Striatal and thalamic automatic segmentation, morphology, and clinical correlates in Parkinsonism: Parkinson's disease, multiple system atrophy and progressive supranuclear palsy.

Parkinson's disease (PD), multisystem atrophy (MSA), and progressive supranuclear palsy (PSP) present similarly with bradykinesia, tremor, rigidity, and cognitive impairments. Neuroimaging studies have found differential changes in the nigrostriatal pathway in these disorders, however whether the volume and shape of specific regions within this pathway can distinguish between atypical Parkinsonian disorders remains to be determined. This paper investigates striatal and thalamic volume and morphology as distinguishing biomarkers, and their relationship to neuropsychiatric symptoms. Automatic segmentation to calculate volume and shape analysis of the caudate nucleus, putamen, and thalamus were performed in 18 PD patients, 12 MSA, 15 PSP, and 20 healthy controls, then correlated with clinical measures. PSP bilateral thalami and right putamen were significantly smaller than controls, but not MSA or PD. The left caudate and putamen significantly correlated with the Neuropsychiatric Inventory total score. Bilateral thalamus, caudate, and left putamen had significantly different morphology between groups, driven by differences between PSP and healthy controls. This study demonstrated that PSP patient striatal and thalamic volume and shape are significantly different when compared with controls. Parkinsonian disorders could not be differentiated on volumetry or morphology, however there are trends for volumetric and morphological changes associated with PD, MSA, and PSP.

Diffusion microstructure imaging in progressive supranuclear palsy: reduced axonal volumes in the superior cerebellar peduncles, dentato-rubro-thalamic tracts, ventromedial thalami, and frontomesial white matter.

Differentiating between Parkinson's disease (PD) and atypical Parkinson syndromes such as progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and corticobasal degeneration is challenging. Diffusion microstructure imaging (DMI) was analyzed in patients with clinically suspected atypical Parkinson syndromes and healthy controls. In an exploration cohort, the spatial distribution of PSP-related changes of DMI parameters were evaluated in a voxel-wise analysis and a region-of-interest (ROI)-based approach was established. The diagnostic performance was subsequently tested in an independent validation cohort. In the exploration cohort, 53 PSP patients were compared to a pooled comparison group of 19 patients with PD, 26 patients with MSA, 7 patients with corticobasal syndrome, and 25 healthy controls. PSP patients showed widespread axonal loss in the superior cerebellar peduncles, the dentato-rubro-thalamic tracts, the thalami and the frontal white matter (each P < 0.001). In the validation cohort consisting of 12 patients with PSP vs. 13 patients with other movement disorders, the accuracy of this ROI-based approach for identifying the PSP was highest in the thalamus and the frontal white matter (accuracy 0.96 each). This DMI approach can identify PSP patients on an individual level in a collective with suspected atypical Parkinson syndromes and allows further insight on microstructural alterations in vivo.

Diagnostic Performance of 123I-FPCIT SPECT Specific Binding Ratio in Progressive Supranuclear Palsy: Use of Core Clinical Features and MRI for Comparison.

OBJECTIVE. Progressive supranuclear palsy (PSP) is listed as a core clinical feature in the Movement Disorder Society 2017 criteria, along with ocular motor dysfunction, postural instability, akinesia, and cognitive dysfunction. Imaging evidence shows predominant mid-brain atrophy and postsynaptic striatal dopaminergic degeneration as two supportive features. The purpose of this study was to investigate the diagnostic performance of 123I-N- ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl) nortropane (123I-FP-CIT) SPECT by comparing it with evaluation of core clinical features and MRI in the diagnosis of PSP. MATERIALS AND METHODS. The study included 53 patients with clinically suspected PSP who had undergone 123I-FP-CIT SPECT and MRI examinations. MR parkinsonism index (MRPI) was used as the MRI index. For the 123I-FP-CIT SPECT index, specific binding ratio (SBR) was calculated as the average of the right and left SBRs. RESULTS. In regard to core clinical features, ocular motor dysfunction was present in 15 of 20 (75.0%) patients with the diagnosis of probable PSP (p < 0.0001). Calculation of the diagnostic performance of the imaging parameters showed that MRPI (cutoff > 11.6) had 85.0% sensitivity, 100% specificity, and 94.3% accuracy. SBR (cutoff < 3.7) had 95.0% sensitivity, 36.4% specificity, and 58.5% accuracy. CONCLUSION. Iodine-123-labeled FP-CIT SPECT has high sensitivity, and MRI has high specificity in the diagnosis of PSP. Because these tools have complementary roles, reach ing a more confident clinical diagnosis of PSP may be possible when both are used.

