Atrophy In Progressive Supranuclear Palsy Research Articles

Structural parameters are superior to eigenvector centrality in detecting progressive supranuclear palsy with machine learning & multimodal MRI

Progressive supranuclear palsy (PSP) is an atypical Parkinsonian syndrome characterized initially by falls and eye movement impairment. This multimodal imaging study aimed at eliciting structural and functional disease-specific brain alterations. T1-weighted and resting-state functional MRI were applied in multi-centric cohorts of PSP and matched healthy controls. Midbrain, cerebellum, and cerebellar peduncles showed severely low gray/white matter volume, whereas thinner cortical gray matter was observed in cingulate cortex, medial and temporal gyri, and insula. Eigenvector centrality analyses revealed regionally specific alterations. Multivariate pattern recognition classified patients correctly based on gray and white matter segmentations with up to 98 % accuracy. Highest accuracies were obtained when restricting feature selection to the midbrain. Eigenvector centrality indices yielded an accuracy around 70 % in this comparison; however, this result did not reach significance. In sum, the study reveals multimodal, widespread brain changes in addition to the well-known midbrain atrophy in PSP. Alterations in brain structure seem to be superior to eigenvector centrality parameters, in particular for prediction with machine learning approaches.

Stepwise Functional Brain Architecture Correlates with Atrophy in Progressive Supranuclear Palsy.

Stepwise functional connectivity (SFC) detects whole-brain functional couplings of a selected region of interest at increasing link-step topological distances. This study applied SFC to test the hypothesis that stepwise architecture propagating from the disease epicenter would shape patterns of brain atrophy in patients with progressive supranuclear palsy-Richardson's syndrome (PSP-RS). Thirty-six patients with PSP-RS and 44 age-matched healthy control subjects underwent brain magnetic resonance imaging on a 3-T scanner. The disease epicenter was defined as the peak of atrophy observed in an independent cohort of 13 cases with postmortem confirmation of PSP pathology and used as seed region for SFC analysis. First, we explored SFC rearrangements in patients with PSP-RS, as compared with age-matched control subjects. Subsequently, we tested SFC architecture propagating from the disease epicenter as a determinant of brain atrophy distribution. The disease epicenter was identified in the left midbrain tegmental region. Compared with age-matched control subjects, patients with PSP-RS showed progressively widespread decreased SFC of the midbrain with striatal and cerebellar regions through direct connections and sensorimotor cortical regions through indirect connections. A correlation was found between average link-step distance from the left midbrain in healthy subjects and brain volumes in patients with PSP-RS (r = 0.38, P < 0.001). This study provides comprehensive insights into the topology of functional network rearrangements in PSP-RS and demonstrates that the brain architectural topology, as described by SFC propagating from the disease epicenter, shapes the pattern of atrophic changes in PSP-RS. Our findings support the view of a network-based pathology propagation in this primary tauopathy. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Stepwise functional brain architecture from disease epicenter correlates with atrophy in progressive supranuclear palsy (P11-6.001)

