Critical Appraisal of the Current Role of Myocardial Perfusion Imaging in the Management of Acute Chest Pain.

This paper describes the evolution of nuclear cardiology techniques in the setting of acute coronary syndromes. Since the 1970s, the contribution of nuclear cardiology has been fundamental in delineating the physiopathology and diagnosis of acute myocardial infarction, when electrocardiogram (ECG) did not provide the diagnosis and when cardiac enzyme assessments were at a very early stage. In this clinical situation, at that time the role of pyrophosphate scintigraphy and antimyosin antibodies was important in ensuring diagnostic precision. However, these methods showed limitations and were abandoned in the late 80s and early 90s when therapeutic applications such as thrombolytic therapy, and primary-and rescue-percutaneous coronary intervention (PCI) were introduced. Beginning in the mid-80s, the introduction and widespread use of perfusion tracers such as 99mTc labelled compounds and technological advances such as SPECT, allowed to assess the efficacy of thrombolysis and early revascularization, as well as to assess in depth myocardial salvage. Currently, perfusion SPECT, especially using fast imaging techniques and dedicated cardiac SPECT with solid-state detectors, allows a quick confirmation or exclusion of acute coronary syndromes, particularly in low-to-intermediate likelihood of coronary artery disease (CAD), especially when there are absolute or relative contraindications to the use of coronary computed tomographic angiography (CCTA).

Atypical brain FDG-PET patterns increase the risk of long-term cognitive and motor progression in Parkinson's disease.

INTRODUCTION: Brain hypometabolism patterns have been previously associated with cognitive decline in Parkinson's disease (PD). Our aim is to evaluate the impact of single-subject fluorodeoxyglucose (FDG)-PET brain hypometabolism on long-term cognitive and motor outcomes in PD. METHODS: Forty-nine non-demented PD patients with baseline brain FDG-PET data underwent an extensive clinical follow-up for 8 years. The ability of FDG-PET to predict long-term cognitive and motor progression was evaluated using Cox regression and mixed ANCOVA models. RESULTS: Participants were classified according to FDG-PET pattern in PD with typical (n = 26) and atypical cortical metabolism (n = 23). Patients with atypical brain hypometabolic patterns showed higher incidence of dementia (60% vs 3%; HR = 18.3), hallucinations (56% vs 7%, HR = 7.3) and faster motor decline compared to typical pattern group. CONCLUSION: This study argues for specific patterns of FDG-PET cortical hypometabolism in PD as a prognostic marker for long term cognitive and motor outcomes at single-subject level.

Dopaminergic connectivity reconfiguration in the dementia with Lewy bodies continuum.

INTRODUCTION: The impairment of nigrostriatal dopaminergic network is a core feature of dementia with Lewy bodies (DLB). The involvement and reconfiguration of extranigrostriatal dopaminergic circuitries in the DLB continuum is still theme of debate. We aim to investigate in vivo the dynamic changes of local and long-distance dopaminergic networks across DLB continuum. METHODS: Forty-nine patients (including 29 with dementia and 20 prodromal cases) and fifty-two controls entered the study. Each subject underwent a standardized clinical and neurological examination and performed Brain SPECT to measuring brain dopamine transporter (DAT) density. Spatially normalized images underwent the occipital-adjusted specific binding to obtain parametric data. The ANCOVA was applied to assess 123I-FP-CIT differences between pDLB, overt-DLB and CG, considering age, gender, and motor impairment as variables of no interest. Between-nodes correlation analysis measured molecular connectivity within the ventral and dorsal dopaminergic networks. RESULTS: Prodromal DLB and DLB patients showed comparable nigrostriatal deficits in basal ganglia regions compared with CG. Molecular connectivity analyses revealed extensive connectivity losses, more in ventral than in dorsal dopaminergic network in DLB dementia. Conversely, the prodromal group showed increased connectivity compared to CG, mostly putamen-thalamus-cortical and striatal-cortical connectivity. CONCLUSIONS: This study indicates a comparable basal ganglia deficit in nigrostriatal projections in DLB continuum and supports a different reorganization of extra-striatal dopaminergic connectivity in the prodromal phases of DLB. The shift from an increased to a decreased bilateral putamen-thalamus-cortex connectivity might be a hallmark of transition from prodromal to dementia DLB stages.