Thalamic and cerebellar hypoperfusion in single photon emission computed tomography may differentiate multiple system atrophy and progressive supranuclear palsy.

Neuroimaging in the context of examining atypical parkinsonian tauopathies is an evolving matter. Positron emission tomography and single photon emission computed tomography (SPECT) bring tools, which may be reasonable in supplementary examination, however, cannot be interpreted as a criterion standard for correct diagnosis. The aim of this observational study was to assess the differentiating potential of perfusion SPECT in 3 types of atypical parkinsonisms: multiple system atrophy parkinsonian type (MSA-P), corticobasal syndrome (CBS), and progressive supranuclear palsy (PSP). The study was carried out using the comparison of standard deviations of perfusion in patients from these 3 groups. Data obtained from 10 patients with clinical diagnosis MSA-P, 14 patients with CBS and 21 patients with PSP, which were analyzed using Tukey honest significant difference post-hoc test, revealed significant differences of perfusion P < .05 between MSA-P and PSP within the cerebellum and thalamus. No significant differences between CBS and PSP were observed.

Morphometric analysis of thalamic volume in progressive supranuclear palsy: In vivo evidence of regionally specific bilateral thalamic atrophy.

We investigated whether differences were detectable in the volume and shape of the dorsal thalamus on magnetic resonance imaging in patients with progressive supranuclear palsy (PSP). Manual segmentation of the left and right thalami on magnetic resonance imaging scans occurred in 22 patients with clinically diagnosed PSP and 23 healthy controls; thalamic volumes (left, right, total) were calculated. Between group differences were explored by multivariate analysis of co-variance, using age and intracranial volume as covariates. Analysis of the shape of the thalamus was performed using the spherical harmonic point distribution method software package. Patients with PSP were found to have significant bilateral thalamic atrophy on magnetic resonance imaging; there was significant shape deflation over the anterior-lateral and anterior-ventral surfaces bilaterally, and over the right caudal thalamus. Recognizing decreased thalamic morphology in PSP patients in vivo may be an important component of an ensemble of diagnostic biomarkers in the future, particularly given the difficulty of distinguishing PSP from other Parkinsonian conditions early in the disease course.

Intrinsic functional connectivity alterations in progressive supranuclear palsy: Differential effects in frontal cortex, motor, and midbrain networks.

BACKGROUND: The topography of functional network changes in progressive supranuclear palsy can be mapped by intrinsic functional connectivity MRI. The objective of this study was to study functional connectivity and its clinical and behavioral correlates in dedicated networks comprising the cognition-related default mode and the motor and midbrain functional networks in patients with PSP. METHODS: Whole-brain-based "resting-state" functional MRI and high-resolution T1-weighted magnetic resonance imaging data together with neuropsychological and video-oculographic data from 34 PSP patients (22 with Richardson subtype and 12 with parkinsonian subtype) and 35 matched healthy controls were subjected to network-based functional connectivity and voxel-based morphometry analysis. RESULTS: After correction for global patterns of brain atrophy, the group comparison between PSP patients and controls revealed significantly decreased functional connectivity (P < 0.05, corrected) in the prefrontal cortex, which was significantly correlated with cognitive performance (P = 0.006). Of note, midbrain network connectivity in PSP patients showed increased connectivity with the thalamus, on the one hand, whereas, on the other hand, lower functional connectivity within the midbrain was significantly correlated with vertical gaze impairment, as quantified by video-oculography (P = 0.004). PSP Richardson subtype showed significantly increased functional motor network connectivity with the medial prefrontal gyrus. CONCLUSIONS: PSP-associated neurodegeneration was attributed to both decreased and increased functional connectivity. Decreasing functional connectivity was associated with worse behavioral performance (ie, dementia severity and gaze palsy), whereas the pattern of increased functional connectivity may be a potential adaptive mechanism. © 2017 International Parkinson and Movement Disorder Society.

High affinity radiopharmaceuticals based upon lansoprazole for PET imaging of aggregated tau in Alzheimer's disease and progressive supranuclear palsy: synthesis, preclinical evaluation, and lead selection.

