Impact of attenuation correction of radiotherapy hardware for positron emission tomography-magnetic resonance in ano-rectal radiotherapy patients.

BACKGROUND: Positron Emission Tomography-Magnetic Resonance (PET-MR) scanners could improve ano-rectal radiotherapy planning through improved Gross Tumour Volume (GTV) delineation and enabling dose painting strategies using metabolic measurements. This requires accurate quantitative PET images acquired in the radiotherapy treatment position. PURPOSE: This study aimed to evaluate the impact on GTV delineation and metabolic parameter measurement of using novel Attenuation Correction (AC) maps that included the radiotherapy flat couch, coil bridge and anterior coil to see if they were necessary. METHODS: Seventeen ano-rectal radiotherapy patients received a 18 F $\mathrm{^{18}F}$ -FluoroDeoxyGlucose PET-MR scan in the radiotherapy position. PET images were reconstructed without ( CTAC std $\mathrm{CTAC_{std}}$ ) and with ( CTAC cba $\mathrm{CTAC_{cba}}$ ) the radiotherapy hardware included. Both AC maps used the same Computed Tomography image for patient AC. Semi-manual and threshold GTVs were delineated on both PET images, the volumes compared and the Dice coefficient calculated. Metabolic parameters: Standardized Uptake Values SUV max $\mathrm{SUV_{max}}$ , SUV mean $\mathrm{SUV_{mean}}$ and Total Lesion Glycolysis (TLG) were compared using paired t-tests with a Bonferroni corrected significance level of p = 0.05 / 8 = 0.006 $p = 0.05/8 = 0.006$ . RESULTS: Differences in semi-manual GTV volumes between CTAC cba $\mathrm{CTAC_{cba}}$ and CTAC std $\mathrm{CTAC_{std}}$ were approaching statistical significance (difference - 15.9 % ± 1.6 % $-15.9\%\pm 1.6\%$ , p = 0.007 $p = 0.007$ ), with larger differences in low FDG-avid tumours ( SUV mean < 8.5 g mL - 1 $\mathrm{SUV_{mean}} < 8.5\;\mathrm{g\: mL^{-1}}$ ). The CTAC cba $\mathrm{CTAC_{cba}}$ and CTAC std $\mathrm{CTAC_{std}}$ GTVs were concordant with Dice coefficients 0.89 ± 0.01 $0.89 \pm 0.01$ (manual) and 0.98 ± 0.00 $0.98 \pm 0.00$ (threshold). Metabolic parameters were significantly different, with SUV max $\mathrm{SUV_{max}}$ , SUV mean $\mathrm{SUV_{mean}}$ and TLG differences of - 11.5 % ± 0.3 % $-11.5\%\ \pm 0.3\%$ ( p < 0.001 $p < 0.001$ ), - 11.6 % ± 0.3 % $-11.6\% \pm 0.3\%$ ( p < 0.001 $p < 0.001$ ) and - 13.7 % ± 0.6 % $-13.7\%\ \pm 0.6\%$ ( p = 0.003 $p = 0.003$ ) respectively. The TLG difference resulted in 1/8 rectal cancer patients changing prognosis group, based on literature TLG cut-offs, when using CTAC cba $\mathrm{CTAC_{cba}}$ rather than CTAC std $\mathrm{CTAC_{std}}$ . CONCLUSIONS: This study suggests that using AC maps with the radiotherapy hardware included is feasible for patient imaging. The impact on tumour delineation was mixed and needs to be evaluated in larger cohorts. However using AC of the radiotherapy hardware is important for situations where accurate metabolic measurements are required, such as dose painting and treatment prognostication.

Electromyography in the prognostication of recovery in patients with acute peripheral facial nerve palsy: A systematic review.