Correlation between brain glucose metabolism (18F-FDG) and cerebral blood flow with amyloid tracers (18F-Florbetapir) in clinical routine: Preliminary evidences.

OBJECTIVE: This study compared the performance of 18F-Florbetapir PET/CT early acquisitions to 18F-FDG PET/CT. METHODS: We included 12 patients who underwent 18F-FDG PET/CT and a dual-time 18F-Florbetapir PET/CT (1-6 min early-scan and 50 min late-scan). PET/CT were analyzed visually by three nuclear medicine physicians with different experience using a four-point scale (0 = no reduction, 1 = slight, 2 = moderate, 3 = severe reduction) for 18F-Florbetapir early-phase and 18F-FDG images in 10 cortical regions (bilateral frontal, temporal, parietal, occipital, posterior cingulate/precuneus), and 18F-Florbetapir late-phase in the same cortical regions using a three-point scale (0 = normal, 1 = abnormal with minor plaques, 2 = abnormal with major plaques). We used SPM12 for semiquantitative analysis applying a ROI-based correlation analysis (considering precuneus as target region and normalized for the mean global binding), a covariance-analysis taking precuneus as target and a comparison of global DMN (default mode network). RESULTS: Inter-reader agreement was high (Cohen's kappa 0.762 for 18F-FDG, 0.775 for 18F-Florbetapir early-phase and 0.794 for late-phase). Regional visual scores of early-phase and 18F-FDG were significantly correlated (ρ = 0.867). Also ROI-based analysis, global brain visual analysis and DMN comparison revealed concordant results, especially at parietal and precuneus (p < 0.001). CONCLUSIONS: 18F-Florbetapir early-phase scans significantly correlate on quantitative and visual images with 18F-FDG-PET/CT scans, suggesting that amyloid tracer could be instead of 18F-FDG.

In vivo human molecular neuroimaging of dopaminergic vulnerability along the Alzheimer's disease phases.

BACKGROUND: Preclinical and pathology evidence suggests an involvement of brain dopamine (DA) circuitry in Alzheimer's disease (AD). We in vivo investigated if, when, and in which target regions [123I]FP-CIT-SPECT regional binding and molecular connectivity are damaged along the AD course. METHODS: We retrospectively selected 16 amyloid-positive subjects with mild cognitive impairment due to AD (AD-MCI), 22 amyloid-positive patients with probable AD dementia (AD-D), and 74 healthy controls, all with available [123I]FP-CIT-SPECT imaging. We tested whether nigrostriatal vs. mesocorticolimbic dopaminergic targets present binding potential loss, via MANCOVA, and alterations in molecular connectivity, via partial correlation analysis. Results were deemed significant at p < 0.05, after Bonferroni correction for multiple comparisons. RESULTS: We found significant reductions of [123I]FP-CIT binding in both AD-MCI and AD-D compared to controls. Binding reductions were prominent in the major targets of the ventrotegmental-mesocorticolimbic pathway, namely the ventral striatum and the hippocampus, in both clinical groups, and in the cingulate gyrus, in patients with dementia only. Within the nigrostriatal projections, only the dorsal caudate nucleus showed reduced [123I]FP-CIT binding, in both groups. Molecular connectivity assessment revealed a widespread loss of inter-connections among subcortical and cortical targets of the mesocorticolimbic network only (poor overlap with the control group as expressed by a Dice coefficient ≤ 0.25) and no alterations of the nigrostriatal network (high overlap with controls, Dice coefficient = 1). CONCLUSION: Local- and system-level alterations of the mesocorticolimbic dopaminergic circuitry characterize AD, already in prodromal disease phases. These results might foster new therapeutic strategies for AD. The clinical correlates of these findings deserve to be carefully considered within the emergence of both neuropsychiatric symptoms and cognitive deficits.

