Metabolic network alterations as a supportive biomarker in dementia with Lewy bodies with preserved dopamine transmission.

PURPOSE: Metabolic network analysis of FDG-PET utilizes an index of inter-regional correlation of resting state glucose metabolism and has been proven to provide complementary information regarding the disease process in parkinsonian syndromes. The goals of this study were (i) to evaluate pattern similarities of glucose metabolism and network connectivity in dementia with Lewy bodies (DLB) subjects with subthreshold dopaminergic loss compared to advanced disease stages and to (ii) investigate metabolic network alterations of FDG-PET for discrimination of patients with early DLB from other neurodegenerative disorders (Alzheimer's disease, Parkinson's disease, multiple system atrophy) at individual patient level via principal component analysis (PCA). METHODS: FDG-PETs of subjects with probable or possible DLB (n = 22) without significant dopamine deficiency (z-score < 2 in putamen binding loss on DaT-SPECT compared to healthy controls (HC)) were scaled by global-mean, prior to volume-of-interest-based analyses of relative glucose metabolism. Single region metabolic changes and network connectivity changes were compared against HC (n = 23) and against DLB subjects with significant dopamine deficiency (n = 86). PCA was applied to test discrimination of patients with DLB from disease controls (n = 101) at individual patient level. RESULTS: Similar patterns of hypo- (parietal- and occipital cortex) and hypermetabolism (basal ganglia, limbic system, motor cortices) were observed in DLB patients with and without significant dopamine deficiency when compared to HC. Metabolic connectivity alterations correlated between DLB patients with and without significant dopamine deficiency (R2 = 0.597, p < 0.01). A PCA trained by DLB patients with dopamine deficiency and HC discriminated DLB patients without significant dopaminergic loss from other neurodegenerative parkinsonian disorders at individual patient level (area-under-the-curve (AUC): 0.912). CONCLUSION: Disease-specific patterns of altered glucose metabolism and altered metabolic networks are present in DLB subjects without significant dopaminergic loss. Metabolic network alterations in FDG-PET can act as a supporting biomarker in the subgroup of DLB patients without significant dopaminergic loss at symptoms onset.

Dopaminergic imaging in degenerative parkinsonisms, an established clinical diagnostic tool.

Parkinson's disease (PD) and other neurodegenerative parkinsonisms are characterised by loss of striatal dopaminergic neurons. Dopamine functional deficits can be measured in vivo using positron emission tomography (PET) and single-photon emission computed tomography (SPECT) ligands assessing either presynaptic (e.g. dopamine synthesis and storage, transporter density) or postsynaptic terminals (i.e. D2 receptors availability). Nuclear medicine imaging thus helps the clinician to separate degenerative forms of parkinsonism with other neurological conditions, e.g. essential tremor or drug-induced parkinsonism. With the present study, we aimed at summarizing the current evidence about dopaminergic molecular imaging in the diagnostic evaluation of PD, atypical parkinsonian syndromes and dementia with Lewy bodies (DLB), as well as its potential to distinguish these conditions and to estimate disease progression. In fact, PET/SPECT methods are clinically validated and have been increasingly integrated into diagnostic guidelines (e.g. for PD and DLB). In addition, there is novel evidence on the classification properties of extrastriatal signal. Finally, dopamine imaging has an outstanding potential to detect neurodegeneration at the premotor stage, including REM-sleep behavior disorder and olfactory loss. Therefore, inclusion of subjects at an early stage for clinical trials can largely benefit from a validated in vivo biomarker such as presynaptic dopamine pathways PET/SPECT assessment.

Sex differences in dementia with Lewy bodies: an imaging study of neurotransmission pathways.

