Correlations of gray matter volume with peripheral cytokines in Parkinson's disease.

INTRODUCTION: Peripheral cytokine levels may affect specific brain volumes. Few studies have examined this possible relationship. OBJECTIVE: In a case-control study, we used magnetic resonance imaging (MRI) voxel-based morphological analysis techniques to examine the relationship between gray matter volume changes and cognitive, motor and emotional dysfunction as well as between gray matter volume changes and peripheral blood cytokine levels. METHOD: A total of 134 subjects, comprising 66 PD patients and 68 healthy controls, were recruited. Peripheral venous blood was collected to measure the concentrations of 12 cytokines, including IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17, IFN-α, IFN-γ, and TNF-α. All the subjects also underwent MRI, where 3D-T1-weighted MR images were used for the analysis. In addition, the Montreal Cognitive Assessment (MoCA), Mini-Mental Status Examination (MMSE), Unified Parkinson's disease Rating Scale (UPDRS), Hamilton Anxiety Scale (HAMA), and Hamilton Depression Scale (HAMD) scores were assessed in PD patients. Statistical parameter mapping 12 software was used for the statistical analysis of the images. RESULT: Compared with control patients, PD patients presented decreased gray matter volume (GMV) in the bilateral frontal lobe, temporal lobe, parietal lobe, occipital lobe, insula, and right cerebellar lobule VIII. Regional GMV in the temporal lobe, parietal lobe, and cerebellum was correlated with MoCA, MMSE, UPDRS, HAMA, and HAMD scores in PDs. In addition, the regional GMV in PDs was correlated with the concentrations of cytokines, including IL-4, IL-6, IFN-γ, and TNF-α. The IL-6 concentration was negatively correlated with the UPDRS-IV score. CONCLUSION: PD patients exhibit gray matter atrophy in a wide range of brain regions, which are symmetrically distributed and mainly concentrated in the frontal and temporal lobes, and these changes may be linked to motor disorders and neuropsychiatric manifestations. Cytokine concentrations in peripheral blood are correlated with regional gray matter volume in PDs, and the IL-6 level affects gray matter volume in the left precentral gyrus and the manifestation of motor complications.

Association of Gene Expression and Tremor Network Structure.