Comparison between N13NH3-PET and 99mTc-Tetrofosmin-CZT SPECT in the evaluation of absolute myocardial blood flow and flow reserve.

BACKGROUND: PET/CT is the standard for quantitative assessments of myocardial blood flow (MBF), but it requires short-lived-tracers, costly, and not widely available. SPECT with Cadmium Zinc Telluride (CZT) detectors allows dynamic acquisition and quantitation of MBF. The study aims were to compare MBF measurements by 99mTc-tetrofosmin-CZT to N13NH3 PET/CT after regadenoson-induced coronary hyperemia and to evaluate the effect of attenuation correction (AC). METHODS: 54 patients were evaluated at rest and during vasodilation by 99mTc-tetrofosmin-CZT and N13NH3 PET/CT within 2 weeks. MBF and MBF reserve (MFR) were measured by CZT with or without AC (NAC). RESULTS: The global rest MBF was 0.76 ± 0.19 mL/min/gr by PET and 0.76 ± 0.24 by AC-CZT (P = NS) and 1.14 ± 0.4 by NAC-CZT (P < 0.001 vs PET and AC-CZT). Stress MBF was higher when measured by PET than AC-CZT (1.87 ± 0.45 vs 1.62 ± 0.68 mL/min/gr, P < 0.0008), but lower than NAC-CZT (2.36 ± 1.1, P < 0.0003). The MBF reserve ratio (MFR) was higher by PET than AC-CZT (2.52 ± 0.56 vs 2.22 ± 1 (P < 0.009) and NAC-CZT (2.18 ± 1.0, P < 0.004). Linear regression was better between PET (MFR and stress MBF) and AC-CZT than between PET and NAC-CZT. ROC curve analysis showed the significant ability of AC-CZT to predict MFR < 2 and stress MBF < 1.7 (AUC = 0.75 and 0.82 respectively) and to differentiate between normal and CAD patients (AUC = 0.747 and 0.892 for MFR and stress MBF, respectively). CONCLUSIONS: Our data show a reasonable correlation between MBF and MFR measured by N13NH3-PET and 99mTc-Tetrofosmin-CZT SPECT. NAC-CZT overestimates MBF. AC is recommended when using CZT for measuring MBF.

18F-FDG PET/CT in the Diagnosis and Follow-up of Balint Syndrome.

ABSTRACT: Balint syndrome is a rare neurological disorder characterized by simultanagnosia, optic ataxia, and ocular apraxia, and its etiology can be very heterogeneous. Diagnosis is based on neuropsychological evaluation, but brain radiological and nuclear medicine imaging also plays an important role. Because few case reports have been published in literature, in this work, we present 2 patients affected by Balint syndrome in which 18F-FDG PET/CT helped in the diagnosis and follow-up.

Comparison of visual criteria for amyloid-PET reading: could criteria merging reduce inter-rater variability?

BACKGROUND: Three different amyloid tracers labeled with 18-flourine have been introduced into clinical use. The leaflets of tracers indicate different visual criteria for PET reporting. In clinical practice, it is not yet ascertained whether these criteria are equivalent in terms of diagnostic accuracy or if anyone is better than another. We aimed to evaluate the inter and intra-rater variability of visual assessment of 18F-Florbetapir PET/CT images among six independent readers with different clinical experience. METHODS: We analyzed 252 PET/CT scans, visually assessed by each reader three times, applying independently the three different reading criteria proposed. Each reader evaluated the regional uptake specifying for each cortical region a numeric value of grading of positivity in order to assign a final score. At the end of each reading a level of confidence was determined by assigning a score from 0 (negative) to 4 (positive). After first reading, those cases in which the evaluations by two experienced readers did not match (discordant cases) were independently reevaluated merging all the three different visual interpretation criteria. RESULTS: Good agreement was observed for visual interpretation among the six readers' confidence-level using independently the three visual reading criteria: ICC=0.83 (0.80-0.86) for 18F-florbetapir, ICC=0.84 (0.81-0.87) for 18F-florbetaben, and ICC=0.86 (0.83-0.88) for 18F-flutemetamol reading. A good inter-rater agreement was observed for final-score too: ICC=0.74 (0.70-0.78) for 18F-florbetapir; ICC=0.82 (0.79-0.85) for 18F-florbetaben; ICC=0.84 (0.81-0.87) for 18F-flutemetamol. Intra-rater agreement was good for final-score (from 0.76 to 0.90; P<0.001) and confidence-level (Spearman's rho from 0.89 to 1.00; P<0.001). Disagreement between the two experienced readers was observed in 22 of 252 cases (9%). The agreement converged over a second round of independent reading in 12 of 22 cases (54%), by merging all the criteria. CONCLUSIONS: All the criteria proposed are useful to determine the grading of positivity or negativity of amyloid deposition and their merging improves the diagnostic confidence and provides a better agreement.