PURPOSE: Dementia with Lewy bodies (DLB) is characterized by a wide clinical and biological heterogeneity, with sex differences reported in both clinical and pathologically confirmed DLB cohorts. No research evidence is available on sex differences regarding molecular neurotransmission. This study aimed to assess whether sex can influence neurotransmitter systems in patients with probable DLB (pDLB). METHODS: We included 123 pDLB patients (male/female: 77/46) and 78 control subjects (male/female: 34/44) for comparison, who underwent 123I-FP-CIT SPECT imaging. We assessed sex differences in the dopaminergic activity of the nigrostriatal and mesolimbic systems using regional-based and voxel-wise analyses of 123I-FP-CIT binding. We tested whether sex-specific binding alterations would also pertain to the serotoninergic and noradrenergic systems by applying spatial correlation analyses. We applied molecular connectivity analyses to assess potential sex differences in the dopaminergic pathways. RESULTS: We found comparable 123I-FP-CIT binding decreases in the striatum for pDLB males and females compared to controls. However, pDLB females showed lower binding in the extrastriatal projections of the nigrostriatal and mesolimbic dopaminergic systems compared to pDLB males. According to the spatial correlation analysis, sex-specific molecular alterations were also associated with serotonergic and noradrenergic systems. Nigrostriatal and mesolimbic systems' connectivity was impaired in both groups, with males showing local alterations and females presenting long-distance disconnections between subcortical and cortical regions. CONCLUSIONS: Sex-specific differences in 123I-FP-CIT binding were found in our cohort, namely, a trend for lower 123I-FP-CIT binding in females, significant in the presence of a pDLB diagnosis. pDLB females showed also different patterns of connectivity compared to males, mostly involving extrastriatal regions. The results suggest the presence of a sex-related regional vulnerability to alpha-synuclein pathology, possibly complicated also by the higher prevalence of Alzheimer's disease co-pathology in females, as previously reported in pDLB populations.

A 3D deep learning model to predict the diagnosis of dementia with Lewy bodies, Alzheimer's disease, and mild cognitive impairment using brain 18F-FDG PET.

PURPOSE: The purpose of this study is to develop and validate a 3D deep learning model that predicts the final clinical diagnosis of Alzheimer's disease (AD), dementia with Lewy bodies (DLB), mild cognitive impairment due to Alzheimer's disease (MCI-AD), and cognitively normal (CN) using fluorine 18 fluorodeoxyglucose PET (18F-FDG PET) and compare model's performance to that of multiple expert nuclear medicine physicians' readers. MATERIALS AND METHODS: Retrospective 18F-FDG PET scans for AD, MCI-AD, and CN were collected from Alzheimer's disease neuroimaging initiative (556 patients from 2005 to 2020), and CN and DLB cases were from European DLB Consortium (201 patients from 2005 to 2018). The introduced 3D convolutional neural network was trained using 90% of the data and externally tested using 10% as well as comparison to human readers on the same independent test set. The model's performance was analyzed with sensitivity, specificity, precision, F1 score, receiver operating characteristic (ROC). The regional metabolic changes driving classification were visualized using uniform manifold approximation and projection (UMAP) and network attention. RESULTS: The proposed model achieved area under the ROC curve of 96.2% (95% confidence interval: 90.6-100) on predicting the final diagnosis of DLB in the independent test set, 96.4% (92.7-100) in AD, 71.4% (51.6-91.2) in MCI-AD, and 94.7% (90-99.5) in CN, which in ROC space outperformed human readers performance. The network attention depicted the posterior cingulate cortex is important for each neurodegenerative disease, and the UMAP visualization of the extracted features by the proposed model demonstrates the reality of development of the given disorders. CONCLUSION: Using only 18F-FDG PET of the brain, a 3D deep learning model could predict the final diagnosis of the most common neurodegenerative disorders which achieved a competitive performance compared to the human readers as well as their consensus.

Adopting transfer learning for neuroimaging: a comparative analysis with a custom 3D convolution neural network model.

BACKGROUND: In recent years, neuroimaging with deep learning (DL) algorithms have made remarkable advances in the diagnosis of neurodegenerative disorders. However, applying DL in different medical domains is usually challenged by lack of labeled data. To address this challenge, transfer learning (TL) has been applied to use state-of-the-art convolution neural networks pre-trained on natural images. Yet, there are differences in characteristics between medical and natural images, also image classification and targeted medical diagnosis tasks. The purpose of this study is to investigate the performance of specialized and TL in the classification of neurodegenerative disorders using 3D volumes of 18F-FDG-PET brain scans. RESULTS: Results show that TL models are suboptimal for classification of neurodegenerative disorders, especially when the objective is to separate more than two disorders. Additionally, specialized CNN model provides better interpretations of predicted diagnosis. CONCLUSIONS: TL can indeed lead to superior performance on binary classification in timely and data efficient manner, yet for detecting more than a single disorder, TL models do not perform well. Additionally, custom 3D model performs comparably to TL models for binary classification, and interestingly perform better for diagnosis of multiple disorders. The results confirm the superiority of the custom 3D-CNN in providing better explainable model compared to TL adopted ones.