BACKGROUND: Transcriptomic changes in the essential tremor (ET)-associated cerebello-thalamo-cortical "tremor network" and their association to brain structure have not been investigated. OBJECTIVE: The aim was to characterize molecular changes associated with network-level imaging-derived phenotypes (IDP) found in ET. METHODS: We performed an imaging-transcriptomic study in British adults using imaging-genome-wide association study summary statistics (UK Biobank "BIG40" cohort; n = 33,224, aged 40-69 years). We imputed imaging-transcriptomic associations for 184 IDPs and analyzed functional enrichment of gene modules and aggregate network-level phenotypes. Validation was performed in cerebellar-tissue RNA-sequencing data from ET patients and controls (n = 55). RESULTS: Among 237,896 individual predicted gene expression levels for 6063 unique genes/transcripts, we detected 2269 genome-wide significant associations (Bonferroni P < 2.102e-7, 0.95%). These were concentrated in intracellular volume fraction measures of white matter pathways and in genes with putative links to tremor (MAPT, ARL17A, KANSL1, SPPL2C, LRRC37A4P, PLEKHM1, and FMNL1). Whole-tremor-network cortical thickness was associated with a gene module linked to mitochondrial organization and protein quality control (r = 0.91, P = 2e-70), whereas white-gray T1-weighted magnetic resonance imaging (MRI) contrast in the tremor network was associated with a gene module linked to sphingolipid synthesis and ethanolamine metabolism (r = -0.90, P = 2e-68). Imputed association effect sizes and RNA-sequencing log-fold change in the validation dataset were significantly correlated for cerebellar peduncular diffusion MRI phenotypes, and there was a close overlap of significant associations between both datasets for gray matter phenotypes (χ2 = 6.40, P = 0.006). CONCLUSIONS: The identified genes and processes are potential treatment targets for ET, and our results help characterize molecular changes that could in future be used for patient treatment selection or prognosis prediction. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Risk of aspiration pneumonia and hospital mortality in Parkinson disease: A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: This study was undertaken to conduct a meta-analysis on the prevalence of aspiration pneumonia (AP) and hospital mortality in Parkinson disease (PD) as well as the risk of AP in PD patients compared to controls. METHODS: We searched MEDLINE and Embase from inception to 19 March 2024 to identify cross-sectional, cohort, and case-control studies comparing the frequency of AP and hospital mortality in PD patients. We computed risk ratios (RRs) with accompanying 95% confidence intervals (CIs) for each study and pooled the results using a random-effects meta-analysis. RESULTS: A total of 781 studies were initially screened, and 13 studies involving 541,785,587 patients were included. Patients with PD had >3 times higher risk of AP compared to controls (RR = 3.30, 95% CI = 1.82-6.00, p < 0.0001). This increased risk was similar in both cohort studies (RR = 3.01, 95% CI = 1.10-8.24, p = 0.03) and case-control studies (RR = 3.86, 95% CI = 3.84-3.87, p < 0.00001). The prevalence of AP in 12 studies was 2.74% (95% CI = 1.69-4.41), and hospital mortality was 10% in six studies (10.0%, 95% CI = 5.32-18.0). Prevalence of AP was higher in studies with smaller sample size (5.26%, 95% CI = 3.08-8.83 vs. 2.06%, 95% CI = 1.19-3.55, p = 0.02). CONCLUSIONS: Our meta-analysis showed that patients with PD had >3 times higher risk of AP, with an average 2.74% prevalence and 10.0% hospital mortality. Early recognition and treatment of AP in PD patients will help reduce morbidity and mortality. A multidisciplinary holistic approach is needed to address the multifactorial causes of AP.

Multimodal analysis of gene expression from postmortem brains and blood identifies synaptic vesicle trafficking genes to be associated with Parkinson's disease.

OBJECTIVE: We aimed to identify key susceptibility gene targets in multiple datasets generated from postmortem brains and blood of Parkinson's disease (PD) patients and healthy controls (HC). METHODS: We performed a multitiered analysis to integrate the gene expression data using multiple-gene chips from 244 human postmortem tissues. We identified hub node genes in the highly PD-related consensus module by constructing protein-protein interaction (PPI) networks. Next, we validated the top four interacting genes in 238 subjects (90 sporadic PD, 125 HC and 23 Parkinson's Plus Syndrome (PPS)). Utilizing multinomial logistic regression analysis (MLRA) and receiver operating characteristic (ROC), we analyzed the risk factors and diagnostic power for discriminating PD from HC and PPS. RESULTS: We identified 1333 genes that were significantly different between PD and HCs based on seven microarray datasets. The identified MEturquoise module is related to synaptic vesicle trafficking (SVT) dysfunction in PD (P < 0.05), and PPI analysis revealed that SVT genes PPP2CA, SYNJ1, NSF and PPP3CB were the top four hub node genes in MEturquoise (P < 0.001). The levels of these four genes in PD postmortem brains were lower than those in HC brains. We found lower blood levels of PPP2CA, SYNJ1 and NSF in PD compared with HC, and lower SYNJ1 in PD compared with PPS (P < 0.05). SYNJ1, negatively correlated to PD severity, displayed an excellent power to discriminating PD from HC and PPS. CONCLUSIONS: This study highlights that SVT genes, especially SYNJ1, may be promising markers in discriminating PD from HCs and PPS.

Appropriateness of lumbar spine radiography and factors influencing imaging ordering patterns: paving the path toward value-driven health care.