Transcranial magnetic stimulation and amyloid markers in mild cognitive impairment: impact on diagnostic confidence and diagnostic accuracy.

BACKGROUND: The development of diagnostic tools capable of accurately identifying the pathophysiology of mild cognitive impairment (MCI) has become a crucial target considering the claim that disease-modifying treatments should be administered as early as possible in the disease course. Transcranial magnetic stimulation (TMS) protocols have demonstrated analytical validity in discriminating different forms of dementia; however, its value in daily clinical practice in MCI subjects is still unknown. OBJECTIVE: To evaluate the clinical value of TMS compared to amyloid markers on diagnostic confidence and accuracy in MCI subjects, considering clinicians' expertise. METHODS: One hundred seven MCI subjects were included and classified as MCI-Alzheimer disease (MCI-AD), MCI-frontotemporal dementia (MCI-FTD), MCI-dementia with Lewy bodies (MCI-DLB), or MCI-other in a three-step process based on (i) demographic, clinical, and neuropsychological evaluation (clinical work-up); (ii) clinical work-up PLUS amyloidosis markers or clinical work-up PLUS TMS measures; and (iii) clinical work-up PLUS both markers. Two blinded neurologists with different clinical expertise were asked to express a diagnostic confidence for each MCI subgroup, and ROC curve analyses were performed at each step. RESULTS: The addition of TMS markers to clinical work-up significantly increased the diagnostic confidence for MCI-AD (p = 0.003), MCI-FTD (p = 0.044), and MCI-DLB (p = 0.033) compared to clinical work-up alone, but not for MCI-other (p > 0.05). No significant differences between the add-on effect of TMS and the add-on effect of amyloid markers to clinical work-up were observed (p > 0.732), while the diagnostic confidence further increased when both markers were available. The greater the clinical expertise, the greater the flexibility in considering alternative diagnosis, and the greater the ability to modify diagnostic confidence with TMS and amyloid markers. CONCLUSIONS: TMS in addition to routine clinical assessment in MCI subjects has a significant effect on diagnostic accuracy and confidence, comparable to well-established biomarkers of amyloidosis.

Extrastriatal dopaminergic and serotonergic pathways in Parkinson's disease and in dementia with Lewy bodies: a 123I-FP-CIT SPECT study.

PURPOSE: The aim of the study was to evaluate extrastriatal dopaminergic and serotonergic pathways in patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB) using 123I-FP-CIT SPECT imaging. METHODS: The study groups comprised 56 PD patients without dementia, 41 DLB patients and 54 controls. Each patient underwent a standardized neurological examination and 123I-FP-CIT SPECT. Binding in nigrostriatal and extrastriatal regions of interest was calculated in each patient from spatially normalized images. The occipital-adjusted specific to nondisplaceable binding ratio (SBR) in the different regions was compared among the PD patients, DLB patients and controls adjusting for the effects of age, sex, disease duration and serotonergic/dopaminergic treatment. Covariance analysis was used to determine the correlates of local and long-distance regions with extrastriatal 123I-FP-CIT deficits. RESULTS: Both PD and DLB patients showed lower 123I-FP-CIT SPECT SBR in several regions beyond the nigrostriatal system, especially the insula, cingulate and thalamus. DLB patients showed significantly lower 123I-FP-CIT SBR in the thalamus than controls and PD patients. Thalamic and cingulate 123I-FP-CIT SBR deficits were correlated, respectively, with limbic serotonergic and widespread cortical monoaminergic projections only in DLB patients but exhibited only local correlations in PD patients and controls. CONCLUSION: PD and DLB patients both showed insular dopamine deficits, whereas impairment of thalamic serotonergic pathways was specifically associated with DLB. Longitudinal studies are necessary to determine the clinical value of the assessment of extrastriatal 123I-FP-CIT SPECT.