Microglial activation and tau burden predict cognitive decline in Alzheimer's disease.

Tau pathology, neuroinflammation, and neurodegeneration are key aspects of Alzheimer's disease. Understanding whether these features predict cognitive decline, alone or in combination, is crucial to develop new prognostic measures and enhanced stratification for clinical trials. Here, we studied how baseline assessments of in vivo tau pathology (measured by 18F-AV-1451 PET), neuroinflammation (measured by 11C-PK11195 PET) and brain atrophy (derived from structural MRI) predicted longitudinal cognitive changes in patients with Alzheimer's disease pathology. Twenty-six patients (n = 12 with clinically probable Alzheimer's dementia and n = 14 with amyloid-positive mild cognitive impairment) and 29 healthy control subjects underwent baseline assessment with 18F-AV-1451 PET, 11C-PK11195 PET, and structural MRI. Cognition was examined annually over the subsequent 3 years using the revised Addenbrooke's Cognitive Examination. Regional grey matter volumes, and regional binding of 18F-AV-1451 and 11C-PK11195 were derived from 15 temporo-parietal regions characteristically affected by Alzheimer's disease pathology. A principal component analysis was used on each imaging modality separately, to identify the main spatial distributions of pathology. A latent growth curve model was applied across the whole sample on longitudinal cognitive scores to estimate the rate of annual decline in each participant. We regressed the individuals' estimated rate of cognitive decline on the neuroimaging components and examined univariable predictive models with single-modality predictors, and a multi-modality predictive model, to identify the independent and combined prognostic value of the different neuroimaging markers. Principal component analysis identified a single component for the grey matter atrophy, while two components were found for each PET ligand: one weighted to the anterior temporal lobe, and another weighted to posterior temporo-parietal regions. Across the whole-sample, the single-modality models indicated significant correlations between the rate of cognitive decline and the first component of each imaging modality. In patients, both stepwise backward elimination and Bayesian model selection revealed an optimal predictive model that included both components of 18F-AV-1451 and the first (i.e. anterior temporal) component for 11C-PK11195. However, the MRI-derived atrophy component and demographic variables were excluded from the optimal predictive model of cognitive decline. We conclude that temporo-parietal tau pathology and anterior temporal neuroinflammation predict cognitive decline in patients with symptomatic Alzheimer's disease pathology. This indicates the added value of PET biomarkers in predicting cognitive decline in Alzheimer's disease, over and above MRI measures of brain atrophy and demographic data. Our findings also support the strategy for targeting tau and neuroinflammation in disease-modifying therapy against Alzheimer's disease.

Associations among education, age, and the dementia with Lewy bodies (DLB) metabolic pattern: A European-DLB consortium project.

INTRODUCTION: We assessed the influence of education as a proxy of cognitive reserve and age on the dementia with Lewy bodies (DLB) metabolic pattern. METHODS: Brain 18F-fluorodeoxyglucose positron emission tomography and clinical/demographic information were available in 169 probable DLB patients included in the European DLB-consortium database. Principal component analysis identified brain regions relevant to local data variance. A linear regression model was applied to generate age- and education-sensitive maps corrected for Mini-Mental State Examination score, sex (and either education or age). RESULTS: Age negatively covaried with metabolism in bilateral middle and superior frontal cortex, anterior and posterior cingulate, reducing the expression of the DLB-typical cingulate island sign (CIS). Education negatively covaried with metabolism in the left inferior parietal cortex and precuneus (making the CIS more prominent). DISCUSSION: These findings point out the importance of tailoring interpretation of DLB biomarkers considering the concomitant effect of individual, non-disease-related variables such as age and cognitive reserve.

Metabolic patterns across core features in dementia with lewy bodies.