OBJECTIVES: Needle electromyography (EMG) may be used to characterise the severity of the injury in acute peripheral facial nerve palsy (FNP) to predict recovery and guide management, but its prognostic value and clinical utility remain controversial. The aim of this systematic review was to evaluate the role of EMG to prognosticate the recovery of facial motor function in patients with acute peripheral FNP. DESIGN: A comprehensive search strategy was applied in PubMed, Embase, and Web of Science based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The main outcome measure was the accuracy of EMG in predicting long-term facial function at least 6 months following symptom onset. RESULTS: Eleven studies were included comprising 3837 participants, with 91.6% of these diagnosed with Bell's palsy (BP). In BP patients, the positive predictive value and negative predictive value for a good outcome based on EMG findings ranged from 82.1% to 100% and 66.7% to 80.5%, respectively, with two out of three studies finding that EMG remained a significant predictor of the outcome on multivariate analysis. Three studies addressed the role of EMG in non-idiopathic FNP with two of these studies supporting EMG to predict prognosis. CONCLUSIONS: EMG is a useful tool to gain insight into the likely outcome to guide management decisions and counsel patients on their expectations, particularly in BP. However, given inconsistencies in its application and lack of evidence around non-idiopathic FNP, it should not currently be relied on to predict recovery. Ultimately, its prognostic value and widespread adoption are dependent on the implementation of a clear and standardised protocol in future high-quality studies and routine clinical settings.

Neuropsychological Impairments and Their Cognitive Architecture in Mild Cognitive Impairment (MCI) with Lewy Bodies and MCI-Alzheimer's Disease.

OBJECTIVE: The present study aimed to clarify the neuropsychological profile of the emergent diagnostic category of Mild Cognitive Impairment with Lewy bodies (MCI-LB) and determine whether domain-specific impairments such as in memory were related to deficits in domain-general cognitive processes (executive function or processing speed). METHOD: Patients (n = 83) and healthy age- and sex-matched controls (n = 34) underwent clinical and imaging assessments. Probable MCI-LB (n = 44) and MCI-Alzheimer's disease (AD) (n = 39) were diagnosed following National Institute on Aging-Alzheimer's Association (NIA-AA) and dementia with Lewy bodies (DLB) consortium criteria. Neuropsychological measures included cognitive and psychomotor speed, executive function, working memory, and verbal and visuospatial recall. RESULTS: MCI-LB scored significantly lower than MCI-AD on processing speed [Trail Making Test B: p = .03, g = .45; Digit Symbol Substitution Test (DSST): p = .04, g = .47; DSST Error Check: p < .001, g = .68] and executive function [Trail Making Test Ratio (A/B): p = .04, g = .52] tasks. MCI-AD performed worse than MCI-LB on memory tasks, specifically visuospatial (Modified Taylor Complex Figure: p = .01, g = .46) and verbal (Rey Auditory Verbal Learning Test: p = .04, g = .42) delayed recall measures. Stepwise discriminant analysis correctly classified the subtype in 65.1% of MCI patients (72.7% specificity, 56.4% sensitivity). Processing speed accounted for more group-associated variance in visuospatial and verbal memory in both MCI subtypes than executive function, while no significant relationships between measures were observed in controls (all ps > .05). CONCLUSIONS: MCI-LB was characterized by executive dysfunction and slowed processing speed but did not show the visuospatial dysfunction expected, while MCI-AD displayed an amnestic profile. However, there was considerable neuropsychological profile overlap and processing speed mediated performance in both MCI subtypes.

Accuracy of dopaminergic imaging as a biomarker for mild cognitive impairment with Lewy bodies.

BACKGROUND: Dopaminergic imaging is an established biomarker for dementia with Lewy bodies, but its diagnostic accuracy at the mild cognitive impairment (MCI) stage remains uncertain. AIMS: To provide robust prospective evidence of the diagnostic accuracy of dopaminergic imaging at the MCI stage to either support or refute its inclusion as a biomarker for the diagnosis of MCI with Lewy bodies. METHOD: We conducted a prospective diagnostic accuracy study of baseline dopaminergic imaging with [123I]N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl)nortropane single-photon emission computerised tomography (123I-FP-CIT SPECT) in 144 patients with MCI. Images were rated as normal or abnormal by a panel of experts with access to striatal binding ratio results. Follow-up consensus diagnosis based on the presence of core features of Lewy body disease was used as the reference standard. RESULTS: At latest assessment (mean 2 years) 61 patients had probable MCI with Lewy bodies, 26 possible MCI with Lewy bodies and 57 MCI due to Alzheimer's disease. The sensitivity of baseline FP-CIT visual rating for probable MCI with Lewy bodies was 66% (95% CI 52-77%), specificity 88% (76-95%) and accuracy 76% (68-84%), with positive likelihood ratio 5.3. CONCLUSIONS: It is over five times as likely for an abnormal scan to be found in probable MCI with Lewy bodies than MCI due to Alzheimer's disease. Dopaminergic imaging appears to be useful at the MCI stage in cases where Lewy body disease is suspected clinically.