Long-term efficacy of docosahexaenoic acid (DHA) for Spinocerebellar Ataxia 38 (SCA38) treatment: An open label extension study.

INTRODUCTION: Spinocerebellar Ataxia 38 (SCA38) is caused by ELOVL5 gene mutation, with significant reduction of serum docosahexaenoic acid (DHA) levels. DHA supplementation has been proven effective at short-term follow-up. In the present paper, we evaluated long-term safety and efficacy of 600 mg/day oral DHA in SCA38 by a 2-year open label extension study. METHODS: Nine SCA38 patients underwent standardised clinical assessment at 62 (T1), 82 (T2) and 104 (T3) weeks, and compared to pre-treatment scores (T0). Brain 18-Fluorodeoxyglucose Positron Emission Tomography and electroneurography were performed at T0 and T3. RESULTS: We found a significant maintenance of clinical symptom improvement at each follow-up time-point (p < 0.001) as compared to T0, a sustained increase of cerebellar metabolism at T3 as compared to T0 (p = 0.013), and no worsening of neurophysiological parameters. No side effect was recorded. CONCLUSIONS: Long-term DHA supplementation is an eligible treatment for SCA38.

Emerging topics and practical aspects for an appropriate use of amyloid PET in the current Italian context.

In May 2017 some representatives of the Italian nuclear medicine and neurological communities spontaneously met to discuss the issues emerged during the first two years of routine application of amyloid PET with fluorinated radiopharmaceuticals in the real world. The limitations of a binary classification of scans, the possibility to obtain early images as a surrogate marker of regional cerebral bloos flow, the need for (semi-)quantification and, thus, the opportunity of ranking brain amyloidosis, the correlation with Aß42 levels in the cerebrospinal fluid, the occurrence and biological meaning of uncertain/boderline scans, the issue of incidental amyloidosis, the technical pittfalls leading to false negative/positive results, the position of the tool in the diagnostic flow-chart in the national reality, are the main topics that have been discussed. Also, a card to justify the examination to be filled by the dementia specialist and a card for the nuclear medicine physician to report the exam in detail have been approved and are available in the web, which should facilitate the creation of a national register, as previewed by the 2015 intersocietal recommendation on the use of amyloid PET in Italy. The content of this discussion could stimulate both public institutions and companies to support further research on these topics.

The impact of transcranial magnetic stimulation on diagnostic confidence in patients with Alzheimer disease.

BACKGROUND: Cholinergic dysfunction is a key abnormality in Alzheimer disease (AD) that can be detected in vivo with transcranial magnetic stimulation (TMS) protocols. Although TMS has clearly demonstrated analytical validity, its clinical utility is still debated. In the present study, we evaluated the incremental diagnostic value, expressed in terms of diagnostic confidence of Alzheimer disease (DCAD; range 0-100), of TMS measures in addition to the routine clinical diagnostic assessment in patients evaluated for cognitive impairment as compared with validated biomarkers of amyloidosis. METHODS: One hundred twenty patients with dementia were included and scored in terms of DCAD in a three-step assessment based on (1) demographic, clinical, and neuropsychological evaluations (clinical work-up); (2) clinical work-up plus amyloid markers (cerebrospinal fluid or amyloid positron emission tomographic imaging); and (3) clinical work-up plus TMS intracortical connectivity measures. Two blinded neurologists were asked to review the diagnosis and diagnostic confidence at each step. RESULTS: TMS measures increased the discrimination of DCAD in two clusters (AD-like vs FTD-like) when added to the clinical and neuropsychological evaluations with levels comparable to established biomarkers of brain amyloidosis (cluster distance of 55.1 for clinical work-up alone, 76.0 for clinical work-up plus amyloid markers, 80.0 for clinical work-up plus TMS). Classification accuracy for the "gold standard" diagnosis (dichotomous - AD vs FTD - variable) evaluated in the three-step assessment, expressed as AUC, increased from 0.82 (clinical work-up alone) to 0.98 (clinical work-up plus TMS) and to 0.99 (clinical work-up plus amyloidosis markers). CONCLUSIONS: TMS in addition to routine assessment in patients with dementia has a significant effect on diagnosis and diagnostic confidence that is comparable to well-established amyloidosis biomarkers.