Abnormally aggregated tau is the hallmark pathology of tauopathy neurodegenerative disorders and is a target for development of both diagnostic tools and therapeutic strategies across the tauopathy disease spectrum. Development of carbon-11- or fluorine-18-labeled radiotracers with appropriate affinity and specificity for tau would allow noninvasive quantification of tau burden using positron emission tomography (PET) imaging. We have synthesized [(18)F]lansoprazole, [(11)C]N-methyl lansoprazole, and [(18)F]N-methyl lansoprazole and identified them as high affinity radiotracers for tau with low to subnanomolar binding affinities. Herein, we report radiosyntheses and extensive preclinical evaluation with the aim of selecting a lead radiotracer for translation into human PET imaging trials. We demonstrate that [(18)F]N-methyl lansoprazole, on account of the favorable half-life of fluorine-18 and its rapid brain entry in nonhuman primates, favorable kinetics, low white matter binding, and selectivity for binding to tau over amyloid, is the lead compound for progression into clinical trials.

Selective impairment of action-verb naming and comprehension in progressive supranuclear palsy.

Some previous studies in brain-damaged patients suggested that neural systems in the left temporal lobe might be crucial in the production and comprehension of nouns, while analogous systems in posterior frontal cortical areas might be involved in the production and comprehension of verbs. We assessed performance on neuropsychological tasks of production and comprehension of nouns and action-verbs in 10 patients with progressive supranuclear palsy (PSP) and in 10 age-matched healthy controls. PSP patients also underwent measurements of regional cerebral blood flow by means of single photon emission computed tomography (SPECT), using 99mTc-Ethyl Cysteinate Dimer. In all PSP patients, SPECT showed a significant hypoperfusion in the inferior frontal gyrus (IFG). PSP patients performed significantly worse than controls on all lexical-semantic tasks, except for the auditory lexical decision task on nouns. Within PSP patients, however, a significantly lower performance was observed on action-verbs as compared to nouns on various lexical-semantic tasks (oral and written confrontation naming, auditory and visual single-word comprehension). Analysis of individual performance revealed heterogeneous patterns of neuropsychological impairment in different PSP patients. Despite some difficulty in drawing clear-cut conclusions about the locus of functional damage, we hypothesise that in most of our PSP patients such selective impairment in the production and in the comprehension of action-verbs could be due to semantic deficits affecting the conceptual category of actions. These findings are consistent with the hypothesis that in PSP a dysfunction of neural systems in posterior frontal cortical areas (mainly involving the IFG) critical for processing the conceptual category of actions might result in a selective impairment of production and comprehension of action-verbs.

Fluorodeoxyglucose positron emission tomography in Richardson's syndrome and progressive supranuclear palsy-parkinsonism.

BACKGROUND: We hypothesized that postural instability and cognitive decline in patients with Richardson's syndrome could be a consequence of reduced thalamic and frontal metabolism. Severe Parkinsonian signs in patients with progressive supranuclear palsy-parkinsonism may be reflected by alterations in putaminal metabolism. METHODS: Eleven patients with Richardson's syndrome, 8 patients with progressive supranuclear palsy-parkinsonism, 12 with Parkinson's disease, and 10 controls underwent clinical assessment and fluorodeoxyglucose positron emission tomography (PET). RESULTS: Richardson's syndrome patients showed pronounced thalamic hypometabolism, and patients with progressive supranuclear palsy-parkinsonism pronounced putaminal hypometabolism, compared to all other investigated groups. The putamen/thalamus uptake ratio differentiated progressive supranuclear palsy-parkinsonism from Richardson's syndrome (area under the curve 5 0.86) and from Parkinson's disease (area under the curve 5 0.80) with acceptable accuracy. Frontal hypometabolism was predominantly found in Richardson's syndrome patients. CONCLUSIONS: Richardson's syndrome, progressive supranuclear palsy-parkinsonism and Parkinson's disease showed different metabolic patterns in fluorodeoxyglucose PET.

PSP as distinguished from CBD, MSA-P and PD by clinical and imaging differences at an early stage.

OBJECTIVE: Because it is often difficult to precisely diagnose and distinguish progressive supranuclear palsy (PSP) from corticobasal degeneration (CBD), multiple system atrophy-parkinsonism (MSA-P) and Parkinson's disease (PD) at the onset of the disease, we compared the patients and clarified the features of these diseases. METHODS: We compared 77 PSP, 26 CBD, 26 MSA-P and 166 PD patients from clinical and imaging points of view including cerebral blood flow (CBF) in the frontal eye field. RESULTS: The clinical characteristics of PSP were supranuclear gaze disturbance, optokinetic nystagmus (OKN) impairment and falls at the first visit. On head MRI, midbrain tegmentum atrophy was much more frequently detected in PSP than in all of the other groups. Heart-to-mediastinum average count ratio (H/M) in iodine-123 meta-iodobenzyl guanidine ((123)I-MIBG) myocardial scintigraphy was not decreased in PSP, CBD, MSA-P and PD-Yahr 1 (-1), but patients of PD-2, 3, 4 and 5 showed a significant decrease compared with the PSP group. The CBF in the left frontal eye field of PD-3 group and that in right frontal eye field of PD-3 and PD-4 groups were lower than that of PSP group, although other groups showed a tendency without a significant decrease compared with PSP group. CONCLUSION: PSP is distinguishable from CBD, MSA-P and PD even at the early stage with extra-ocular movement (EOM) disturbance, falls, atrophy of the midbrain tegmentum, and H/M in (123)I-MIBG myocardial scintigraphy, and the reduction of CBF in area 8 could serve as a supplemental diagnostic method for distinguishing PSP from PD-3 or PD-4.

