and 2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane single photon emission computed tomography FP-CIT SPECT). MCI-LB was diagnosed if two or more diagnostic features of dementia with Lewy bodies were present (visual hallucinations, cognitive fluctuations, motor parkinsonism, rapid eye movement sleep behaviour disorder or positive FP-CIT SPECT). A Lewy body Neuropsychiatric Supportive Symptom Count (LBNSSC) was calculated based on the presence or absence of the supportive neuropsychiatric symptoms defined by the 2017 DLB diagnostic criteria: non-visual hallucinations, delusions, anxiety, depression and apathy. RESULTS MCI-LB (n = 41) had a higher LBNSSC than MCI-AD (n = 24; 1.8 ± 1.1 v. 0.7 ± 0.9, p = 0.001). 67% of MCI-LB had two or more of those symptoms, compared with 16% of MCI-AD (Likelihood ratio = 4.2, p < 0.001). MCI-LB subjects scored lower on tests of attention, visuospatial function and verbal fluency. However, cognitive test scores alone did not accurately differentiate MCI-LB from MCI-AD. CONCLUSIONS MCI-LB is associated with neuropsychiatric symptoms and a cognitive profile similar to established DLB. This supports the concept of identifying MCI-LB based on the presence of core diagnostic features of DLB and abnormal FP-CIT SPECT imaging. The presence of supportive neuropsychiatric clinical features identified in the 2017 DLB diagnostic criteria was helpful in differentiating between MCI-LB and MCI-AD.

Beta-amyloid deposition maps onto hippocampal and subiculum atrophy in dementia with Lewy bodies

Although dementia with Lewy bodies (DLB) is a synucleinopathy, it is frequently accompanied by beta amyloid (Aβ) accumulation. Elucidating the relationships of Aβ with gray matter atrophy in DLB may yield insights regarding the contributions of comorbid Alzheimers disease to its disease progression. Twenty healthy controls and 25 DLB subjects underwent clinical assessment, [18F]-Florbetapir, and 3T magnetic resonance imaging. FreeSurfer was used to estimate cortical thickness and subcortical volumes, and PetSurfer was used to quantify [18F]-Florbetapir standardized uptake value ratio. Principal component analysis was used to identify the dominant Aβ component for correlations with regional cortical thickness, hippocampal subfields, and subcortical structures. Relative to healthy controls, the DLB group demonstrated increased Aβ in widespread regions encompassing the frontal and temporoparietal cortices, whereas cortical thinning was restricted to the temporal lobe. Among DLB subjects, the Aβ component was significantly associated with more severe hippocampal and subiculum atrophy. These findings may reflect an early process of superimposed AD-like atrophy in DLB, thereby conferring support for the therapeutic potential of anti-Aβ interventions in people with DLB.

Diagnostic accuracy of dopaminergic imaging in prodromal dementia with Lewy bodies

Background Dopaminergic imaging has high diagnostic accuracy for dementia with Lewy bodies (DLB) at the dementia stage. We report the first investigation of dopaminergic imaging at the prodromal stage. Methods We recruited 75 patients over 60 with mild cognitive impairment (MCI), 33 with probable MCI with Lewy body disease (MCI-LB), 15 with possible MCI-LB and 27 with MCI with Alzheimers disease. All underwent detailed clinical, neurological and neuropsychological assessments and FP-CIT [123I-N-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)] dopaminergic imaging. FP-CIT scans were blindly rated by a consensus panel and classified as normal or abnormal. Results The sensitivity of visually rated FP-CIT imaging to detect combined possible or probable MCI-LB was 54.2% [95% confidence interval (CI) 39.2–68.6], with a specificity of 89.0% (95% CI 70.8–97.6) and a likelihood ratio for MCI-LB of 4.9, indicating that FP-CIT may be a clinically important test in MCI where any characteristic symptoms of Lewy body (LB) disease are present. The sensitivity in probable MCI-LB was 61.0% (95% CI 42.5–77.4) and in possible MCI-LB was 40.0% (95% CI 16.4–67.7). Conclusions Dopaminergic imaging had high specificity at the pre-dementia stage and gave a clinically important increase in diagnostic confidence and so should be considered in all patients with MCI who have any of the diagnostic symptoms of DLB. As expected, the sensitivity was lower in MCI-LB than in established DLB, although over 50% still had an abnormal scan. Accurate diagnosis of LB disease is important to enable early optimal treatment for LB symptoms.

A new visual rating scale for Ioflupane imaging in Lewy body disease

Background Dopaminergic loss on 123I-Ioflupane brain imaging is a recognised biomarker for dementia with Lewy bodies. It is usually assessed using a visual rating scale developed for Parkinsons disease, which may not be optimal for dementia with Lewy bodies, as patterns of dopaminergic loss can be different. Objectives We aimed to develop a new visual rating scale for 123I-Ioflupane brain images in Lewy body disease that encompasses appearances seen in dementia with Lewy bodies, and validate this against autopsy diagnosis. Methods Four experienced observers developed and tested a new scale consisting of two metrics, reflecting overall loss and heterogeneity of loss. 66 subjects were used during development including clinical diagnoses of Alzheimers disease (n = 14), Parkinsons disease (n = 9), Parkinsons disease dementia (n = 9), dementia with Lewy bodies (n = 15) and normal controls (n = 19). The scale was then tested on an independent group of 46 subjects with autopsy confirmed diagnosis: Alzheimers disease (n = 11), Parkinsons disease (n = 3), Parkinsons disease dementia (n = 15), dementia with Lewy bodies (n = 12), normal controls (n = 4) and Frontotemporal dementia (n = 1). Results In the autopsy validation the sensitivity and specificity of the new scale for Lewy body disease was 97% and 100% respectively, compared with the standard scale which had the same sensitivity (97%), but lower specificity (80%). The new scale had excellent inter rater reliability (intra-class correlation coefficient 0.93). Conclusion A new robust and reliable rating scale is described that straightforwardly captures the visual appearance of 123I-Ioflupane brain images. It demonstrated high accuracy in autopsy confirmed cases and offers advantages over the existing visual rating scale.

