Atrophy In Progressive Supranuclear Palsy Research Articles

Intrinsic connectivity network disruption in progressive supranuclear palsy

Progressive supranuclear palsy (PSP) has been conceptualized as a large-scale network disruption, but the specific network targeted has not been fully characterized. We sought to delineate the affected network in patients with clinical PSP. Using task-free functional magnetic resonance imaging, we mapped intrinsic connectivity to the dorsal midbrain tegmentum (dMT), a region that shows focal atrophy in PSP. Two healthy control groups (1 young, 1 older) were used to define and replicate the normal connectivity pattern, and patients with PSP were compared to an independent matched healthy control group on measures of network connectivity. Healthy young and older subjects showed a convergent pattern of connectivity to the dMT, including brainstem, cerebellar, diencephalic, basal ganglia, and cortical regions involved in skeletomotor, oculomotor, and executive control. Patients with PSP showed significant connectivity disruptions within this network, particularly within corticosubcortical and cortico-brainstem interactions. Patients with more severe functional impairment showed lower mean dMT network connectivity scores. This study defines a PSP-related intrinsic connectivity network in the healthy brain and demonstrates the sensitivity of network-based imaging methods to PSP-related physiological and clinical changes.

Clinical and cognitive correlations of regional gray matter atrophy in progressive supranuclear palsy

BackgroundProgressive supranuclear palsy is the most common neurodegenerative bradykinetic-rigid syndrome after Parkinson's disease. Several volumetric studies have revealed a widespread cortical and subcortical gray matter atrophy, however the correlations between the pattern of gray matter loss and clinical-cognitive features have been poorly investigated. MethodsBy using 3-T magnetic-resonance imaging and voxel-based morphometry we compared gray matter volume in 15 patients with progressive supranuclear palsy, 15 patients with Parkinson's disease and 15 healthy controls. All patients underwent a clinical and neuropsychological evaluation. ResultsIn agreement with previous studies, patients with progressive supranuclear palsy, compared to patients with Parkinson's disease and healthy controls, showed a reduced gray matter volume in several cortical and subcortical areas including cerebellum, frontal, temporal and parahippocampal cortical structures. We did not find any significant gray matter volume changes when comparing patients with Parkinson's disease vs healthy controls. Among different significant correlations between motor-cognitive features and gray matter loss, we detected a significant correlation between fronto-cerebellar gray matter atrophy and executive cognitive impairment in patients with progressive supranuclear palsy. ConclusionsOur findings confirm that gray matter loss in patients with progressive supranuclear palsy involves several brain areas and suggest that cerebellar atrophy may play a role in the pathogenesis of cognitive dysfunction in patients with progressive supranuclear palsy due to a disruption of its modulation on executive functions.

Tideglusib, a GSK-3 inhibitor, reduces progression of brain atrophy in progressive supranuclear palsy

Tideglusib, a GSK-3 inhibitor, reduces progression of brain atrophy in progressive supranuclear palsy

Imaging Brain Atrophy in Progressive Supranuclear Palsy and Corticobasal Syndromes: Potential for Diagnosis and Monitoring of Disease Progression

SUMMARY The progressive supranuclear palsy syndrome (PSPS) and corticobasal syndrome (CBS) are atypical parkinsonian disorders that are both associated with characteristic patterns of atrophy that can be detected on MRI and can be diagnostically useful for the clinician. Much recent work has focused on developing imaging biomarkers, particularly utilizing measurements of the brainstem, which can differentiate PSPS from CBS and other parkinsonian disorders. The utility of longitudinal measures of atrophy as biomarkers of disease progression has also been assessed with a view to how these measures could be utilized in clinical treatment trials. Here, these studies are reviewed and the potential value of imaging biomarkers to aid diagnosis and monitor disease progression in PSPS and CBS will be discussed.

Teaching Neuro Images : “Penguin” or “hummingbird” sign and midbrain atrophy in progressive supranuclear palsy

An 82-year-old man presented to us with a 2-year history of progressive difficulty walking. On examination, he had bradykinesia, bradyphrenia, …