The demand for diagnostic imaging continues to rise. Against the backdrop of rising health care costs and finite resources, this has prompted a paradigm shift toward value-driven patient care. Inappropriate imaging is a barrier toward achieving this goal, which runs counter to prevailing evidence-based guidelines and contributes to rising healthcare costs. Our objective was to evaluate the appropriateness of lumbar spine X-rays in a tertiary referral Emergency Department (ED) and assess whether physicians' specialization and years of experience influence appropriateness. A total of 1030 lumbar spine radiographs performed in the ED of an academic medical center over a consecutive 3-month period were reviewed retrospectively. Referral indications were reviewed for adherence to 2021 American College of Radiology appropriateness guidelines for lower back pain, and referral patterns were evaluated among physician groups based on specialists' training and years in practice. 63.8% of lumbar spine radiographs were appropriate, with trauma being the most common indication. 36.2% of orders were inappropriate, with lower back pain of <6 weeks duration being the most common indication. Significant differences in inappropriate orders were found (P < .001) across physician groups: qualified Emergency Medicine specialists (20.9% inappropriate orders), specialists in training (27.8%), and non-specialists with ≥3 (60.0%) and <3 (36.9%) years in practice, respectively. Approximately one-third of lumbar spine radiographs performed in the ED were inappropriately ordered by American College of Radiology guidelines; specialists training and years in practice affected referral patterns. Integrating evidence-based appropriateness guidelines into the physician order workflow and targeting older non-specialists may promote more judicious imaging and reduce health care costs.

NOTCH2NLC GGC Repeat Expansions Are Associated with Sporadic Essential Tremor: Variable Disease Expressivity on Long-Term Follow-up.

We screened 662 subjects comprising 462 essential tremor (ET) subjects (285 sporadic, 125 with family history, and 52 probands from well-characterized ET pedigrees) and 200 controls and identified pathogenic NOTCH2NLC GGC repeat expansions in 4 sporadic ET patients. Two patients were followed up for >1 decade; one with 90 repeats remained an ET phenotype that did not evolve after 40 years, whereas another patient with 107 repeats developed motor symptoms and cognitive impairment after 8 to 10 years. Neuroimaging in this patient revealed severe leukoencephalopathy; diffusion-weighted imaging hyperintensity in the corticomedullary junction and skin biopsy revealed intranuclear inclusions suggestive of intranuclear inclusion body disease (NIID). No GGC repeats of >60 units were detected in familial ET cases and controls, although 4 ET patients carried 47 to 53 "intermediate" repeats. NOTCH2NLC GGC repeat expansions can be associated with sporadic ET. Carriers presenting with a pure ET phenotype may or may not convert to NIID up to 4 decades after initial tremor onset. ANN NEUROL 2020;88:614-618.

The splenial angle: a novel radiological index for idiopathic normal pressure hydrocephalus.

OBJECTIVES: To evaluate the utility of the splenial angle (SA), an axial angular index of lateral ventriculomegaly measured on diffusion tensor MRI color fractional anisotropy maps, in differentiating NPH from Alzheimer's disease (AD), Parkinson's disease (PD), and healthy controls (HC), and post-shunt changes in NPH, compared to Evans' index and callosal angle. METHODS: Evans' index, callosal angle, and SA were measured on brain MRI of 76 subjects comprising equal numbers of age- and sex-matched subjects from each cohort of NPH, AD, PD, and HC by two raters. Receiver operating characteristics (ROC) and multivariable analysis were used to assess the screening performance of each measure in differentiating and predicting NPH from non-NPH groups respectively. Temporal changes in the measures on 1-year follow-up MRI in 11 NPH patients (with or without ventriculoperitoneal shunting) were also assessed. RESULTS: Inter-rater and intra-rater reliability were excellent for all measurements (intraclass correlation coefficients > 0.9). Pairwise comparison showed that SA was statistically different between NPH and AD/PD/HC subjects (p < 0.0001). SA performed the best in predicting NPH, with an area under the ROC curve of > 0.98, and was the only measure left in the final model of the multivariable analysis. Significant (p < 0.01) change in SA was seen at follow-up MRI of NPH patients who were shunted compared to those who were not. CONCLUSIONS: The SA is readily measured on axial DTI color FA maps compared to the callosal angle and shows superior performance differentiating NPH from neurodegenerative disorders and sensitivity to ventricular changes in NPH after surgical intervention. KEY POINTS: • The splenial angle is a novel simple angular radiological index proposed for idiopathic normal pressure hydrocephalus, measured in the ubiquitous axial plane on DTI color fractional anisotropy maps. • The splenial angle quantitates the compression and stretching of the posterior callosal commissural fibers alongside the distended lateral ventricles in idiopathic normal pressure hydrocephalus (NPH) using tools readily accessible in clinical practice and shows excellent test-retest reliability. • Splenial angle outperforms Evans' index and callosal angle in predicting NPH from healthy, Parkinson's disease, and Alzheimer's disease subjects on ROC analysis with an area under the curve of > 0.98 and is sensitive to morphological ventricular changes in NPH patients after ventricular shunting.