Single-subject SPM FDG-PET patterns predict risk of dementia progression in Parkinson disease.

OBJECTIVE: To evaluate the statistical parametric mapping (SPM) procedure for fluorodeoxyglucose (FDG)-PET imaging as a possible single-subject marker of progression to dementia in Parkinson disease (PD). METHODS: Fifty-four consecutive patients with PD without dementia (age at onset of 59.9 ± 10.1 years, disease duration of 5.3 ± 3.4 years) entered the study. The patients underwent an extensive motor and cognitive assessment and a single-subject FDG-PET SPM evaluation at baseline. A 4-year follow-up provided disease progression and dementia diagnosis. RESULTS: The FDG-PET SPM was evaluated by 2 expert raters allowing the identification of a "typical PD pattern" in 29 patients, whereas 25 patients presented with "atypical patterns," namely, dementia with Lewy bodies (DLB)-like (n = 12), Alzheimer disease (AD)-like (n = 6), corticobasal syndrome (CBS)-like (n = 5), and frontotemporal dementia (FTD)-like (n = 2). At 4-year follow-up, 13 patients, all showing atypical brain metabolic patterns at baseline, progressed to dementia (PD dementia). The DLB- and AD-like SPM patterns were the best predictor for incident dementia (p < 0.005, sensitivity 85%, specificity 88%), independently from demographics or cognitive baseline classification. CONCLUSIONS: This study suggests that FDG-PET SPM at the single-subject level might help in identifying patients with PD at risk of developing dementia.

Attenuation correction in myocardial perfusion imaging affects the assessment of infarct size in women with previous inferior infarct.

BACKGROUND: Myocardial perfusion imaging is a well-established diagnostic tool in patients with known or suspected coronary artery disease. Numerous clinical trials have shown that attenuation correction (AC) in single photon emission computed tomography (SPECT) improves the diagnostic accuracy of myocardial perfusion imaging over non-AC SPECT, differentiating between scar and attenuation artifacts. We have previously shown that attenuation artifacts produce an overestimation of the size of inferior infarcts in the male population. It is assumed that women are less affected by inferior attenuation artifacts than men. PURPOSE: The aim of this study is to evaluate the role of AC in the assessment of infarct size in female patients with a history of myocardial inferior infarct. PATIENTS AND METHODS: We studied a population of 66 consecutive women, with a history of previous inferior myocardial infarct, by SPECT/computed tomography (CT) with 370+370 MBq of technetium-99m labeled compounds by a 2-day stress-rest protocol. Both AC and uncorrected gated-SPECT/CT studies were reconstructed after scatter and motion correction by ordered-subset expectation maximization iterative reconstruction and resolution recovery. The coregistration of the transmission and emission scans was verified for all patients; any misalignment was realigned manually. Uncorrected and corrected SPECT images were analyzed by software QPS/QGS package using a 17-segment model. For each segment, perfusion and wall motion were quantified using a five-point score according to the American Society of Nuclear Cardiology guidelines. Summed stress, summed rest score (SRS), and summed difference score of the inferior left ventricle wall (inferior, inferoseptal, inferolateral, and apical inferior segments) were calculated. A linear correlation was used to assess the relationship between perfusion and the regional wall motion score as determined by uncorrected gated-SPECT. RESULTS: The results of quantitative analysis of non-AC and CT-AC SPECT images, respectively, were as follows: summed stress score: 9.47±5.01 and 6.58±4.77% (P<0.001); SRS was 6.05±5.02 and 4.14±4.12% (P<0.001); the summed difference score was 2.92±2.74 and 2.52±2.63% (P=NS), respectively. The correlation between corrected and uncorrected SRS and the regional summed wall motion score of the same segment was R=0.31 versus R=0.34. CONCLUSION: In the female population, like in men, attenuation artifacts affect the calculation of the infarct size of the inferior wall, with overestimation of the infarct size in uncorrected images. The AC regional perfusion score (SRS) better correlates with the regional wall motion score of the inferior wall in women with previous inferior infarct.