Brainstem atrophy on routine MR study in pallidopontonigral degeneration

Sirs, Pallidopontonigral degeneration (PPND) is an autosomal dominant inherited disorder which belongs to the spectrum of frontotemporal dementia linked to chromosome 17 (FTDP-17). It is caused by the N279K mutation in the gene encoding the microtubule-associated protein tau on chromosome 17 [3, 11]. Clinically, PPND is characterized by early and prominent parkinsonism with mild cognitive and behavioral changes, with some differences in clinical presentation between four branches of the PPND kindred [9, 11, 13]. Pathologically, PPND presents with neuronal loss and gliosis, most pronounced in the globus pallidus, pontine and mesencephalic tegmentum and substantia nigra [7, 13]. Immunohistochemistry reveals extensive neuronal and glial tau pathology [7, 8]. Routine magnetic resonance (MR) scanning performed in PPND patients reveals bilateral cortical atrophy, ventricular enlargement, narrowing of the substantia nigra pars compacta and atrophy of the pontine tegmentum [4]. Arvanitakis et al. [1] stressed prominent temporal atrophy in five affected PPND subjects; this was also seen in one asymptomatic N279K mutation carrier who converted to affected status 8 months after the MR study. In some FTDP-17 cases with the MAPT mutation, atrophy of the midbrain and pons was observed at autopsy [14]. Our previous pathological and MR studies confirmed profound brainstem atrophy in progressive supranuclear palsy (PSP) [10, 12]. Because PPND shares some clinical and pathological features with other atypical parkinsonian disorders [1, 8, 9], we decided to examine whether brainstem atrophy is also a feature of PPND and, if so, whether this feature may facilitate the differential diagnosis of PPND. We examined six pathologically confirmed PPND patients [three males, symptom duration 7 ± 3 years, age at death (AAD) 53 ± 5 years] and a historical series [10] of five pathologically confirmed PSP patients [three males, symptom duration 6 ± 2 years, AAD 77 ± 8 years]. The control group consisted of 25 healthy subjects, age and gender-matched to the PPND patients. The time interval between MR imaging and death was 50 ± 13 months in the PPND group and 45 ± 8 months in the PSP group. Six morphometric parameters of the midbrain (MB) and pons were measured on T1-weighted midsagittal and axial MR scans with Image Analyzer software. The technique of MR scanning and image analysis have been described in detail earlier [10]. The Mann–Whitney test was applied. A P value\0.05 was considered to be significant. Results of the study are summarized in Table 1. Midsagittal midbrain (MB) area and the MB area/pons area ratio were significantly smaller in PPND patients than in the controls (Fig. 1a, b), with the PSP cases showing even more pronounced midbrain atrophy. Other measurements did not differ between the PSP and PPND patients. Mean J. L. Slowinski K. J. Schweitzer A. Imamura R. J. Uitti A. J. Strongosky Z. K. Wszolek (&) Department of Neurology, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL 32224, USA e-mail: wszolek.zbigniew@mayo.edu

MRI derived brain atrophy in PSP and MSA-P

Progressive supranuclear palsy (PSP) and multiple system (MSA) atrophy are associated with progressive brain atrophy. Serial MRI can be applied in order to measure this change in brain volume and to calculate atrophy rates. We evaluated MRI derived whole brain and regional atrophy rates as potential markers of progression in PSP and the Parkinsonian variant of multiple system atrophy (MSA-P). 17 patients with PSP, 9 with MSA-P and 18 healthy controls underwent two MRI brain scans. MRI scans were registered, and brain and regional atrophy rates (midbrain, pons, cerebellum, third and lateral ventricles) measured. Sample sizes required to detect the effect of a proposed disease-modifying treatment were estimated. The effect of scan interval on the variance of the atrophy rates and sample size was assessed. Based on the calculated yearly rates of atrophy, for a drug effect equivalent to a 30% reduction in atrophy, fewer PSP subjects are required in each treatment arm when using midbrain rather than whole brain atrophy rates (183 cf. 499). Fewer MSA-P subjects are required, using pontine/cerebellar, rather than whole brain atrophy rates (164/129 cf. 794). A reduction in the variance of measured atrophy rates was observed with a longer scan interval. Regional rather than whole brain atrophy rates calculated from volumetric serial MRI brain scans in PSP and MSA-P provide a more practical and powerful means of monitoring disease progression in clinical trials.

Voxel-based morphometry in autopsy proven PSP and CBD

The aim of this study was to compare the patterns of grey and white matter atrophy on MRI in autopsy confirmed progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), and to determine whether the patterns vary depending on the clinical syndrome. Voxel-based morphometry was used to compare patterns of atrophy in 13 PSP and 11 CBD subjects and 24 controls. PSP and CBD subjects were also subdivided into those with a dominant dementia or extrapyramidal syndrome. PSP subjects showed brainstem atrophy with involvement of the cortex and underlying white matter. Frontoparietal grey and subcortical grey matter atrophy occurred in CBD. When subdivided, PSP subjects with an extrapyramidal syndrome had more brainstem atrophy and less cortical atrophy than CBD subjects with an extrapyramidal syndrome. PSP subjects with a dementia syndrome had more subcortical white matter atrophy than CBD subjects with a dementia syndrome. These results show regional differences between PSP and CBD that are useful in predicting the underlying pathology, and help to shed light on the in vivo distribution of regional atrophy in PSP and CBD.