Evaluation of trigeminal nerve tractography using two-fold-accelerated simultaneous multi-slice readout-segmented echo planar diffusion tensor imaging.

OBJECTIVES: Simultaneous multi-slice (SMS) imaging with short repetition time (TR) accelerates diffusion tensor imaging (DTI) acquisitions. However, its impact when combined with readout-segmented echo planar imaging (RESOLVE) on the cranial nerves given the challenging skull base/posterior fossa terrain is unexplored. We evaluated the reliability of trigeminal nerve DTI metrics using SMS with RESOLVE-DTI. METHODS: Eight healthy controls and six patients with unilateral trigeminal neuralgia (TN) underwent brain MRI scan. Three different RESOLVE-DTI protocols were performed on a 3-T MRI system: non-SMS (TR = 4330 ms), SMS with identical TR (4330 ms), and SMS with short TR (2400 ms). Pontine signal-to-noise ratio (SNR) and DTI metrics of the trigeminal nerve streamlines tracked by two independent raters using deterministic tractography and standardized tracking protocol were obtained. These were statistically analyzed and compared across the three protocols using intra-rater and inter-rater intraclass correlation coefficients (ICCs), one-way analysis of variance (ANOVA), post hoc analysis, and linear regression. RESULTS: On visual screening, there were no artifacts across the trigeminal nerves. All data also cleared objective image quality assurance analysis. Pontine SNR was similar for the two SMS protocols and higher for the non-SMS RESOLVE-DTI (F(2,36) = 4.40, p = 0.02). Intra-rater and inter-rater ICCs were very good (> 0.85). Trigeminal nerve DTI metrics were consistently measured by the three protocols, revealing significant linear relationships between non-SMS- and SMS-derived DTI metrics. CONCLUSION: SMS RESOLVE-DTI enables fast and reliable evaluation of microstructural integrity of the trigeminal nerve, with potential application in the clinical management of TN. KEY POINTS: • Readout-segmented diffusion-weighted echo planar imaging (RESOLVE-DTI) reduces image distortion artifacts in the posterior fossa but its long acquisition time limits clinical utility. • Simultaneous multi-slice (SMS) imaging combined with RESOLVE-DTI provides reliable trigeminal nerve tractography with potential applications in trigeminal neuralgia. • Two-fold-accelerated RESOLVE-DTI yields comparable trigeminal nerve streamlines and DTI metrics while near-halving acquisition time.

Callosal angle in idiopathic normal pressure hydrocephalus: small angular mal-rotations of the coronal plane affect measurement reliability.