Docosahexaenoic acid is a beneficial replacement treatment for spinocerebellar ataxia 38.

OBJECTIVE: Spinocerebellar ataxia 38 (SCA38) is caused by mutations in the ELOVL5 gene, which encodes an elongase involved in the synthesis of polyunsaturated fatty acids, including docosahexaenoic acid (DHA). As a consequence, DHA is significantly reduced in the serum of SCA38 subjects. In the present study, we evaluated the safety of DHA supplementation, its efficacy for clinical symptoms, and changes of brain functional imaging in SCA38 patients. METHODS: We enrolled 10 SCA38 patients, and carried out a double-blind randomized placebo-controlled study for 16 weeks, followed by an open-label study with overall 40-week DHA treatment. At baseline and at follow-up visit, patients underwent standardized clinical assessment, brain 18-fluorodeoxyglucose positron emission tomography, electroneurography, and ELOVL5 expression analysis. RESULTS: After 16 weeks, we showed a significant pre-post clinical improvement in the DHA group versus placebo, using the Scale for the Assessment and Rating of Ataxia (SARA; mean difference [MD] = +2.70, 95% confidence interval [CI] = +0.13 to + 5.27, p = 0.042). At 40-week treatment, clinical improvement was found significant by both SARA (MD = +2.2, 95% CI = +0.93 to + 3.46, p = 0.008) and International Cooperative Ataxia Rating Scale (MD = +3.8, 95% CI = +1.39 to + 6.41, p = 0.02) scores; clinical data were corroborated by significant improvement of cerebellar hypometabolism (statistical parametric mapping analyses, false discovery rate corrected). We also showed a decreased expression of ELOVL5 in patients' blood at 40 weeks as compared to baseline. No side effect was recorded. INTERPRETATION: DHA supplementation is a safe and effective treatment for SCA38, showing an improvement of clinical symptoms and cerebellar hypometabolism. Ann Neurol 2017;82:615-621.

Cerebral PET glucose hypometabolism in subjects with mild cognitive impairment and higher EEG high-alpha/low-alpha frequency power ratio.

In Alzheimer's disease (AD) research, both 2-deoxy-2-(18F)fluoro-D-glucose (FDG) positron emission tomography (PET) and electroencephalography (EEG) are reliable investigational modalities. The aim of this study was to investigate the associations between EEG High-alpha/Low-alpha (H-alpha/L-alpha) power ratio and cortical glucose metabolism. A total of 23 subjects with mild cognitive impairment (MCI) underwent FDG-PET and EEG examinations. H-alpha/L-alpha power ratio was computed for each subject and 2 groups were obtained based on the increase of the power ratio. The subjects with higher H-alpha/L-alpha power ratio showed a decrease in glucose metabolism in the hub brain areas previously identified as typically affected by AD pathology. In subjects with higher H-alpha/L-alpha ratio and lower metabolism, a "double alpha peak" was identified in the EEG spectrum and a U-shaped correlation between glucose metabolism and increase of H-alpha/L-alpha power ratio has been found. Moreover, in this group, a conversion rate of 62.5% at 24 months was detected, significantly different from the chance percentage expected. The neurophysiological meaning of the interplay between alpha oscillations and glucose metabolism and the possible interest of the H-alpha/L-alpha power ratio as a clinical biomarker in AD have been discussed.

Altered brain metabolic connectivity at multiscale level in early Parkinson's disease.