Clinical and imaging correlates of amyloid deposition in dementia with Lewy bodies

Background: Amyloid deposition is common in dementia with Lewy bodies, but its pathophysiological significance is unclear.

Cardiac sympathetic innervation associates with autonomic dysfunction in chronic fatigue syndrome – a pilot study

Despite hemodynamic abnormalities being well documented in chronic fatigue syndrome (CFS), it remains unclear the nature of the underlying autonomic nervous system problems that underpin these findings. Studies performed in subgroups of those with CFS suggest cardiac sympathetic denervation. Meta-iodo-benzylguanidine (MIBG) imaging provides a quantitative measure of cardiac sympathetic innervation. Clinically, cardiac MIBG scanning is used to estimate local myocardial sympathetic nerve damage in heart disease and dysautonomia, particularly abnormalities arising due to sympathetic innervation [1,2]. In this study, we explored potential mechanisms that underpin the autonomic abnormalities seen in CFS using I125 MIBG participants that fulfilled Fukuda diagnostic criteria for CFS [3]. Participants were excluded if screened positive for a major depressive episode (Structured Clinical Interview for the Diagnostic and Statistical Manual for Mental Disorders). Fatigue was measured using the Fatigue Impact Scale (FIS). Autonomic function was measured continuously during 10 minute supine rest using the Taskforce Monitor (CNSystems; Graz, Austria) to derive heart rate and blood pressure variability and baroreflex sensitivity (BRS) (spectral analysis and the autoregressive model). Low frequency (LF) and high frequency (HF) bands were reported for heart rate, systolic and diastolic blood pressure variability and LF/HF ratio. These variability indices reflect autonomic control, with greater HF values reflecting greater vagal (parasympathetic) modulation and higher LF values indicating predominantly sympathetic modulation. The LF/HF ratio has been argued to capture ‘sympathovagal balance’ and higher values suggest greater sympathetic dominance [4]. Myocardial innervation imaging with Iodine-123-meta-iodo-benzylguanidine (123 I-MIBG) scintigraphy provides a non-invasive tool for the investigation of cardiac sympathetic innervation. MIBG is an analogue of guanethidine and is taken up by the post-ganglionic presynaptic nerve endings of the adrenergic nervous system. After depolarisation, MIBG is released into the synaptic cleft like noradrenaline but is not metabolised. Labelling MIBG with iodine-123 (123-I) permits visualisation of adrenergic innervation in vivo [5]. During the scintigraphic method of myocardial imaging 123-I-MIBG is intravenously administered at rest and imaging is performed after 10–30 minutes. Planar images with anterior views are used to evaluate cardiac sympathetic function. Regions of interest are set in the heart and mediastinum to obtain mean counts in each, after which H/M ratios are calculated to provide a degree of accumulation in the heart. Upper limit of normal is defined as <2.6. Increased sympathetic activity is associated with a low myocardial MIBG. Statistical analysis was performed using GraphPad PRISM. Nine CFS subjects underwent MIBG. Mean ± SD age 51 ± 6.7 with five females. Length of history was 17 ± 11 years (range 7–28). Mean H/M ratio was 2.94 ± 0.7 with 6/9 (67%) of the CFS patients having values above the upper limit of normal. There were no significant correlations between MIBG findings and length of history (data not shown). There were significant correlations between H/M ratio and BRS at rest (p = .008;

FP-CIT IMAGING IN MILD NEUROCOGNITIVE DISORDER WITH LEWY BODIES

(RSNs) that best discriminate SCI, MCI, and AD groups from each other, and determine the relation of discriminative networks to cognitive functions. Methods: 37 SCI, 26 MCI and 8 AD participants underwent detailed neuropsychological assessment and resting state MRI. RSNs were obtained by using independent component analysis (ICA) in Group-ICA fMRI Toolbox (GIFT). Scores representing the expression level of specific networks in each subject were obtained by calculating the dot product of the subject’s and group spatial maps. Results: Forward conditional binary logistic regression analysis between SCI and MCI groups yielded 2 ICs that could discriminate the groups with an accuracy of 61.9% (p<0.02; R1⁄40.16). In the MCI group, salience network (SN) scores were higher and the posterior default mode network (DMN) scores were lower. Logistic regression analysis between the SCI and AD groups yielded 3 ICs with a discrimination accuracy of 88.9% (p<0.001; R1⁄40.54). The expression of the SN was higher, while the expression of the posterior and parahippocampal sub-components of the DMN were lower in AD group. Finally, logistic regression analysis between MCI and AD groups yielded 2 discriminative ICs with accuracy of 82.4% (p<0.05; R1⁄40.26). Expression scores of both the posterior DMN and the language network were lower in AD group. With regard to the relationship between network expression scores and cognitive scores of the overall sample, a number of positive correlations with the DMN and negative with the SN are found (r values range between -.30 and .37, p<.02). Conclusions: Our findings are in line with previous research showing that connectivity changes within and among the particular ICNs are discriminatory among different stages of the AD continuum; further research is needed to show whether these could be used as a biomarker in the individual level. This study is supported by Turkish Scientific and Technological Research Council (TUBITAK) Project #114E053 and Turkish Ministry of Development Project #2010K120330.