OBJECTIVE: To identify brain regions whose metabolic impairment contributes to dementia with Lewy bodies (DLB) clinical core features expression and to assess the influence of severity of global cognitive impairment on the DLB hypometabolic pattern. METHODS: Brain fluorodeoxyglucose positron emission tomography and information on core features were available in 171 patients belonging to the imaging repository of the European DLB Consortium. Principal component analysis was applied to identify brain regions relevant to the local data variance. A linear regression model was applied to generate core-feature-specific patterns controlling for the main confounding variables (Mini-Mental State Examination [MMSE], age, education, gender, and center). Regression analysis to the locally normalized intensities was performed to generate an MMSE-sensitive map. RESULTS: Parkinsonism negatively covaried with bilateral parietal, precuneus, and anterior cingulate metabolism; visual hallucinations (VH) with bilateral dorsolateral-frontal cortex, posterior cingulate, and parietal metabolism; and rapid eye movement sleep behavior disorder (RBD) with bilateral parieto-occipital cortex, precuneus, and ventrolateral-frontal metabolism. VH and RBD shared a positive covariance with metabolism in the medial temporal lobe, cerebellum, brainstem, basal ganglia, thalami, and orbitofrontal and sensorimotor cortex. Cognitive fluctuations negatively covaried with occipital metabolism and positively with parietal lobe metabolism. MMSE positively covaried with metabolism in the left superior frontal gyrus, bilateral-parietal cortex, and left precuneus, and negatively with metabolism in the insula, medial frontal gyrus, hippocampus in the left hemisphere, and right cerebellum. INTERPRETATION: Regions of more preserved metabolism are relatively consistent across the variegate DLB spectrum. By contrast, core features were associated with more prominent hypometabolism in specific regions, thus suggesting a close clinical-imaging correlation, reflecting the interplay between topography of neurodegeneration and clinical presentation in DLB patients. Ann Neurol 2019;85:715-725.

In vivo neuroinflammation and cerebral small vessel disease in mild cognitive impairment and Alzheimer's disease.

INTRODUCTION: Associations between cerebral small vessel disease (SVD) and inflammation have been largely examined using peripheral blood markers of inflammation, with few studies measuring inflammation within the brain. We investigated the cross-sectional relationship between SVD and in vivo neuroinflammation using [11C]PK11195 positron emission tomography (PET) imaging. METHODS: Forty-two participants were recruited (according to NIA-AA guidelines, 14 healthy controls, 14 mild Alzheimer's disease, 14 amyloid-positive mild cognitive impairment). Neuroinflammation was assessed using [11C]PK11195 PET imaging, a marker of microglial activation. To quantify SVD, we assessed white matter hyperintensities (WMH), enlarged perivascular spaces, cerebral microbleeds and lacunes. Composite scores were calculated for global SVD burden, and SVD subtypes of hypertensive arteriopathy and cerebral amyloid angiopathy (CAA). General linear models examined associations between SVD and [11C]PK11195, adjusting for sex, age, education, cognition, scan interval, and corrected for multiple comparisons via false discovery rate (FDR). Dominance analysis directly compared the relative importance of hypertensive arteriopathy and CAA scores as predictors of [11C]PK11195. RESULTS: Global [11C]PK11195 binding was associated with SVD markers, particularly in regions typical of hypertensive arteriopathy: deep microbleeds (ß=0.63, F(1,35)=35.24, p<0.001), deep WMH (ß=0.59, t=4.91, p<0.001). In dominance analysis, hypertensive arteriopathy score outperformed CAA in predicting [11C]PK11195 binding globally and in 28 out of 37 regions of interest, especially the medial temporal lobe (ß=0.66-0.76, t=3.90-5.58, FDR-corrected p (pFDR)=<0.001-0.002) and orbitofrontal cortex (ß=0.51-0.57, t=3.53-4.30, pFDR=0.001-0.004). CONCLUSION: Microglial activation is associated with SVD, particularly with the hypertensive arteriopathy subtype of SVD. Although further research is needed to determine causality, our study suggests that targeting neuroinflammation might represent a novel therapeutic strategy for SVD.

Metabolic Correlates of Dopaminergic Loss in Dementia with Lewy Bodies.