Cognitive Decline in Mild Cognitive Impairment With Lewy Bodies or Alzheimer Disease: A Prospective Cohort Study.

OBJECTIVE: We explored whether the mild cognitive impairment (MCI) stages of dementia with Lewy bodies (DLB) and Alzheimer disease (AD) differ in their cognitive profiles, and longitudinal progression. DESIGN: A prospective, longitudinal design was utilized with annual follow-up (Max 5 years, Mean 1.9, standard deviation 1.1) after diagnosis. Participants underwent repeated cognitive testing, and review of their clinical diagnosis and symptoms, including evaluation of core features of DLB. SETTING: This was an observational study of independently living individuals, recruited from local healthcare trusts in North East England, UK. PARTICIPANTS: An MCI cohort (n = 76) aged ≥60 years was utilized, differentially diagnosed with MCI due to AD (MCI-AD), or possible/probable MCI with Lewy bodies (MCI-LB). MEASUREMENTS: A comprehensive clinical and neuropsychological testing battery was administered, including ACE-R, trailmaking tests, FAS verbal fluency, and computerized battery of attention and perception tasks. RESULTS: Probable MCI-LB presented with less impaired recognition memory than MCI-AD, greater initial impairments in verbal fluency and perception of line orientation, and thereafter demonstrated an expedited decline in visuo-constructional functions in the ACE-R compared to MCI-AD. No clear diagnostic group differences were found in deterioration speeds for global cognition, language, overall memory, attention or other executive functions. CONCLUSION: These findings provide further evidence for differences in severity and decline of visuospatial dysfunctions in DLB compared with AD; further exploration is required to clarify when and how differences in attention, executive, and memory functions emerge, as well as speed of decline to dementia.

Uniformity of cardiac 123I-MIBG uptake on SPECT images in older adults with normal cognition and patients with dementia.

INTRODUCTION: Some studies report that assessing regional 123I-cardiac MIBG uptake can aid in the diagnosis of Lewy body disease, but others report heterogeneity in healthy controls. We aimed to evaluate regional cardiac MIBG uptake patterns in healthy older adults and patients with dementia. METHODS: 31 older adults with normal cognition, 15 Alzheimer's disease (AD), and 17 Dementia with Lewy bodies (DLB) patients were recruited. 5 individuals had previous myocardial infarction. Participants with sufficient cardiac uptake for regional SPECT analysis (29/31 controls, 15/15 AD, 5/17 DLB) had relative uptake pattern recorded. Controls were assessed for risk of future cardiovascular events using QRISK2, a validated online tool. RESULTS: In controls uptake was reduced in the inferior wall (85%), apex (23%), septum (15%), and lateral wall (8%). AD and DLB showed similar patterns to controls. Lung or liver interference was present in 61% of cases. Myocardial infarction cases showed regional reductions in uptake, but normal/borderline planar uptake. In controls, there was no relationship between cardiovascular risk score and uptake pattern. CONCLUSIONS: Significant variability of regional cardiac 123I-MIBG uptake is common in cases with normal planar cardiac uptake. Heterogeneity of regional uptake appears non-specific and unlikely to aid in the diagnosis of Lewy body disease.

Correction: A case of malignant hyperlactaemic acidosis appearing upon treatment with the mono-carboxylase transporter 1 inhibitor AZD3965.

Since the publication of this paper the authors noticed an error in the listed authors, where Alexandros Siskos was listed as Alexandros Sitkos. This has now been corrected.

A case of malignant hyperlactaemic acidosis appearing upon treatment with the mono-carboxylase transporter 1 inhibitor AZD3965.

A 47-year-old man with metastatic melanoma presented with refractory hyperlactaemic acidosis following the first dose of the mono-carboxylase transporter 1 inhibitor AZD3965 within a "first time in man" clinical trial. The mechanism of the agent and the temporal relationship suggested that this event was potentially drug related and recruitment was suspended. However, urinary metabolomics showed extensive abnormalities even prior to drug administration, leading to investigations for an underlying metabolic disorder. The lack of clinical symptoms from the elevated lactate and low blood glucose suggested a diagnosis of "hyper-Warburgism", where the high tumour burden was associated with extensive glucose uptake and lactate efflux from malignant cells, and the subsequent impact on blood biochemistry. This was supported by an FDG-PET scan showing extensive glucose uptake in numerous metastases and lack of uptake in the brain. A review of the literature showed 16 case reports of "hyper-Warburgism" in non-haematological malignancies, none of them with melanoma, with most associated with a poor outcome. The patient was treated symptomatically, but died 2 months later. The development of AZD3965 continues with the exclusion of patients with elevated plasma lactate at screening added to the protocol as a safety measure.Trial identification number ClinicalTrials.Gov. NCT01791595.