Brain perfusion differences in parkinsonian disorders.

We aimed to objectively examine the brain perfusion differences between PD, Parkinson variant of multiple system atrophy, and progressive supranuclear palsy. (99m) Tc ethylcysteinate dimer single-photon emission CT (SPECT) was performed in 28 patients with PD, 12 with Parkinson variant of multiple system atrophy, 19 with progressive supranuclear palsy, and 17 age- and sex-matched control subjects. A voxel-by-voxel group analysis, using statistical parametric mapping 8, was performed to detect the differences of regional cerebral blood flow among three diseases and control groups. Regional cerebral blood flow was measured using the noninvasive Patlak plot method and calculated using a fully automated region of interest technique. Progressive supranuclear palsy showed decreased regional cerebral blood flow in the cingulate gyrus and thalamus, whereas Parkinson variant of multiple system atrophy showed decreased regional cerebral blood flow in the cerebellum, compared with other patients and controls. Regional cerebral blood flow in the thalamus could be used to discriminate progressive supranuclear palsy from other diseases and control subjects with high sensitivity. These findings suggest that parkinsonian disorders, such as PD, Parkinson variant of multiple system atrophy, and progressive supranuclear palsy show a distinct SPECT pattern in the frontal cortex, thalamus, and cerebellum. Moreover, the measurements of regional cerebral blood flow in the thalamus and cerebellum may be helpful in screening for the differential diagnosis of parkinsonian syndrome.

Postural imbalance and falls in PSP correlate with functional pathology of the thalamus.

OBJECTIVE: To determine how postural imbalance and falls are related to regional cerebral glucose metabolism (PET) and functional activation of the cerebral postural network (fMRI) in patients with progressive supranuclear palsy (PSP). METHODS: Sixteen patients with PSP, who had self-monitored their frequency of falls, underwent a standardized clinical assessment, posturographic measurement of balance during modified sensory input, and a resting [¹8F]FDG-PET. In addition, patients performed an fMRI paradigm using mental imagery of standing. Results were compared to healthy controls (n = 16). RESULTS: The frequency of falls/month in patients (range 1-40) correlated with total PSP rating score (r = 0.90). Total sway path in PSP significantly correlated with frequency of falls, especially during modulated sensory input (eyes open: r = 0.62, eyes closed: r = 0.67, eyes open/head extended: r = 0.84, eyes open/foam-padded platform: r = 0.87). Higher sway path values and frequency of falls were associated with decreased regional glucose metabolism (rCGM) in the thalamus (sway path: r = -0.80, falls: r = -0.64) and increased rCGM in the precentral gyrus (sway path: r = 0.79, falls: r = 0.64). Mental imagery of standing during fMRI revealed a reduced activation of the mesencephalic brainstem tegmentum and the thalamus in patients with postural imbalance and falls. CONCLUSIONS: The new and clinically relevant finding of this study is that imbalance and falls in PSP are closely associated with thalamic dysfunction. Deficits in thalamic postural control get most evident when balance is assessed during modified sensory input. The results are consistent with the hypothesis that reduced thalamic activation via the ascending brainstem projections may cause postural imbalance in PSP.

Identification by [99mTc]ECD SPECT of anterior cingulate hypoperfusion in progressive supranuclear palsy, in comparison with Parkinson's disease.