To explore the effects of PD pathology on brain connectivity, we characterized with an emergent computational approach the brain metabolic connectome using [18F]FDG-PET in early idiopathic PD patients. We applied whole-brain and pathology-based connectivity analyses, using sparse-inverse covariance estimation in thirty-four cognitively normal PD cases and thirty-four age-matched healthy subjects for comparisons. Further, we assessed high-order resting state networks by interregional correlation analysis. Whole-brain analysis revealed altered metabolic connectivity in PD, with local decreases in frontolateral cortex and cerebellum and increases in the basal ganglia. Widespread long-distance decreases were present within the frontolateral cortex as opposed to connectivity increases in posterior cortical regions, all suggestive of a global-scale connectivity reconfiguration. The pathology-based analyses revealed significant connectivity impairment in the nigrostriatal dopaminergic pathway and in the regions early affected by α-synuclein pathology. Notably, significant connectivity changes were present in several resting state networks especially in frontal regions. These findings expand previous imaging evidence of altered connectivity in cognitively stable PD patients by showing pathology-based connectivity changes and disease-specific metabolic architecture reconfiguration at multiple scale levels, from the earliest PD phases. These alterations go well beyond the known striato-cortical connectivity derangement supporting in vivo an extended neural vulnerability in the PD synucleinopathy.

Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly.

The pathway leading from amyloid-ß deposition to cognitive impairment is believed to be a cornerstone of the pathogenesis of Alzheimer's disease (AD). However, what drives amyloid buildup in sporadic nongenetic cases of AD is still unknown. AD brains feature an inflammatory reaction around amyloid plaques, and a specific subset of the gut microbiota (GMB) may promote brain inflammation. We investigated the possible role of the GMB in AD pathogenesis by studying the association of brain amyloidosis with (1) GMB taxa with pro- and anti-inflammatory activity; and (2) peripheral inflammation in cognitively impaired patients. We measured the stool abundance of selected bacterial GMB taxa (Escherichia/Shigella, Pseudomonas aeruginosa, Eubacterium rectale, Eubacterium hallii, Faecalibacterium prausnitzii, and Bacteroides fragilis) and the blood expression levels of cytokines (pro-inflammatory cytokines: CXCL2, CXCL10, interleukin [IL]-1ß, IL-6, IL-18, IL-8, inflammasome complex (NLRP3), tumor necrosis factor-alpha [TNF-α]; anti-inflammatory cytokines: IL-4, IL-10, IL-13) in cognitively impaired patients with (n = 40, Amy+) and with no brain amyloidosis (n = 33, Amy-) and also in a group of controls (n = 10, no brain amyloidosis and no cognitive impairment). Amy+ patients showed higher levels of pro-inflammatory cytokines (IL-6, CXCL2, NLRP3, and IL-1ß) compared with both controls and with Amy- patients. A reduction of the anti-inflammatory cytokine IL-10 was observed in Amy+ versus Amy-. Amy+ showed lower abundance of E. rectale and higher abundance of Escherichia/Shigella compared with both healthy controls (fold change, FC = -9.6, p < 0.001 and FC = +12.8, p < 0.001, respectively) and to Amy- (FC = -7.7, p < 0.001 and FC = +7.4, p = 0.003). A positive correlation was observed between pro-inflammatory cytokines IL-1ß, NLRP3, and CXCL2 with abundance of the inflammatory bacteria taxon Escherichia/Shigella (rho = 0.60, p < 0.001; rho = 0.57, p < 0.001; and rho = 0.30, p = 0.007, respectively) and a negative correlation with the anti-inflammatory E. rectale (rho = -0.48, p < 0.001; rho = -0.25, p = 0.024; rho = -0.49, p < 0.001). Our data indicate that an increase in the abundance of a pro-inflammatory GMB taxon, Escherichia/Shigella, and a reduction in the abundance of an anti-inflammatory taxon, E. rectale, are possibly associated with a peripheral inflammatory state in patients with cognitive impairment and brain amyloidosis. A possible causal relation between GMB-related inflammation and amyloidosis deserves further investigation.