Amyloid Imaging and Longitudinal Clinical Progression in Dementia With Lewy Bodies.

OBJECTIVE: Significant amyloid deposition is present in approximately half of all cases of dementia with Lewy bodies (DLB). We sought to determine whether amyloid deposition was associated with more rapid clinical decline over 1 year. METHODS: Twenty-eight participants had a baseline clinical assessment and amyloid PET scan, followed by a further clinical assessment after 1 year. Changes in clinical measures were compared with amyloid deposition assessed by visual rating and cortical standardized uptake value ratio. RESULTS: Amyloid deposition on visual rating was associated with greater decline in Mini-Mental State Examination and daily function over 1 year. There was no correlation between cortical standardized uptake value ratio and clinical measures. CONCLUSIONS: This study provides further evidence for a link between amyloid deposition and clinical progression in DLB. Pathologies such as amyloid, and their interaction with α-synuclein, remain possible treatment targets in 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 Alzheimer's disease. All underwent detailed clinical, neurological and neuropsychological assessments and FP-CIT [123I-N-fluoropropyl-2ß-carbomethoxy-3ß-(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.

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. OBJECTIVE: The objective of this study was to investigate the relationship between amyloid deposition and clinical profile, gray matter volume, and brain perfusion in dementia with Lewy bodies. METHODS: Dementia with Lewy bodies (n = 37), Alzheimer's disease (n = 20), and controls (n = 20) underwent a thorough clinical assessment, 3T MRI, and early- and late-phase 18 F-Florbetapir PET-CT to assess cortical perfusion and amyloid deposition, respectively. Amyloid scans were visually categorized as positive or negative. Image analysis was carried out using statistical parametric mapping (SPM) 8. RESULTS: There were no significant differences between amyloid-positive and amyloid-negative dementia with Lewy bodies cases in age (P = .78), overall cognitive impairment (P = .83), level of functional impairment (P = .80), or any other clinical or cognitive scale. There were also no significant differences in hippocampal or gray matter volumes. However, amyloid-positive dementia with Lewy bodies cases had lower medial temporal lobe perfusion (P = .03) than amyloid-negative cases, although a combination of medial temporal lobe perfusion, hippocampal volume, and cognitive measures was unable to accurately predict amyloid status in dementia with Lewy bodies. CONCLUSIONS: Amyloid deposition was not associated with differences in clinical or neuropsychological profiles in dementia with Lewy bodies, but was associated with imaging evidence of medial temporal lobe dysfunction. The presence of amyloid in dementia with Lewy bodies cannot be identified on the basis of clinical and other imaging features and will require direct assessment via PET imaging or CSF. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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 Alzheimer's disease MCI (MCI-AD). METHODS: Participants were ⩾60 years old with MCI. Each had a thorough clinical and neuropsychological assessment and 2ß-carbomethoxy-3ß-(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.

Evaluating a radiotherapy deep learning synthetic CT algorithm for PET-MR attenuation correction in the pelvis.