BACKGROUND: Striatal dopamine deficiency and metabolic changes are well-known phenomena in dementia with Lewy bodies and can be quantified in vivo by 123 I-Ioflupane brain single-photon emission computed tomography of dopamine transporter and 18 F-fluorodesoxyglucose PET. However, the linkage between both biomarkers is ill-understood. OBJECTIVE: We used the hitherto largest study cohort of combined imaging from the European consortium to elucidate the role of both biomarkers in the pathophysiological course of dementia with Lewy bodies. METHODS: We compared striatal dopamine deficiency and glucose metabolism of 84 dementia with Lewy body patients and comparable healthy controls. After normalization of data, we tested their correlation by region-of-interest-based and voxel-based methods, controlled for study center, age, sex, education, and current cognitive impairment. Metabolic connectivity was analyzed by inter-region coefficients stratified by dopamine deficiency and compared to healthy controls. RESULTS: There was an inverse relationship between striatal dopamine availability and relative glucose hypermetabolism, pronounced in the basal ganglia and in limbic regions. With increasing dopamine deficiency, metabolic connectivity showed strong deteriorations in distinct brain regions implicated in disease symptoms, with greatest disruptions in the basal ganglia and limbic system, coincident with the pattern of relative hypermetabolism. CONCLUSIONS: Relative glucose hypermetabolism and disturbed metabolic connectivity of limbic and basal ganglia circuits are metabolic correlates of dopamine deficiency in dementia with Lewy bodies. Identification of specific metabolic network alterations in patients with early dopamine deficiency may serve as an additional supporting biomarker for timely diagnosis of dementia with Lewy bodies. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Extrastriatal 123I-FP-CIT SPECT impairment in Parkinson's disease - the PPMI cohort.

BACKGROUND: Neuropathological data and nuclear medicine imaging show extensive serotonergic impairment in Parkinson's disease (PD). We undertook a case-controlled analysis of 123I-FP-CIT SPECT images to measure extrastriatal serotonergic transporters (SERT) in PD using the Parkinson's Progression Markers Initiative (PPMI) cohort. METHODS: We included all PD (n = 154) and Control subjects (n = 62) with available 123I-FP-CIT SPECT imaging and high-resolution T1-weighted MRI for coregistration (PD: mean age 61.6 years, 62% male, disease duration 26 months, MDS-UPDRS III score 22). 123I-FP-CIT SPECT images were processed with PETPVE12 using an exploratory voxel-wise analysis including partial-volume effect correction. Linear regressions were performed in the PD group to assess correlations between region of interest 123I-FP-CIT uptake and clinical motor and non-motor impairment. RESULTS: Compared to Controls, PD exhibited an uptake reduction in bilateral caudate nucleus, putamen, insula, amygdala and right pallidum (family-wise error (FWE)-corrected p <  0.05). While lower putaminal uptake on the contralateral side to clinically more affected side was associated with higher MDS-UPDRS III score (p = 0.022), we found a trend association between higher geriatric depression scale and lower pallidum uptake (p = 0.09). Higher SCOPA-AUT gastrointestinal subscore was associated with lower uptake in mean putamen and caudate nucleus (p = 0.01 to 0.03), whereas urological subscore was inversely correlated with mean caudate nucleus, putamen, and pallidum uptake (p = 0.002 to 0.03). REM sleep behaviour disorder screening questionnaire was associated with lower 123I-FP-CIT binding in caudate nucleus, putamen and pallidum (all p <  0.05). No significant association was found for Montreal Cognitive Assessment (all p > 0.45) or excessive daytime sleepiness (all p > 0.29). CONCLUSIONS: In addition to the well-established striatal deficit, this study provides evidence of a major extrastriatal 123I-FP-CIT impairment, and therefore of an altered serotonergic transmission in early PD.

Distinct spatiotemporal patterns for disease duration and stage in Parkinson's disease.

PURPOSE: To assess correlations between the degree of dopaminergic depletion measured using single-photon emission computed tomography (SPECT) and different clinical parameters of disease progression in Parkinson's disease (PD). METHODS: This retrospective study included 970 consecutive patients undergoing (123)I-ioflupane SPECT scans in our institution between 2003 and 2013, from which we selected a study population of 411 patients according to their clinical diagnosis: 301 patients with PD (69.4 ± 11.0 years, of age, 163 men) and 110 patients with nondegenerative conditions included as controls (72.7 ± 8.0 years of age, 55 men). Comprehensive and operator-independent data analysis included spatial normalization into standard space, estimation of the mean uptake values in the striatum (caudate nucleus + putamen) and voxel-wise correlation between SPECT signal intensity and disease stage as well as disease duration in order to investigate the spatiotemporal pattern of the dopaminergic nigrostriatal degeneration. To compensate for potential interactions between disease stage and disease duration, one parameter was used as nonexplanatory coregressor for the other. RESULTS: Increasing disease stage was associated with an exponential decrease in (123)I-ioflupane uptake (R(2) = 0.1501) particularly in the head of the ipsilateral caudate nucleus (p < 0.0001), whereas increasing disease duration was associated with a linear decrease in (123)I-ioflupane uptake (p < 0.0001; R(2) = 0.1532) particularly in the contralateral anterior putamen (p < 0.0001). CONCLUSION: We observed two distinct spatiotemporal patterns of posterior to anterior dopaminergic depletion associated with disease stage and disease duration in patients with PD. The developed operator-independent reference database of 411 (123)I-ioflupane SPECT scans can be used for clinical and research applications.