Longitudinal MRI in progressive supranuclear palsy and multiple system atrophy: rates and regions of atrophy

The rate of brain atrophy and its relationship to clinical disease progression in progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) is not clear. Twenty-four patients with PSP, 11 with MSA-P (Parkinsonian variant), 12 with Parkinson's disease, and 18 healthy control subjects were recruited for serial MRI scans, clinical assessments and formal neuropsychological evaluations in order to measure brain atrophy during life and its association with disease progression in PSP and MSA-P. Serial scans were registered and rates of whole brain atrophy calculated from the brain-boundary shift integral. Regional rates of atrophy were calculated in the brainstem (midbrain and pons), the cerebellum, the lateral and third ventricles as well as frontal and posterior inferior brain regions, by locally registering to a region of interest in order to derive a local boundary shift integral (BSI). 82% of recruited subjects completed serial MRI scans (17 PSP, 9 MSA-P, 9 Parkinson's disease patients and 18 healthy controls). Mean (SD) annualized rates of whole-brain atrophy were greatest in PSP: 1.2% (1.0%), three times that in controls. Mean (SD) midbrain atrophy rates in PSP, 2.2% (1.5%), were seven times greater than in healthy controls. In MSA-P, atrophy rates were greatest in the pons: 4.5% (3.2%), over 20 times that in controls and three times the rate of pontine atrophy in PSP. Atrophy rates in Parkinson's disease were not significantly different from control rates of atrophy. Variability in the atrophy rates was lower when calculated using the BSI rather than manual measurements. Worsening motor deficit was associated with midbrain atrophy in PSP, and ponto-cerebellar atrophy in MSA-P. Worsening executive dysfunction was associated with increased rates of frontal atrophy in PSP. Cerebellar atrophy rates were better discriminators of MSA-P than cross-sectional volumes. We confirm that serial MRI can be applied to measure whole brain and regional atrophy rates in PSP and MSA-P. Regional rather than whole-brain atrophy rates better discriminate PSP and MSA-P from healthy controls. Clinico-radiological associations suggest these regional atrophy rates have potential as markers of disease progression in trials of novel therapies.

Midbrain atrophy in progressive supranuclear palsy: comparison of two dimensional planimetric- with three dimensional volumetric measurements

Two-dimensional (2D) planimetric measurements of the brainstem could be useful to differentiate patients with the clinical diagnosis of progressive supranuclear palsy (PSP) from those with other parkinsonian disorders intra vitam (1). However, planimetric 2D measurements of small structures may be inaccurate owing to partial volume effects, which depend on the rater-dependent selection of the midsagittal image and the manual traces to identify the structure. We aim here to compare the use of 2D with three-dimensional (3D) volumetric measurements. On a semiautomated basis, we measured 33 patients diagnosed with PSP (Eight confirmed at autopsy)(2). All measured brain regions were normalized by the total intracranial volume (TICV). Although the normalized midbrain volume was the most powerful predictor to discriminate between PSP patients and control subjects, there was some overlap between these two groups (Figure B). We found that the midbrain atrophy in patients with PSP correlated with the Hoehn and Yahr Scale, bradykinesia, gait disturbance, and falls (Table). We applied a 2D technique (1) which consists in a manual tracing of brainstem structures on a midsaggital MRI-slice followed by an automatic planimetric measurement on the images of our patients with PSP (n=33) and corticobasal degeneration (CBD; n=18) and age-matched control subjects (n=22). To this purpose, we reconstructed the midsagittal plane using the anterior and posterior commissures as landmarks. We found this feature useful to discriminate between these groups (Figure A). Therefore, 2D measurements discriminate not only PSP patients from control subjects but also from those with CBD. In contrast to our volumetric approach, the 2D determination of the midbrain showed no significant correlation with clinical variables (Table). Thus, 2D measurement of the brainstem appears to be a useful clinical tool to rapidly discriminate PSP from control and other atypical parkinsonian syndromes, but should be questioned as a surrogate marker to evaluate disease severity or disease progression. For clinicoanatomic correlation, the 3D-volumetric approach appears to be superior.

Clinical deficits correlate with regional cerebral atrophy in progressive supranuclear palsy

Most cerebral imaging studies of patients with progressive supranuclear palsy (PSP) have noted subtle atrophy, although the full extent of atrophy and any correlates to clinical features have not been determined. We used voxel-based morphometry analysis of grey matter, white matter and CSF on MRI brain scans to map the statistical probability of regional tissue atrophy in 21 patients with PSP, 17 patients with Parkinson's disease and 23 controls. PSP and Parkinson's disease cohorts were selected to approximate the mid-stages of their respective disease courses. Where regions of significant tissue atrophy were identified in a disease group relative to controls, the probability of tissue loss within those regions was correlated with global indices of motor disability, and behavioural and cognitive disturbance for that disease group. Minimal regional atrophy was observed in Parkinson's disease. PSP could be distinguished from both controls and Parkinson's disease by symmetrical tissue loss in the frontal cortex (maximal in the orbitofrontal and medial frontal cortices), subcortical nuclei (midbrain, caudate and thalamic) as well as periventricular white matter. For PSP, motor deficits correlated with atrophy of the caudate and motor cingulate, while behavioural changes related to atrophy in the orbitofrontal cortex and midbrain. These data suggest that intrinsic neurodegeneration of specific subcortical nuclei and frontal cortical subregions together contribute to motor and behavioural disturbances in PSP and differentiate this disorder from Parkinson's disease within 2-4 years of symptom onset.