BACKGROUND: Positron emission tomography-magnetic resonance (PET-MR) attenuation correction is challenging because the MR signal does not represent tissue density and conventional MR sequences cannot image bone. A novel zero echo time (ZTE) MR sequence has been previously developed which generates signal from cortical bone with images acquired in 65 s. This has been combined with a deep learning model to generate a synthetic computed tomography (sCT) for MR-only radiotherapy. This study aimed to evaluate this algorithm for PET-MR attenuation correction in the pelvis. METHODS: Ten patients being treated with ano-rectal radiotherapy received a [Formula: see text]F-FDG-PET-MR in the radiotherapy position. Attenuation maps were generated from ZTE-based sCT (sCTAC) and the standard vendor-supplied MRAC. The radiotherapy planning CT scan was rigidly registered and cropped to generate a gold standard attenuation map (CTAC). PET images were reconstructed using each attenuation map and compared for standard uptake value (SUV) measurement, automatic thresholded gross tumour volume (GTV) delineation and GTV metabolic parameter measurement. The last was assessed for clinical equivalence to CTAC using two one-sided paired t tests with a significance level corrected for multiple testing of [Formula: see text]. Equivalence margins of [Formula: see text] were used. RESULTS: Mean whole-image SUV differences were -0.02% (sCTAC) compared to -3.0% (MRAC), with larger differences in the bone regions (-0.5% to -16.3%). There was no difference in thresholded GTVs, with Dice similarity coefficients [Formula: see text]. However, there were larger differences in GTV metabolic parameters. Mean differences to CTAC in [Formula: see text] were [Formula: see text] (± standard error, sCTAC) and [Formula: see text] (MRAC), and [Formula: see text] (sCTAC) and [Formula: see text] (MRAC) in [Formula: see text]. The sCTAC was statistically equivalent to CTAC within a [Formula: see text] equivalence margin for [Formula: see text] and [Formula: see text] ([Formula: see text] and [Formula: see text]), whereas the MRAC was not ([Formula: see text] and [Formula: see text]). CONCLUSION: Attenuation correction using this radiotherapy ZTE-based sCT algorithm was substantially more accurate than current MRAC methods with only a 40 s increase in MR acquisition time. This did not impact tumour delineation but did significantly improve the accuracy of whole-image and tumour SUV measurements, which were clinically equivalent to CTAC. This suggests PET images reconstructed with sCTAC would enable accurate quantitative PET images to be acquired on a PET-MR scanner.

Practical use of DAT SPECT imaging in diagnosing dementia with Lewy bodies: a US perspective of current guidelines and future directions.

Background: Diagnosing Dementia with Lewy Bodies (DLB) remains a challenge in clinical practice. The use of 123I-ioflupane (DaTscan™) SPECT imaging, which detects reduced dopamine transporter (DAT) uptake-a key biomarker in DLB diagnosis-could improve diagnostic accuracy. However, DAT imaging is underutilized despite its potential, contributing to delays and suboptimal patient management. Methods: This review evaluates DLB diagnostic practices and challenges faced within the U.S. by synthesizing information from current literature, consensus guidelines, expert opinions, and recent updates on DaTscan FDA filings. It contrasts DAT SPECT with alternative biomarkers, provides recommendations for when DAT SPECT imaging may be indicated and discusses the potential of emerging biomarkers in enhancing diagnostic approaches. Results: The radiopharmaceutical 123I-ioflupane for SPECT imaging was initially approved in Europe (2000) and later in the US (2011) for Parkinsonism/Essential Tremor. Its application was extended in 2022 to include the diagnosis of DLB. DaTscan's diagnostic efficacy for DLB, with its sensitivity, specificity, and predictive values, confirms its clinical utility. However, US implementation faces challenges such as insurance barriers, costs, access issues, and regional availability disparities. Conclusion: 123I-ioflupane SPECT Imaging is indicated for DLB diagnosis and differential diagnosis of Alzheimer's Disease, particularly in uncertain cases. Addressing diagnostic obstacles and enhancing physician-patient education could improve and expedite DLB diagnosis. Collaborative efforts among neurologists, geriatric psychiatrists, psychologists, and memory clinic staff are key to increasing diagnostic accuracy and care in DLB management.

Hypothalamic involvement in multiple system atrophy: A structural MRI study.

OBJECTIVE: To investigate hypothalamic atrophy and its clinical correlates in multiple system atrophy (MSA) in-vivo. BACKGROUND: MSA is characterized by autonomic dysfunction and parkinsonian/cerebellar manifestations. The hypothalamus regulates autonomic and homeostatic functions and is also involved in memory and learning processes. METHODS: 11 MSA, 18 Parkinson's Disease (PD) and 18 Healthy Controls (HC) were included in this study. A validated and automated hypothalamic segmentation tool was applied to 3D-T1-weighted images acquired on a 3T MRI scanner. MSA hypothalamic volumes were compared to those of PD and HC. Furthermore, the association between hypothalamic volumes and scores of autonomic, depressive, sleep and cognitive manifestations were investigated. RESULTS: Posterior hypothalamus volume was reduced in MSA compared to controls (t = 2.105, p = 0.041) and PD (t = 2.055, p = 0.046). Total hypothalamus showed a trend towards a reduction in MSA vs controls (t = 1.676, p = 0.101). Reduced posterior hypothalamus volume correlated with worse MoCA scores in the parkinsonian (MSA + PD) group and in each group separately, but not with autonomic, sleep, or depression scores. CONCLUSIONS: In-vivo structural hypothalamic involvement may be present in MSA. Reduced posterior hypothalamus volume, which includes the mammillary bodies and lateral hypothalamus, is associated with worse cognitive functioning. Larger studies on hypothalamic involvement in MSA and its clinical correlates are needed.