Pure Progressive Ataxia and Palatal Tremor (PAPT) Associated with a New Polymerase Gamma (POLG) Mutation.

Progressive ataxia with palatal tremor (PAPT) is a syndrome caused by cerebellar and brainstem lesions involving the dentato-rubro-olivary tract and associated with hypertrophic olivary degeneration. Etiologies include acquired posterior fossa lesions (e.g. tumors, superficial siderosis, and inflammatory diseases) and genetic disorders, such as glial fibrillary acidic protein (GFAP) and polymerase gamma (POLG) mutations. We describe the case of a 52-year-old man who developed pure progressive ataxia and palatal tremor. Genetic analysis has shown that he is compound heterozygote for a known pathogenic (W748S) and a novel POLG variant (I1185N). Patients with POLG recessive mutations usually manifest a more complex clinical picture, including polyneuropathy and epilepsy; our case emphasizes the need to consider a genetic origin in a seemingly sporadic and pure PAPT.

Joan of Arc: Sanctity, witchcraft or epilepsy?

OBJECTIVE: The objective of this article is to describe whether Joan of Arc had epilepsy and how that may have influenced her sense of mission and ability to encourage thousands of people to help her to chase the English out of France. METHODS: Documentation of her Trial of Condemnation in 1431 provides a description of her episodes of experienced voices and visions. RESULTS: From the age of thirteen, Joan of Arc experienced frequent episodes of auditory hallucinations associated with elementary or complex visual hallucinations (e.g., a great light or human faces). These had sudden onset, lasting seconds or minutes at most, and occurred when awake or during sleep, arousing her. Some could be triggered by an auditory stimulus. She had no disorganized thought between the episodes. CONCLUSIONS: The semiology of the episodes is very suggestive of epileptic seizures, which have been considered as ecstatic by some authors or as partial epilepsy with auditory features by others, which seems more concordant with the ictal symptoms. The auditory and visual hallucinations could have had a religious content because during her childhood and adolescence, she was brought up in a religious environment, insomuch as this content first undefined only appeared after a few seizures. We can suppose that such hallucinations, without the knowledge of their medical origin, gave her a sense of divine mission, hence, a real strength to try to accomplish the orders she heard during the episodes. Her role during the Hundred Years' War and her narration of her strange episodes led her to be burned for heresy at the age of nineteen, yet rehabilitated 25 years later and to be canonized for her achievements in 1920. This article is part of a Special Issue entitled "Epilepsy, Art, and Creativity".

Distinctive clinical and imaging trajectories in SWEDD and Parkinson's disease patients.

A proportion of patients clinically diagnosed with Parkinson's disease (PD) can have a 123I-FP-CIT-SPECT scan without evidence of dopaminergic deficit (SWEDD), generating a debate about the underlying biological mechanisms. This study investigated differences in clinical features, 123I-FP-CIT binding, molecular connectivity, as well as clinical and imaging progression between SWEDD and PD patients. We included 36 SWEDD, 49 de novo idiopathic PD, and 49 healthy controls with 123I-FP-CIT-SPECT from the Parkinson's Progression Markers Initiative. Clinical and imaging 2-year follow-ups were available for 27 SWEDD and 40 PD. Regional-based and voxel-wise analysis assessed dopaminergic integrity in dorsal and ventral striatal, as well as extrastriatal regions, at baseline and follow-up. Molecular connectivity analyses evaluated dopaminergic pathways. Spatial correlation analyses tested whether 123I-FP-CIT-binding alterations would also pertain to the serotoninergic system. SWEDD and PD patients showed comparable symptoms at baseline, except for hyposmia, which was more severe for PD. PD showed significantly lower striatal and extrastriatal 123I-FP-CIT-binding compared to SWEDD and controls. SWEDD exhibited lower binding than controls in striatal regions, insula, and olfactory cortex. Both PD and SWEDD showed extensive altered connectivity of dopaminergic pathways, however, with major impairment in the mesocorticolimbic system for SWEDD. Motor symptoms and dopaminergic deficits worsened after 2 years for PD only. The limited dopaminergic impairment and its stability over time observed for SWEDD, as well as the presence of extrastriatal 123I-FP-CIT binding alterations and prevalent mesocorticolimbic connectivity impairment, suggest other mechanisms contributing to SWEDD pathophysiology.