PURPOSE: The callosal angle (CA) is a useful biomarker in the diagnosis and management of idiopathic normal pressure hydrocephalus (NPH). Used incorrectly, CA measurements are variable, affecting its reliability as a clinical tool. Our objectives are to evaluate (i) reproducibility of established CA measurements between trained raters and (ii) impact of minor angular mal-rotations of the true coronal plane on CA measurements. METHODS: CAs were measured by two independent raters on three-dimensional isovolumetric T1-weighted brain MRI of NPH patients and healthy controls using the established true coronal plane reformatted orthogonal to the plane containing the anterior-posterior commissural (AC-PC) line at the level of the posterior commissure. CA changes were subsequently evaluated when the coronal plane was mal-rotated by ± 5° and ± 10° in anterior-posterior and clockwise-anticlockwise directions. Inter-rater reliability of CA measurements was assessed using the intraclass correlation coefficient (ICC). RESULTS: On the true coronal plane, inter-rater ICC was excellent (0.973) for NPH patients and good (0.875) for controls. On mal-rotated coronal plane setups, ICC for CA was worse in controls (0.484-0.886) than NPH (0.879-0.981) groups and in clockwise-anticlockwise (0.484-0.956) than anterior-posterior (0.503-0.981) mal-rotations. CA changes secondary to mal-rotations from the true coronal plane were significant in NPH patients (P < 0.0001 to 0.0378) but not in controls (P > 0.1). CONCLUSION: This is the first demonstration of how small angular mal-rotations of the coronal plane used for CA measurement affect its value and inter-rater reliability, highlighting the importance of a standardized protocol when measuring the CA in NPH workup.

Differentiating Parkinson's disease motor subtypes using automated volume-based morphometry incorporating white matter and deep gray nuclear lesion load.

BACKGROUND: Periventricular leukoaraiosis may be an important pathological change in postural instability gait disorder (PIGD), a motor subtype of Parkinson's disease (PD). Clinical diagnosis of PIGD may be challenging for the general neurologist. PURPOSE: To evaluate 1) the utility of a fully automated volume-based morphometry (Vol-BM) in characterizing imaging diagnostic markers in PD and PIGD, including, 2) novel deep gray nuclear lesion load (GMab), and 3) discriminatory performance of a Vol-BM model construct in classifying the PIGD subtype. STUDY TYPE: Prospective. SUBJECTS: In all, 23 PIGD, 21 PD, and 20 age-matched healthy controls (HC) underwent MRI brain scans and clinical assessments. FIELD STRENGTH/SEQUENCE: 3.0T, sagittal 3D-magnetization-prepared rapid gradient echo (MPRAGE), and fluid-attenuated inversion recovery imaging (FLAIR) sequences. ASSESSMENT: Clinical assessment was conducted by a movement disorder neurologist. The MR brain images were then segmented using an automated multimodal Vol-BM algorithm (MorphoBox) and reviewed by two authors independently. STATISTICAL TESTING: Brain segmentation and clinical parameter differences and dependence were assessed using analysis of variance (ANOVA) and regression analysis, respectively. Logistic regression was performed to differentiate PIGD from PD, and discriminative reliability was evaluated using receiver operating characteristic (ROC) analysis. RESULTS: Significantly higher white matter lesion load (WMab) (P < 0.01), caudate GMab (P < 0.05), and lateral and third ventricular (P < 0.05) volumetry were found in PIGD, compared with PD and HC. WMab, caudate and putamen GMab, and caudate, lateral, and third ventricular volumetry showed significant coefficients (P < 0.005) in linear regressions with balance and gait assessments in both patient groups. A model incorporating WMab, caudate GMab, and caudate GM discriminated PIGD from PD and HC with a sensitivity = 0.83 and specificity = 0.76 (AUC = 0.84). DATA CONCLUSION: Fast, unbiased quantification of microstructural brain changes in PD and PIGD is feasible using automated Vol-BM. Composite lesion load in the white matter and caudate, and caudate volumetry discriminated PIGD from PD and HC, and showed potential in classification of these disorders using supervised machine learning. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2020;51:748-756.

Cryptic asymptomatic parasellar high signal on time-of-flight MR angiography: how to resolve the clinical conundrum.