<h3>Objective:</h3> This study applied SFC to test the hypothesis that topological stepwise architecture propagating from the disease epicenter would shape patterns of grey matter (GM) atrophy in a cohort of patients with progressive supranuclear palsy (PSP). <h3>Background:</h3> MRI connectomics is an ideal tool to test the model of network-based spread of pathological protein aggregates in neurodegenerative disorders. Stepwise functional connectivity (SFC) is a graph-theory-based neuroimaging method, which detects whole-brain functional couplings of a selected region of interest, at increasing link-step topological distances. <h3>Design/Methods:</h3> Twenty-eight patients with PSP and 50 healthy controls underwent brain magnetic resonance imaging (MRI) on a 3T scanner, including 3D-T1 weighted and resting-state functional MRI sequences. GM was parcellated into 90 regions using the Automated Anatomical Labeling (AAL) atlas. Correlations between SFC architecture in controls and atrophy patterns in PSP patients were tested. The disease epicenter was identified as the peak of atrophy observed in an independent cohort of 13 cases with <i>post mortem</i> confirmation of PSP pathology, and used as seed region for SFC analysis. <h3>Results:</h3> The disease epicenter was identified in the left midbrain tegmental region. Compared with controls, PSP patients showed prevalent atrophy in the subcortical GM (mostly, in the thalami and caudate nuclei), but also in frontal, parietal and cerebellar cortical regions. For each region of the AAL atlas, a strong correlation was found between average link-step distance from the left midbrain in controls and mean normalized GM volume in PSP patients (r=0.37, p&lt;0.001). <h3>Conclusions:</h3> Our findings demonstrate that the brain architectural topology, as described by SFC propagating from the disease epicenter, shapes the pattern of atrophic changes in PSP, supporting the view of a network-based pathology propagation in this disease and holding the promise to be used to model disease progression in future longitudinal studies. <b>Disclosure:</b> Dr. Spinelli has nothing to disclose. Miss Ghirelli has nothing to disclose. Miss Bottale has nothing to disclose. Silvia Basaia has nothing to disclose. Ms. Cividini has nothing to disclose. Dr. Volonte has nothing to disclose. Mr. Galantucci has nothing to disclose. Giuseppe Magnani has nothing to disclose. Dr. Caso has nothing to disclose. The institution of Elisa Canu has received research support from Italian Ministry of Health . Dr. Castelnovo has nothing to disclose. Paola Caroppo has nothing to disclose. Sara Prioni has nothing to disclose. Miss Villa has nothing to disclose. Dr. Josephs has nothing to disclose. Dr. Whitwell has nothing to disclose. Federica Agosta has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Philips. Federica Agosta has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier INC. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Nature. The institution of Dr. Filippi has received research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA).

Uncovering spatiotemporal patterns of atrophy in progressive supranuclear palsy using unsupervised machine learning.

To better understand the pathological and phenotypic heterogeneity of progressive supranuclear palsy and the links between the two, we applied a novel unsupervised machine learning algorithm (Subtype and Stage Inference) to the largest MRI data set to date of people with clinically diagnosed progressive supranuclear palsy (including progressive supranuclear palsy-Richardson and variant progressive supranuclear palsy syndromes). Our cohort is comprised of 426 progressive supranuclear palsy cases, of which 367 had at least one follow-up scan, and 290 controls. Of the progressive supranuclear palsy cases, 357 were clinically diagnosed with progressive supranuclear palsy-Richardson, 52 with a progressive supranuclear palsy-cortical variant (progressive supranuclear palsy-frontal, progressive supranuclear palsy-speech/language, or progressive supranuclear palsy-corticobasal), and 17 with a progressive supranuclear palsy-subcortical variant (progressive supranuclear palsy-parkinsonism or progressive supranuclear palsy-progressive gait freezing). Subtype and Stage Inference was applied to volumetric MRI features extracted from baseline structural (T1-weighted) MRI scans and then used to subtype and stage follow-up scans. The subtypes and stages at follow-up were used to validate the longitudinal consistency of subtype and stage assignments. We further compared the clinical phenotypes of each subtype to gain insight into the relationship between progressive supranuclear palsy pathology, atrophy patterns, and clinical presentation. The data supported two subtypes, each with a distinct progression of atrophy: a 'subcortical' subtype, in which early atrophy was most prominent in the brainstem, ventral diencephalon, superior cerebellar peduncles, and the dentate nucleus, and a 'cortical' subtype, in which there was early atrophy in the frontal lobes and the insula alongside brainstem atrophy. There was a strong association between clinical diagnosis and the Subtype and Stage Inference subtype with 82% of progressive supranuclear palsy-subcortical cases and 81% of progressive supranuclear palsy-Richardson cases assigned to the subcortical subtype and 82% of progressive supranuclear palsy-cortical cases assigned to the cortical subtype. The increasing stage was associated with worsening clinical scores, whilst the 'subcortical' subtype was associated with worse clinical severity scores compared to the 'cortical subtype' (progressive supranuclear palsy rating scale and Unified Parkinson's Disease Rating Scale). Validation experiments showed that subtype assignment was longitudinally stable (95% of scans were assigned to the same subtype at follow-up) and individual staging was longitudinally consistent with 90% remaining at the same stage or progressing to a later stage at follow-up. In summary, we applied Subtype and Stage Inference to structural MRI data and empirically identified two distinct subtypes of spatiotemporal atrophy in progressive supranuclear palsy. These image-based subtypes were differentially enriched for progressive supranuclear palsy clinical syndromes and showed different clinical characteristics. Being able to accurately subtype and stage progressive supranuclear palsy patients at baseline has important implications for screening patients on entry to clinical trials, as well as tracking disease progression.