Mapping brain metabolism, connectivity and neurotransmitters topography in early and late onset dementia with lewy bodies.

INTRODUCTION: Early-onset dementia with Lewy bodies (EO-DLB) is associated with rapid cognitive decline and severe neuropsychiatric symptoms at onset. METHODS: Using FDG-PET imaging for 62 patients (21 EO-DLB, 41 LO (late-onset)-DLB), we explored brain hypometabolism, and metabolic connectivity in the whole-brain network and resting-state networks (RSNs). We also evaluated the spatial association between brain hypometabolism and neurotransmitter pathways topography. RESULTS: Direct comparisons between the two clinical subgroups showed that EO-DLB was characterized by a lower metabolism in posterior cingulate/precuneus and occipital cortex. Metabolic connectivity analysis revealed significant alterations in posterior regions in both EO-DLB and LO-DLB. The EO-DLB, however, showed more severe loss of connectivity between occipital and parietal nodes and hyperconnectivity between frontal and cerebellar nodes. Spatial topography association analysis indicated significant correlations between neurotransmitter maps (i.e. acetylcholine, GABA, serotonin, dopamine) and brain hypometabolism in both EO and LO-DLB, with significantly higher metabolic correlation in the presynaptic serotonergic system for EO-DLB, supporting its major dysfunction. CONCLUSIONS: Our study revealed greater brain hypometabolism and loss of connectivity in posterior brain region in EO- than LO-DLB. Serotonergic mapping emerges as a relevant factor for further investigation addressing clinical differences between DLB subtypes.

Panic Attack, Severe Hypophosphatemia and Rhabdomyolysis in the Setting of a Motor Functional Neurological Disorder.

(1) Background: panic attack is often regarded as a benign disorder with variable physical and psychological symptoms. (2) Case Presentation: We here report the case of a 22-year-old patient known for an episode of motor functional neurological disorder a year earlier who presented a panic attack with hyperventilation causing severe hypophosphatemia and rhabdomyolysis, as well as mild tetraparesis. Electrolyte disturbances quickly resolved after phosphate substitution and rehydration. However, clinical signs suggesting a relapse of a motor functional neurological disorder appeared (improved walking with dual tasks). Diagnostic workup, including brain and spinal magnetic resonance imaging, as well as electroneuromyography and genetic testing for hypokalemic periodic paralysis, was unremarkable. Tetraparesis, lack of endurance, and fatigue eventually improved after several months. (3) Conclusions: the present case report highlights the intertwined relationship between a psychiatric disorder, leading to hyperventilation and acute metabolic disturbances, and functional neurological manifestations.

Sex differences in brain metabolic connectivity architecture in probable dementia with Lewy bodies.

We investigated how sex modulates metabolic connectivity alterations in probable dementia with Lewy bodies (pDLB). We included 131 pDLB patients (males/females: 58/73) and similarly aged healthy controls (HC) (male/female: 59/75) with available (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) scans. We assessed (1) sex differences in the whole-brain connectivity, identifying pathological hubs, (2) connectivity alterations in functional pathways of the neurotransmitter systems, (3) Resting State Networks (RSNs) integrity. Both pDLBM (males) and pDLBF (females) shared dysfunctional hubs in the insula, Rolandic operculum, and inferior parietal lobule, but the pDLBM group showed more severe and diffuse whole-brain connectivity alterations. Neurotransmitters connectivity analysis revealed common alterations in dopaminergic and noradrenergic pathways. Sex differences emerged particularly in the Ch4-perisylvian division, with pDLBM showing more severe alterations than pDLBF. The RSNs analysis showed no sex differences, with decreased connectivity strength in the primary visual, posterior default mode, and attention networks in both groups. Extensive connectivity changes characterize both males and females in the dementia stage, with a major vulnerability of cholinergic neurotransmitter systems in males, possibly contributing to the observed different clinical phenotypes.