PURPOSE: Hyperintense parasellar signal on time-of-flight MR angiography (TOF-MRA) in asymptomatic patients may be due to a variety of nonpathological causes and mimic parasellar high flow signal in pathological arteriovenous shunts at the cavernous sinus (CSAVS). This creates a clinical conundrum between diagnosing an aggressive yet asymptomatic CSAVS subtype against exposing patients without CSAVS to potential complications of an invasive angiographic evaluation. We reviewed common nonpathological causes of hyperintense parasellar signal and contrast their imaging features against those of pathological CSAVS and proposed a systemic approach to resolve such conundrum. METHODS: The anatomy of the cavernous sinus (CS) and causes of nonpathological parasellar hyperintense TOF-MRA signal are described and explained with case reviews, illustrations, and reference to published literature where appropriate. Imaging features of proven CSAVS are juxtaposed to aid in radiological differentiation. An algorithm is proposed to manage patients with such incidental TOF-MRA findings. RESULTS: The margins, contour, extent, intensity, and stippling appearance aid in evaluation of pathological versus incidental TOF-MRA parasellar signal, and differentiation of CSAVS from nonpathological causes. Pertinent radiological features are summarized in a table. For unresolved cases suspected for CSAVS, further evaluation with dynamic time-resolved contrast-enhanced MRA is proposed and depicted in a decision tree flow chart. CONCLUSION: Familiarity with the differentiating radiological features and a systematic management workflow could aid in resolving the clinical conundrum of findings of cryptic asymptomatic parasellar TOF-MRA high signal, while facilitating timely detection of the asymptomatic CSAVS.

Hyperfamiliarity in Amnestic and Vascular Mild Cognitive Impairment.

OBJECTIVE: Hyperfamiliarity is a phenomenon where new stimuli are perceived as familiar. Previous studies have demonstrated familiarity disorder in mild cognitive impairment (MCI), but mostly from the perspective of a neuropsychological approach, and the exact correlation of MCI aetiologies with the phenomenon remains uncertain. Based on current evidence suggesting a frontal-subcortical pathway contributing to familiarity processing, we hypothesize that individuals with a vascular aetiology of MCI will likely suffer more familiarity deficits. This study aims to examine the real-life hyperfamiliarity symptoms in amnestic versus vascular MCI. METHODS: Informants of 11 amnestic and 9 vascular cognitive impairment patients were interviewed about the frequency of hyperfamiliarity symptoms in the previous month. MRI brain images of vascular cognitive impairment patients were analysed as well. RESULTS: Patients with vascular cognitive impairment with no dementia (VCIND) showed a significantly higher frequency of hyperfamiliarity for people but not places or objects. Within VCIND patients, overall basal ganglia hyperintensities, particularly in the putamen, were found to significantly correlate to hyperfamiliarity. CONCLUSIONS: Patients with VCIND suffer more real-life hyperfamiliarity during people recognition compared to patients with amnestic mild cognitive impairment (aMCI), despite a comparative global decline in cognitive. This is likely due to impaired memory retrieval and matching processes resulting from subcortical ischaemic lesions.

Vascular tortuosity in relationship with hypertension and posterior fossa volume in hemifacial spasm.

BACKGROUND: Hemifacial spasm (HFS) is a disabling neurological condition. Vascular tortuosity in HFS patients has not been quantified objectively and its relationship with hypertension and posterior fossa volume (PF) is unknown. In a case control magnetic resonance imaging and angiographic (MRI/A) study, we quantified and compared the vascular tortuosity in HFS and controls, and evaluated its relationship with hypertension and PF. METHODS: Using a commercially available vessel probe tool, an index of tortuosity based on vessel over chord length was employed to quantify vascular tortuosity of the vertebral (VA) and basilar arteries (BA) in 79 subjects (40 HFS, 39 controls). RESULTS: The tortuosity index of the BA (1.09 vs 1.16, p = 0.26, 95 % CI 1.07, 1.23), RVA (1.15 vs 1.15, p = 0.83, 95 % CI 1.06, 1.38) and LVA (1.14 vs 1.288, p = 0.16, 95 % CI 1.14, 1.44) was not different between HFS and controls, with adjustments for PF volume and hypertension. CONCLUSIONS: Contrary to popular belief, our study showed that taking into account hypertension and PF volume, vascular tortuosity of the vertebrobasilar arteries is unlikely to be a major etiologic factor in HFS, though its role in select individuals cannot be excluded. The complex interplay of facial nerve hyperexcitability, genetic predisposition, vascular tortuosity, posterior fossa volume and hypertension needs to be further evaluated.