Frontal Atrophy and Executive Dysfunction Relate to Complex Numbers Impairment in Progressive Supranuclear Palsy.

Previous research finds a range of numbers impairments in Parkinsonian syndromes (PS), but has largely focused on how visuospatial impairments impact deficits in basic numerical processes (e.g., magnitude judgments, chunking). Differentiation between these basic functions and more complex numerical processes often utilized in everyday tasks may help elucidate neurocognitive and neuroanatomic bases of numbers deficits in PS. To test neurocognitive and neuroanatomic correlates of complex numerical processing in PS, we assessed number abilities, neuropsychological performance, and cortical thickness in progressive supranuclear palsy (PSP) and Lewy body spectrum disorders (LBSD). Fifty-six patients (LBSD = 35; PSP = 21) completed a Numbers Battery, including basic and complex numerical tasks. The Mini-Mental State Exam (MMSE), letter fluency (LF), and Judgment of Line Orientation (JOLO) assessed global, executive, and visuospatial functioning respectively. Mann-Whitney U tests compared neuropsychological testing and rank-transformed analysis of covariance (ANCOVA) compared numbers performance between groups while adjusting for demographic variables. Spearman's and partial correlations related numbers performance to neuropsychological tasks. Neuroimaging assessed cortical thickness in disease groups and demographically-matched healthy controls. PSP had worse complex numbers performance than LBSD (F = 6.06, p = 0.02) but similar basic numbers performance (F = 0.38, p > 0.1), covarying for MMSE and sex. Across syndromes, impaired complex numbers performance was linked to poor LF (rho = 0.34, p = 0.01) but not JOLO (rho = 0.23, p > 0.05). Imaging revealed significant frontal atrophy in PSP compared to controls, which was associated with worse LF and complex numbers performance. PSP demonstrated selective impairments in complex numbers processing compared to LBSD. This complex numerical deficit may relate to executive dysfunction and frontal atrophy.

Automated volumetric determination of high R2 * regions in substantia nigra: A feasibility study of quantifying substantia nigra atrophy in progressive supranuclear palsy.

The establishment of an unbiased protocol for the automated volumetric measurement of iron-rich regions in the substantia nigra (SN) is clinically important for diagnosing neurodegenerative diseases exhibiting midbrain atrophy, such as progressive supranuclear palsy (PSP). This study aimed to automatically quantify the volume and surface properties of the iron-rich 3D regions in the SN using the quantitative MRI-R2 * map. Three hundred and sixty-seven slices of R2 * map and susceptibility-weighted imaging (SWI) at 3-T MRI from healthy control (HC) individuals and Parkinson's disease (PD) patients were used to train customized U-net++ convolutional neural network based on expert-segmented masks. Age- and sex-matched participants were selected from HC, PD, and PSP groups to automate the volumetric determination of iron-rich areas in the SN. Dice similarity coefficient values between expert-segmented and detected masks from the proposed network were for R2 * maps and for SWI. Reductions in iron-rich SN volume from the R2 * map (SWI) were observed in PSP with area under the receiver operating characteristic curve values of 0.96 (0.89) and 0.98 (0.92) compared with HC and PD, respectively. The mean curvature of the PSP showed SN deformation along the side closer to the red nucleus. We demonstrated the automated volumetric measurement of iron-rich regions in the SN using deep learning can quantify the SN atrophy in PSP compared with PD and HC.

A data-driven model of brain volume changes in progressive supranuclear palsy.