Identifying parkinsonism in mild cognitive impairment.

INTRODUCTION: Clinical parkinsonism is a core diagnostic feature for mild cognitive impairment with Lewy bodies (MCI-LB) but can be challenging to identify. A five-item scale derived from the Unified Parkinson's Disease Rating Scale (UPDRS) has been recommended for the assessment of parkinsonism in dementia. This study aimed to determine whether the five-item scale is effective to identify parkinsonism in MCI. METHODS: Participants with MCI from two cohorts (n = 146) had a physical examination including the UPDRS and [123I]-FP-CIT SPECT striatal dopaminergic imaging. Participants were classified as having clinical parkinsonism (P+) or no parkinsonism (P-), and with abnormal striatal dopaminergic imaging (D+) or normal imaging (D-). The five-item scale was the sum of UPDRS tremor at rest, bradykinesia, action tremor, facial expression, and rigidity scores. The ability of the scale to differentiate P+D+ and P-D- participants was examined. RESULTS: The five-item scale had an AUROC of 0.92 in Cohort 1, but the 7/8 cut-off defined for dementia had low sensitivity to identify P+D+ participants (sensitivity 25%, specificity 100%). Optimal sensitivity and specificity was obtained at a 3/4 cut-off (sensitivity 83%, specificity 88%). In Cohort 2, the five-item scale had an AUROC of 0.97, and the 3/4 cut-off derived from Cohort 1 showed sensitivity of 100% and a specificity of 82% to differentiate P+D+ from P-D- participants. The five-item scale was not effective in differentiating D+ from D- participants. CONCLUSIONS: The five-item scale is effective to identify parkinsonism in MCI, but a lower threshold must be used in MCI compared with dementia.

Associations between COPD related manifestations: a cross-sectional study.

BACKGROUND: Cardiovascular 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. METHODS: We 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. RESULTS: We 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). CONCLUSIONS: Increased 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 REGISTRATION: Lothian NHS Board, Lothian Research Ethics Committee, LREC/2003/8/28.

Serial Nigrostriatal Dopaminergic Imaging in Mild Cognitive Impairment With Lewy Bodies, Alzheimer Disease, and Age-Matched Controls.

BACKGROUND AND OBJECTIVES: Progressive nigrostriatal pathway degeneration occurs in individuals with dementia with Lewy bodies (LB). Our objective was to investigate whether repeat 123[I]-N-(3-fluoropropyl)-2ß-carboxymethoxy-3ß-(4-iodophenyl) nortropane (FP-CIT) single photon emission computed tomography (SPECT) can identify progressive dopaminergic loss in mild cognitive impairment (MCI) with Lewy bodies (MCI-LB). METHODS: Individuals with MCI-LB and MCI due to Alzheimer disease (MCI-AD) underwent comprehensive clinical assessment, 123[I]-FP-CIT SPECT at baseline and annual reviews, and baseline cardiac 123 iodine metaiodobenzylguanidine (I-MIBG). Mixed-effects models were used to investigate changes in 123[I]-FP-CIT specific binding ratio (SBR) in the striatum for each diagnostic group compared with controls. The time interval to the development of a quantitatively abnormal 123[I]-FP-CIT SPECT in the possible and probable MCI-LB groups was determined as the time it took for these groups to reach a striatal uptake 2 SDs below aged-matched controls. Test-retest variation was assessed using baseline and repeat scans in controls. RESULTS: We recruited 20 individuals with MCI-AD, 11 with possible MCI-LB, 25 with probable MCI-LB, and 29 age-matched controls. The mean time between baseline and the final image was 1.6 years (SD = 0.9, range 1.0-4.3). The annual estimated change in SBR was 0.23 for controls (95% CI -0.07 to 0.53), -0.09 (-0.55 to 0.36) for MCI-AD, -0.50 (-1.03 to 0.04) for possible MCI-LB, and -0.48 (-0.89 to -0.06) for probable MCI-LB. The median annual percentage change in SBR in MCI-LB was -5.6% (95% CI -8.2% to -2.9%) and 2.1% (-3.5% to 8.0%) for MCI-AD. The extrapolated time for a normal scan to become abnormal was 6 years. Controls and MCI-AD showed no significant change in dopaminergic binding over time. The mean test-retest variation in controls was 12% (SD 5.5%), which cautions against overinterpretation of small changes on repeat scanning. DISCUSSION: Progressive dopaminergic loss in the striatum is detectable using 123[I]-FP-CIT SPECT in MCI-LB at a group level. In clinical practice, individual change in striatal 123[I]-FP-CIT uptake seems to be of limited diagnostic value because of high test-retest variation. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that longitudinal declines in striatal uptake measured using 123[I]-FP-CIT SPECT are associated with MCI due to Lewy body disease but not MCI due to Alzheimer disease.