PURPOSE: Progressive supranuclear palsy (PSP) is an akinetic-rigid syndrome that can be difficult to differentiate from Parkinson's disease (PD), particularly at an early stage. [99mTc]ethyl cysteinate dimer (ECD) SPECT could represent a widely available tool to assist in the differential diagnosis. In this study we used voxel-based analysis and Computerised Brain Atlas (CBA)-based principal component analysis (PCA) of [99mTc]ECD SPECT data to test whether: (1) specific patterns of rCBF abnormalities can differentiate PSP from controls and PD; (2) networks of dysfunctional brain regions can be found in PSP vs controls and PD. METHODS: Nine PD patients, 16 PSP patients and ten controls were studied with [99mTc]ECD SPECT using a brain-dedicated device (Ceraspect). Voxel-based analysis was performed with statistical parametric mapping. PCA was applied to volume of interest data after spatial normalisation to CBA. RESULTS: The voxel-based analysis showed hypoperfusion of the anterior cingulate and medial frontal cortex in PSP compared with controls and PD. In PSP patients the rCBF impairment extended to the pre-supplementary motor area and prefrontal cortex, areas involved in executive function and motor networks. Compared with PSP patients, PD patients showed a mild rCBF decrease in associative visual areas which could be related to the known impairment of visuospatial function. The PCA identified three principal components differentiating PSP patients from controls and/or PD patients that included groups of cortical and subcortical brain regions with relatively decreased (cingulate cortex, prefrontal cortex and caudate) or increased (parietal cortex) rCBF, representing distinct functional networks in PSP. CONCLUSION: Anterior cingulate hypoperfusion seems to be an early, distinct brain abnormality in PSP as compared with PD.

Sonographic discrimination of corticobasal degeneration vs progressive supranuclear palsy.

OBJECTIVE: To study the use of brain parenchyma sonography (BPS) in discriminating between patients with corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). METHODS: Thirteen patients with PSP and eight with CBD were studied with BPS according to a standardized protocol. RESULTS: Seven (88%) of the eight CBD patients showed marked hyperechogenicity of the substantia nigra (SN) but none of eleven PSP patients (Mann-Whitney U test, p < 0.001). This finding indicated CBD with a positive predictive value of 100%. Marked dilatation of the third ventricle (width > 10 mm) was found in 10 (83%) of 12 PSP patients, but in none of the CBD patients (p < 0.005). BPS measurements of ventricle widths closely matched MRI measurements (Pearson correlation, r = 0.90, p < 0.001). The presence of at least one of the BPS findings 1) marked SN hyperechogenicity and 2) third-ventricle width < 10 mm indicated CBD with a sensitivity of 100%, a specificity of 83%, and a positive predictive value of 80%. Other BPS findings such as echogenicity of lentiform and caudate nuclei and widths of the frontal horns did not discriminate between CBD and PSP. One PSP patient could not be assessed because of insufficient acoustic temporal bone windows. CONCLUSIONS: Substantia nigra hyperechogenicity, reported earlier as characteristic brain parenchyma sonography finding in idiopathic Parkinson disease, is also typical for corticobasal degeneration.

Iodine-123-IBF SPECT evaluation of extrapyramidal diseases.

UNLABELLED: Iodine-123-IBF is a dopaminergic antagonist suitable for SPECT imaging of D2 receptors. Initial animal studies demonstrated that its affinity for D2 receptors is approximately four times that of the commonly used SPECT D2 ligand [123I]IBZM. In this study we investigated whether this higher affinity would lead to an improved accuracy in differentiating between various extrapyramidal diseases. METHODS: SPECT imaging was performed in 17 patients with idiopathic Parkinson's syndrome (IPS); 4 patients with progressive supranuclear palsy (PSP), 2 patients with multiple system atrophy (MSA) and 7 age-matched control subjects. SPECT imaging was performed 5, 60, 120 and 180 min following intravenous bolus injection of 150-250 MBq of [123I]IBF. The ratio of ligand uptake in the basal ganglia and frontal cortex was determined as a measure of receptor status. RESULTS: In PSP and MSA patients, the basal ganglia-to-frontal cortex ratio reached a plateau at 2 hr; in the control subjects and the IPS patients the ratio was steadily increasing. At 3 hr the basal ganglia-to-frontal cortex ratio was 2.66 +/- 0.29 (control subjects), 3.01 +/- 0.41 (IPS), 2.09 +/- 0.22 (PSP) and 2.10 (MSA). In the IPS patients with predominantly one-sided symptoms, the striatum contralateral to symptoms showed a tendency towards relatively increased ligand uptake. Despite the higher affinity of IBF for the D2 receptor compared to IBZM, the separation of individual PSP and MSA patients from the control subjects was not as clear cut as reported for IBZM due to a relatively high variation in the control subjects. We hypothesize that the latter is due to imaging in nonequilibrium conditions. CONCLUSION: The data suggest that IBF-SPECT can help in discriminating extrapyramidal disease. The accuracy might be improved by an administration protocol that allows imaging in "true equilibrium" conditions, such as a bolus injection followed by a constant infusion.