The most common clinical phenotype of progressive supranuclear palsy is Richardson syndrome, characterized by levodopa unresponsive symmetric parkinsonism, with a vertical supranuclear gaze palsy, early falls and cognitive impairment. There is currently no detailed understanding of the full sequence of disease pathophysiology in progressive supranuclear palsy. Determining the sequence of brain atrophy in progressive supranuclear palsy could provide important insights into the mechanisms of disease progression, as well as guide patient stratification and monitoring for clinical trials. We used a probabilistic event-based model applied to cross-sectional structural MRI scans in a large international cohort, to determine the sequence of brain atrophy in clinically diagnosed progressive supranuclear palsy Richardson syndrome. A total of 341 people with Richardson syndrome (of whom 255 had 12-month follow-up imaging) and 260 controls were included in the study. We used a combination of 12-month follow-up MRI scans, and a validated clinical rating score (progressive supranuclear palsy rating scale) to demonstrate the longitudinal consistency and utility of the event-based model’s staging system. The event-based model estimated that the earliest atrophy occurs in the brainstem and subcortical regions followed by progression caudally into the superior cerebellar peduncle and deep cerebellar nuclei, and rostrally to the cortex. The sequence of cortical atrophy progresses in an anterior to posterior direction, beginning in the insula and then the frontal lobe before spreading to the temporal, parietal and finally the occipital lobe. This in vivo ordering accords with the post-mortem neuropathological staging of progressive supranuclear palsy and was robust under cross-validation. Using longitudinal information from 12-month follow-up scans, we demonstrate that subjects consistently move to later stages over this time interval, supporting the validity of the model. In addition, both clinical severity (progressive supranuclear palsy rating scale) and disease duration were significantly correlated with the predicted subject event-based model stage (P < 0.01). Our results provide new insights into the sequence of atrophy progression in progressive supranuclear palsy and offer potential utility to stratify people with this disease on entry into clinical trials based on disease stage, as well as track disease progression.

MIBG myocardial scintigraphy in progressive supranuclear palsy

Background and objectivesMeta-iodobenzylguanidine (MIBG) myocardial scintigraphy is an effective tool for distinguishing Parkinson's disease (PD) from other diseases accompanied by parkinsonism. Unlike other Parkinsonian diseases, in PD, MIBG accumulation in the heart tends to decrease. However, previous studies have reported that a decrease in MIBG accumulation also occurs in progressive supranuclear palsy (PSP). Thus, we analyzed the relationship between the degree of MIBG accumulation decrease, clinical symptoms, and brainstem atrophy in PSP. MethodsWe retrospectively collected data from patients who underwent MIBG myocardial scintigraphy and compared MIBG indices (heart to mediastinum [H/M] ratio, washout rate) between subjects with PSP and other diseases including PD. In addition, we evaluated the relationship between clinical characteristics, MIBG accumulation, and brainstem atrophy in patients with PSP. ResultsPatients with PSP had a significantly lower early H/M ratio compared with multiple system atrophy with predominant parkinsonism (MSA-P) patients, and a control group. In PSP patients there was a correlation between the decrease in delay H/M ratio, atrophy of the pons, and clinical severity as evaluated by Hoehn and Yahr score. ConclusionUnlike in PD, PSP patients exhibited a mild decrease in MIBG accumulation in MIBG myocardial scintigraphy, which may be related to brainstem atrophy.

Progressive supranuclear palsy and idiopathic Parkinson's disease are associated with local reduction of in vivo brain viscoelasticity.

To apply three-dimensional multifrequency MR-elastography (3DMRE) for the measurement of local cerebral viscoelasticity changes in patients with Parkinson's disease (PD) and progressive supranuclear palsy (PSP). T1-weighted anatomical imaging and 3DMRE were performed in 17 PD and 20 PSP patients as well as 12 controls. Two independent viscoelasticity parameters, |G*| and φ, were reconstructed combining seven harmonic vibration frequencies (30-60 Hz). Spatially averaged values were compared by one-way ANOVA, groups were compared using unpaired t test and Mann-Whitney test, respectively. Correlation between clinical data and parameters of brain elasticity and volume were calculated by Pearson's correlation coefficient. In patients, |G*| was significantly reduced in the frontal and mesencephalic regions (p < 0.05). Beyond that, reduced mesencephalic |G*| discriminated PSP from PD (p < 0.05). Neurodegeneration causes significant brain atrophy (p < 0.01) and is pronounced in PSP patients (p < 0.05 vs. PD). Reduced brain viscoelasticity is correlated with brain atrophy in PSP (r=0.64, p=0.002) and PD (r=0.65, p=0.005) patients but not in controls. MRE-measured viscoelasticity reflects local structural changes of brain tissue in PSP and in PD and provides a useful parameter to differentiate neurodegenerative movement disorders based on imaging examinations. • 3D multifrequency MR-elastography reveals diffuse regional changes in brain viscoelasticity in neurodegenerative disorders. • Reduced mesencephalic viscoelasticity separates PD and PSP. • Reduced brain viscoelasticity and brain atrophy as independent hallmarks of neurodegeneration hypothesized.