A Phase I Dose-escalation Study of AZD3965, an Oral Monocarboxylate Transporter 1 Inhibitor, in Patients with Advanced Cancer.

PURPOSE: Inhibition of monocarboxylate transporter (MCT) 1-mediated lactate transport may have cytostatic and/or cytotoxic effects on tumor cells. We report results from the dose-escalation part of a first-in-human trial of AZD3965, a first-in-class MCT1 inhibitor, in advanced cancer. PATIENTS AND METHODS: This multicentre, phase I, dose-escalation and dose-expansion trial enrolled patients with advanced solid tumors or lymphoma and no standard therapy options. Exclusion criteria included history of retinal and/or cardiac disease, due to MCT1 expression in the eye and heart. Patients received daily oral AZD3965 according to a 3+3 then rolling six design. Primary objectives were to assess safety and determine the MTD and/or recommended phase II dose (RP2D). Secondary objectives for dose escalation included measurement of pharmacokinetic and pharmacodynamic activity. Exploratory biomarkers included tumor expression of MCT1 and MCT4, functional imaging of biological impact, and metabolomics. RESULTS: During dose escalation, 40 patients received AZD3965 at 5-30 mg once daily or 10 or 15 mg twice daily. Treatment-emergent adverse events were primarily grade 1 and/or 2, most commonly electroretinogram changes (retinopathy), fatigue, anorexia, and constipation. Seven patients receiving ≥20 mg daily experienced dose-limiting toxicities (DLT): grade 3 cardiac troponin rise (n = 1), asymptomatic ocular DLTs (n = 5), and grade 3 acidosis (n = 1). Plasma pharmacokinetics demonstrated attainment of target concentrations; pharmacodynamic measurements indicated on-target activity. CONCLUSIONS: AZD3965 is tolerated at doses that produce target engagement. DLTs were on-target and primarily dose-dependent, asymptomatic, reversible ocular changes. An RP2D of 10 mg twice daily was established for use in dose expansion in cancers that generally express high MCT1/low MCT4).

Introduction of a Low-Cost and Automated Four-Dimensional Assessment System of the Face.

SUMMARY: Existing automated objective grading systems either fail to consider the face's complex three-dimensional morphology or have poor feasibility and usability. Consumer-based red, green, and blue depth sensors or smartphone integrated three-dimensional hardware can inexpensively collect detailed four-dimensional facial data in real time but are yet to be incorporated into a practical system. This study aimed to evaluate the feasibility of a proof-of-concept automated four-dimensional facial assessment system using a red/green/blue depth sensor (OpenFAS) for use in a standard clinical environment. This study was performed on healthy adult volunteers and patients with facial nerve palsy. The setup consists of the Intel (Santa Clara, Calif.) RealSense SR300 connected to a laptop running the OpenFAS application. The subject sequentially mimics the facial expressions shown on screen. Each frame is landmarked and automatic anthropometric calculations are performed. Any errors during each session were noted. Landmarking accuracy was estimated by comparing the ground-truth position of landmarks annotated manually with those placed automatically. Eighteen participants were included in the study, nine healthy participants and nine patients with facial nerve palsy. Each session was standardized at approximately 106 seconds. A total of 61.8 percent of landmarks were automatically annotated within approximately 1.575 mm of their ground-truth locations. The findings support that OpenFAS is usable and feasible in routine settings, laying down the critical groundwork for a facial assessment system that addresses the shortcomings of existing tools. The iteration of OpenFAS presented in this study is nascent; future work, including improvements to landmarking accuracy, analyses components, and red/green/blue depth technology, is required before clinical application.