0898 Does cellular pathology predict atrophy in progressive supranuclear palsy? A study of the caudate nucleus

0898 Does cellular pathology predict atrophy in progressive supranuclear palsy? A study of the caudate nucleus

Voxel based morphometry reveals a distinct pattern of frontal atrophy in progressive supranuclear palsy

Background: Frontal lobe atrophy is a well known neuropathological feature of progressive supranuclear palsy (PSP), accompanied by characteristic neuropsychological deficits. Objective: To determine subregional frontal lobe atrophy patterns in patients...

Study of the rostral midbrain atrophy in progressive supranuclear palsy

Rostral midbrain atrophy in progressive supranuclear palsy (PSP) is detected by mid-sagittal plain magnetic resonance imaging (MRI). The shape of the atrophy looks like the bill of a hummingbird (hummingbird sign). We studied this sign to elucidate the nature of midbrain atrophy in PSP. Eight patients with PSP, 12 with Parkinson's disease (PD), and 10 normal controls were studied. Using mid-sagittal plain MRI, we measured the rostral and caudal midbrain tegmentum (MT), superior and inferior colliculus, pontine base, and tegmentum. We compared the length of the interpeduncular fossa, which is posterior to the mammillary body, to the diameter of the midbrain tegmentum. The multiple comparison method was used for the statistical analysis. The hummingbird sign was demonstrated in all of the PSP patients studied, and it was not observed in PD patients nor in normal controls. The hummingbird sign in the PSP patients was due to the atrophy of the midbrain tegmentum (rostral and caudal) and to a relative increase in the length of the interpeduncular fossa over that of the anteroposterior diameter of the midbrain tegmentum. The hummingbird sign, which represents the atrophy of the rostral midbrain tegmentum, strongly suggests the involvement of the rostral interstitial nucleus of the medial longitudinal fasciculus in patients with PSP. Demonstration of a hummingbird sign on MRI is thought to be useful for a diagnosis of PSP.

Regional brain atrophy in progressive supranuclear palsy and Lewy body disease

There have been no previous three-dimensional volumetric studies of regional brain atrophy in patients with pathologically confirmed progressive supranuclear palsy (PSP). Postmortem cortical and subcortical volumes were compared with neuropathology in 9 patients with PSP, 15 patients with Parkinson's disease, 10 patients with dementia with Lewy bodies, and 23 controls. Cases with the neuritic pathology of Alzheimer's disease were excluded. The topography of brain atrophy differed according to clinicopathological phenotype. Patients with Parkinson's disease had atrophy confined to the amygdala. Atrophy of the frontal lobe was found in both PSP and dementia with Lewy bodies and correlated with increasing neurofibrillary tangle or Lewy body densities, respectively. Patients with PSP could be differentiated by their marked atrophy of the internal globus pallidus. Further analysis of variance revealed that trends for greater frontal lobe atrophy correlated with clinical dementia in PSP, whereas both greater frontal and hippocampal atrophy and higher densities of Lewy bodies and Lewy neurites correlated with clinical dementia in cases with Lewy bodies. The present study provides evidence for selective regional atrophy that correlates with the underlying pathology of PSP and Lewy body disease.

Cognitive and magnetic resonance imaging aspects of corticobasal degeneration and progressive supranuclear palsy.

To identify cognitive and MRI features important for the clinical diagnosis of corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP); these diseases share several clinical features and are often difficult to distinguish on clinical grounds. Cognitive functions and MRI characteristics were examined in 16 patients with CBD and 28 patients with PSP, all diagnosed according to current clinical criteria (none was examined by autopsy). MRI findings differed significantly between the two groups: 87.5% of patients with CBD but none with PSP had asymmetric frontoparietal atrophy, whereas 89.3% of patients with PSP but only 6.3% of those with CBD had midbrain atrophy. Cognitive examination showed that ideomotor apraxia (De Renzi's test) was significantly more frequent in CBD, and executive functions (Nelson's test) were significantly more impaired in patients with PSP. MRI findings of asymmetric frontoparietal atrophy in CBD and midbrain atrophy in PSP are the most consistent and useful aids to careful clinical evaluation for differentiating between the two diseases.