Predictive Model of Spread of Progressive Supranuclear Palsy Using Directional Network Diffusion.

Several neurodegenerative disorders including Alzheimer’s disease (AD), frontotemporal dementia (FTD), Parkinson’s disease (PD), amyotrophic lateral sclerosis, and Huntington’s disease report aggregation and transmission of pathogenic proteins between cells. The topography of these diseases in the human brain also, therefore, displays a well-characterized and stereotyped regional pattern, and a stereotyped progression over time. This is most commonly true for AD and other dementias characterized by hallmark misfolded tau or alpha-synuclein pathology. Both tau and synuclein appear to propagate within brain circuits using a shared mechanism. The most canonical synucleopathy is PD; however, much less studied is a rare disorder called progressive supranuclear palsy (PSP). The hallmark pathology and atrophy in PSP are, therefore, also highly stereotyped: initially appearing in the striatum, followed by its neighbors and connected cortical areas. In this study, we explore two mechanistic aspects hitherto unknown about the canonical network diffusion model (NDM) of spread: (a) whether the NDM can apply to other common degenerative pathologies, specifically PSP, and (b) whether the directionality of spread is important in explaining empirical data. Our results on PSP reveal two important findings: first, that PSP is amenable to the connectome-based ND modeling in the same way as previously applied to AD and FTD and, second, that the NDM fit with empirical data are significantly enhanced by using the directional rather than the non-directional form of the human connectome. Specifically, we show that both the anterograde model of transmission (some to axonal terminal) and retrograde mode explain PSP topography more accurately than non-directional transmission. Collectively, these data show that the intrinsic architecture of the structural network mediates disease spread in PSP, most likely via a process of trans-neuronal transmission. These intriguing results have several ramifications for future studies.

Brain gray matter abnormalities in progressive supranuclear palsy revisited.

Whole-brain voxel-based morphometry (VBM) studies of progressive supranuclear palsy (PSP) have demonstrated heterogeneous findings regarding gray matter (GM) abnormalities. Here, we used Seed-based d Mapping, a coordinate-based meta-analytic approach to identify consistent regions of GM anomalies across studies of PSP. Totally, 18 original VBM studies, comprising 284 patients with PSP and 367 healthy controls were included. As compared to healthy controls, patients with PSP demonstrated significant GM reductions in both cortical and subcortical regions, including the frontal motor cortices, medial (including anterior cingulate cortex) and lateral frontal cortices, insula, superior temporal gyrus, striatum (putamen and caudate nucleus), thalamus, midbrain, and anterior cerebellum. Our study further suggests that many confounding factors, such as age, male ratio, motor severity, cognitive impairment severity, and illness duration of PSP patients, and scanner field-strength, could contribute to the heterogeneity of GM alterations in PSP across studies. Our comprehensive meta-analysis demonstrates a specific neuroanatomical pattern of GM atrophy in PSP with the involvement of the cortical-subcortical circuitries that mediate vertical supranuclear gaze palsy, motor disabilities (postural instability with falls and parkinsonism), and cognitive-behavioral disturbances. Confounding factors merit attention in future studies.

PB 10 Identifying an imaging biomarker for progressive supranuclear palsy – a combined gray &amp; white matter meta-analysis using ALE and SDM

Background Progressive supranuclear palsy (PSP) is an atypical parkinsonian syndrome. PSP is described by clinical features of vertical gaze palsy and postural instability. Even though midbrain atrophy has been suggested as a hallmark of the disease, it has not been validated systematically so far. Methods To identify disease-specific regional atrophy in PSP, we conducted a systematic and quantitative meta-analysis on structural magnetic resonance imaging (MRI) data. Based on strict inclusion criteria 18 studies were identified in PubMed including 315 patients compared with 393 healthy controls. For analysis, the included studies were separated into studies investigating either gray or white matter atrophy. Ensuring consistent results, we used a unique approach by combining two widely used meta-analytical algorithms. The results of anatomical likelihood estimation (ALE) and Seed-basedDMapping (SDM) were superimposed in a conjunction analysis. Results The analysis of gray matter revealed that clusters in the bilateral thalamus, bilateral anterior insulae, midbrain and bilateral caudate nuclei were consistently identified as effected by both methods, SDM and ALE ( Fig. 1 ). White matter analyses revealed consistent atrophy in the bilateral superior cerebellar pedunculi, cerebral pedunculi, and midbrain. Discussion In light of previous meta-analyses investigating neurodegenerative diseases, our meta- analyses identify atrophy in the gray matter in the midbrain and in the white matter in the cerebral/cerebellar pedunculi and midbrain as disease-specific in PSP. Atrophy in these brain regions is suggested to be incorporated into new revised diagnostic criteria for PSP. The study design enabled high validity and statistical power. We combined two meta-analytic techniques, combined analyses in white and gray matter, and included the biggest cohort of PSP patients to date.

Patterns of Eye Movement Impairment Correlate with Regional Brain Atrophy in Neurodegenerative Parkinsonism

Background: One common feature of neurodegenerative parkinsonism including Parkinson's disease (PD), multisystem atrophy (MSA), and progressive supranuclear palsy (PSP) is altered eye movement control. Characteristic regional structural atrophy patterns in MRI can be observed in PD, MSA, and PSP. Objective: To investigate the association between eye movement disturbances and regional brain atrophy in patients with PD, MSA, and PSP. Methods: High-resolution 3-dimensional T1-weighted MRI images and video-oculographic recordings (EyeLink®) were obtained from 39 PD, 32 PSP, and 18 MSA patients and 24 matched healthy control subjects. Automatic regional volumetric assessment was performed using atlas-based volumetry (ABV). Results: The prevalence of saccadic intrusions as a measure of inhibitory control was significantly increased in PD patients compared to controls (p < 0.001) and negatively correlated with whole brain volume, cerebral brain volume, and occipital lobe volume (p = 0.0057, p = 0.0049, and p = 0.0059, respectively; all p values are false discovery rate corrected). In MSA, smooth pursuit was disturbed by characteristic “catch-up” saccades (p < 0.001) and it was significantly correlated with cerebellar volume (p = 0.004) and pontine volume (p < 0.001). The hallmark of PSP was pathologically slowed vertical peak eye velocities (p < 0.001); the lower the peak eye velocity, the more marked midbrain atrophy (p = 0.007). Conclusions: Foci of regional atrophy correlated with disease-specific eye movement alterations in all investigated parkinsonian syndromes. Oculomotor impairment in PD, predominantly the result of executive dysfunction, was linked to cerebral atrophy. Impairment in the corresponding oculomotor pathways was associated with atrophy of pontocerebellar oculomotor structures in MSA and midbrain atrophy in PSP.

Progression of brain atrophy in PSP and CBS over 6 months and 1 year.

To examine the utility and reliability of volumetric MRI in measuring disease progression in the 4 repeat tauopathies, progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), to support clinical development of new tau-directed therapeutic agents. Six- and 12-month changes in regional MRI volumes and PSP Rating Scale scores were examined in 55 patients with PSP and 33 patients with CBS (78% amyloid PET negative) compared to 30 normal controls from a multicenter natural history study. Longitudinal voxel-based morphometric analyses identified patterns of volume loss, and region-of-interest analyses examined rates of volume loss in brainstem (midbrain, pons, superior cerebellar peduncle), cortical, and subcortical regions based on previously validated atlases. Results were compared to those in a replication cohort of 226 patients with PSP with MRI data from the AL-108-231 clinical trial. Patients with CBS exhibited greater baseline atrophy and greater longitudinal atrophy rates in cortical and basal ganglia regions than patients with PSP; however, midbrain and pontine atrophy rates were similar. Voxel-wise analyses showed distinct patterns of regional longitudinal atrophy in each group as compared to normal controls. The midbrain/pons volumetric ratio differed between diagnoses but remained stable over time. In both patient groups, brainstem atrophy rates were correlated with disease progression measured using the PSP Rating Scale. Volume loss is quantifiable over a period of 6 months in CBS and PSP. Future clinical trials may be able to combine CBS and PSP to measure therapeutic effects.

Quantitative assessment of cerebral gray matter density change in progressive supranuclear palsy using voxel based morphometry analysis and cerebral MR T1-weighted FLAIR imaging

PurposeTo investigate the gray matter (GM) atrophy in Progressive supranuclear palsy (PSP) using T1-weighted Fluid-Attenuated Inversion Recovery (FLAIR) images based on voxel based morphometry (VBM) method. Materials and methodsIn this study, we firstly modified the conventional VBM method to make it can process the T1-weighted FLAIR brain images. Then, we used this method on the 24 PSP patients and 23 healthy age- and sex-matched control subjects to find the local gray matter density changes of PSP patients. ResultsCompared with healthy controls, GM reductions of PSP patients mainly located in the thalamus, basal ganglia, pons, midbrain, insular cortex, frontal cortex, temporal lobe, cerebellum, cingulate cortex and hippocampus. ConclusionWe used the modified VBM technique into T1 FLAIR data to study the brain gray matter atrophy in PSP, and found some new atrophy areas, including pallidum, middle and posterior cingulum, lingual, fusiform gyrus and the post part of inferior temporal gyrus. These areas have not been described in the former VBM studies, but they revealed abnormity in the pathologic and other studies on PSP. Our results might be expected to provide significant underlining neurology information and diagnostic value for PSP.

Clinical correlates and baseline predictors of progressive brain atrophy in progressive supranuclear palsy: results from the AL-108-231 davunetide trial (P5.006)

Clinical correlates and baseline predictors of progressive brain atrophy in progressive supranuclear palsy: results from the AL-108-231 davunetide trial (P5.006)

The binaural masking level difference: cortical correlates persist despite severe brain stem atrophy in progressive supranuclear palsy.

Under binaural listening conditions, the detection of target signals within background masking noise is substantially improved when the interaural phase of the target differs from that of the masker. Neural correlates of this binaural masking level difference (BMLD) have been observed in the inferior colliculus and temporal cortex, but it is not known whether degeneration of the inferior colliculus would result in a reduction of the BMLD in humans. We used magnetoencephalography to examine the BMLD in 13 healthy adults and 13 patients with progressive supranuclear palsy (PSP). PSP is associated with severe atrophy of the upper brain stem, including the inferior colliculus, confirmed by voxel-based morphometry of structural MRI. Stimuli comprised in-phase sinusoidal tones presented to both ears at three levels (high, medium, and low) masked by in-phase noise, which rendered the low-level tone inaudible. Critically, the BMLD was measured using a low-level tone presented in opposite phase across ears, making it audible against the noise. The cortical waveforms from bilateral auditory sources revealed significantly larger N1m peaks for the out-of-phase low-level tone compared with the in-phase low-level tone, for both groups, indicating preservation of early cortical correlates of the BMLD in PSP. In PSP a significant delay was observed in the onset of the N1m deflection and the amplitude of the P2m was reduced, but these differences were not restricted to the BMLD condition. The results demonstrate that although PSP causes subtle auditory deficits, binaural processing can survive the presence of significant damage to the upper brain stem.

Tideglusib reduces progression of brain atrophy in progressive supranuclear palsy in a randomized trial

It is believed that glycogen synthase kinase-3 hyperphosphorylates tau protein in progressive supranuclear palsy (PSP). The Tau Restoration on PSP (TAUROS) trial assessed the glycogen synthase kinase-3 inhibitor tideglusib as potential treatment. For the magnetic resonance imaging (MRI) substudy reported here, we assessed the progression of brain atrophy. TAUROS was a multinational, phase 2, double-blind, placebo-controlled trial in patients with mild-to-moderate PSP who were treated with oral tideglusib (600 mg or 800 mg daily) or with placebo for 1 year. A subset of patients underwent baseline and 52-week MRI. Automated, observer-independent, atlas-based, and mask-based volumetry was done on high-resolution, T1-weighted, three-dimensional data. For primary outcomes, progression of atrophy was compared both globally (brain, cerebrum) and regionally (third ventricle, midbrain, pons) between the active and placebo groups (Bonferroni correction). For secondary outcomes, 15 additional brain structures were explored (Benjamini & Yekutieli correction). In total, MRIs from 37 patient were studied (placebo group, N = 9; tideglusib 600 mg group, N = 19; tideglusib 800 mg group, N = 9). The groups compared well in their demographic characteristics. Clinical results showed no effect of tideglusib over placebo. Progression of atrophy was significantly lower in the active group than in the placebo group for the brain (mean ± standard error of the mean: -1.3% ± 1.4% vs. -3.1% ± 2.3%, respectively), cerebrum (-1.3% ± 1.5% vs. -3.2% ± 2.1%, respectively), parietal lobe (-1.6% ± 1.9% vs. -4.1% ± 3.0%, respectively), and occipital lobe (-0.3% ± 1.8% vs. -2.7% ± 3.2%, respectively). A trend toward reduced atrophy also was observed in the frontal lobe, hippocampus, caudate nucleus, midbrain, and brainstem. In patients with PSP, tideglusib reduced the progression of atrophy in the whole brain, particularly in the parietal and occipital lobes.

The midbrain to pons ratio

MRI-based measurements used to diagnose progressive supranuclear palsy (PSP) typically lack pathologic verification and are not easy to use routinely. We aimed to develop in histologically proven disease a simple measure of the midbrain and pons on sagittal MRI to identify PSP. Measurements of the midbrain and pontine base on midsagittal T1-weighted MRI were performed in confirmed PSP (n = 12), Parkinson disease (n = 2), and multiple system atrophy (MSA) (n = 7), and in controls (n = 8). Using receiver operating characteristic curve analysis, cutoff values were applied to a clinically diagnosed cohort of 62 subjects that included PSP (n = 21), Parkinson disease (n = 10), MSA (n = 10), and controls (n = 21). The mean midbrain measurement of 8.1 mm was reduced in PSP (p < 0.001) with reduction in the midbrain to pons ratio (PSP smaller than MSA; p < 0.001). In controls, the mean midbrain ratio was approximately two-thirds of the pontine base, in PSP it was <52%, and in MSA the ratio was greater than two-thirds. A midbrain measurement of <9.35 mm and ratio of 0.52 had 100% specificity for PSP. In the clinically defined group, 19 of 21 PSP cases (90.5%) had a midbrain measurement of <9.35 mm. We have developed a simple and reliable measurement in pathologically confirmed disease based on the topography of atrophy in PSP with high sensitivity and specificity that may be a useful tool in the clinic.

Gray matter atrophy in progressive supranuclear palsy: meta-analysis of voxel-based morphometry studies

Voxel-based morphometry (VBM) studies have provided cumulative evidence of gray matter (GM) atrophy in patients with progressive supranuclear palsy (PSP) relative to healthy controls (HC). However, not all findings have been entirely concordant. Herein, we performed a quantitative meta-analysis study in order to consistently quantify GM anomalies in PSP. We conducted a systematic search for VBM studies of PSP patients and HC using PubMed and Embase databases from January 2000 to May 2012. Meta-analysis of these VBM studies was performed using a newly improved voxel-based meta-analytic technique, effect-size signed differential mapping. A total of 9 cross-sectional VBM studies that involved 143 PSP patients and 216 HC subjects met the inclusion criteria. Considerable regional GM volume decrease was detected in the thalamus, basal ganglia, midbrain, insular cortex, and frontal cortex. These findings remained largely unchanged following jackknife sensitivity analyses. The present meta-analysis provided evidence of PSP-specific GM atrophy. This finding might help contribute to our understanding of the neurobiological basis underlying PSP.