A comprehensive characterisation of grey and white matter changes in progressive supranuclear palsy (PSP), the second most common extrapyramidal syndrome after Parkinson disease, is still not available.
To evaluate grey and white matter changes in mild PSP patients by voxel based morphometry (VBM) and diffusion tensor imaging (DTI), respectively.
14 mild PSP patients and 14 healthy controls entered the study and underwent a clinical and neuropsychological evaluation according with a standardised assessment. Each subject had a structural magnetic resonance imaging (MRI) study. Processing analysis of MRI data was carried out according to optimised VBM and fractional anisotropy was determined.
Compared with the controls, in PSP patients VBM analysis showed a significant clusters of reduced grey matter in premotor cortex, frontal operculum, anterior insula, hippocampus, and parahippocampal gyrus, bilaterally. With regard to subcortical brain regions, the pulvinar, dorsomedial and anterior nuclei of the thalamus, and superior and inferior culliculum were affected bilaterally. A bilateral decrease in fractional anisotropy in superior longitudinal fasciculus, anterior part of corpus callosum, arcuate fascicolus, posterior thalamic radiations, and internal capsule, probably involving the cortico‐bulbar tracts, was present in PSP patients.
These data provide evidence for both grey and white matter degeneration in PSP from the early disease stage. These structural changes suggest that atrophy of cortical and subcortical structures and neurodegeneration of specific fibre tracts contribute to neurological deficits in PSP.
progressive supranuclear palsy; magnetic resonance imaging; voxel based morphometry; diffusion tensor imaging
Progressive supranuclear palsy (PSP) and frontotemporal lobar degeneration (FTD) are two clinicohistological entities that share a severe prefrontal syndrome. To what extent do the cognitive syndrome and the location of the underlying brain atrophy unify or segregate these entities? Here, we examined the clinical and radiological patterns of frontal involvement and the neural bases of the cognitive dysfunctions observed in the Richardson form of PSP and the behavioral variant of FTD (bvFTD). The cognitive profile and grey and white matter volume of PSP (n = 19) and bvFTD (n = 16) patients and control participants (n = 18) were compared using a standard battery of neuropsychological tests and voxel-based morphometry (VBM), respectively. Analyses of correlations between neuropsychological and morphometric data were additionally performed. The severity and qualitative pattern of cognitive dysfunction was globally similar between the two patient groups. Grey matter volume was decreased in widespread frontal areas and in the temporal uncus in bvFTD, while it was decreased in the frontal and temporal lobes as well as in the thalamus in PSP. We also found an unexpected involvement of the frontal rectal gyrus in PSP patients compared to controls. Correlation analyses yielded different results in the two groups, with no area showing significant correlations in PSP patients, while several frontal and some temporal areas did so in bvFTD patients. In spite of minor neuropsychological and morphological differences, this study shows that the patterns of cognitive dysfunction and atrophy are very similar in PSP and bvFTD. However, executive dysfunction in these diseases may stem from partially divergent cortical and subcortical neural circuits.
Progressive supranuclear palsy (PSP) is associated with pathological changes along the dentatorubrothalamic tract and in premotor cortex. We aimed to assess whether functional neural connectivity is disrupted along this pathway in PSP, and to determine how functional changes relate to changes in structure and diffusion. Eighteen probable PSP subjects and 18 controls had resting-state (task-free) fMRI, diffusion tensor imaging and structural MRI. Functional connectivity was assessed between thalamus and the rest of the brain, and within the basal ganglia, salience and default mode networks (DMN). Patterns of atrophy were assessed using voxel-based morphometry, and patterns of white matter tract degeneration were assessed using tract-based spatial statistics. Reduced in-phase functional connectivity was observed between the thalamus and premotor cortex including supplemental motor area (SMA), striatum, thalamus and cerebellum in PSP. Reduced connectivity in premotor cortex, striatum and thalamus were observed in the basal ganglia network and DMN, with subcortical salience network reductions. Tract degeneration was observed between cerebellum and thalamus and in superior longitudinal fasciculus, with grey matter loss in frontal lobe, premotor cortex, SMA and caudate. SMA functional connectivity correlated with SMA volume and measures of cognitive and motor dysfunction, while thalamic connectivity correlated with degeneration of superior cerebellar peduncles. PSP is therefore associated with disrupted thalamocortical connectivity that is associated with degeneration of the dentatorubrothalamic tract and the presence of cortical atrophy.
Resting state fMRI; functional connectivity; white matter tracts; atrophy; dentatorubrothalamic tract
The clinical presentation in progressive supranuclear palsy (PSP), an atypical parkinsonian disorder, includes varying degrees of frontal dysexecutive symptoms. Using diffusion tensor imaging (DTI) and tractography (DTT), we investigated whether diffusion changes and atrophy of the inferior fronto-occipital fasciculus (IFO) occurs in PSP and if these changes correlate with disease stage and clinical phenotype. The corticospinal tract (CST), which is often involved in PSP, was investigated for comparison.
DTI of the whole brain was performed with a 3 T MR scanner using a single shot-EPI sequence with diffusion encoding in 48 directions. Scans were obtained in patients with PSP (n = 13) and healthy age-matched controls (n = 12). DTT of the IFO and CST was performed with the PRIDE fibre tracking tool (Philips Medical System). Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were calculated and correlated with disease stage and clinical phenotype.
In patients with PSP, significantly decreased FA and increased ADC was found in the frontal part of IFO compared with the medial and occipital parts of IFO, as well as compared to controls. Four of the thirteen patients with PSP showed a marked decrease in the number of tracked voxels in the frontal part of IFO. These findings were most pronounced in patients with severe frontal cognitive symptoms, such as dysexecutive problems, apathy and personality change. There was a strong correlation (r2 = -0.84; p < 0,001) between disease stage and FA and ADC values in the CST.
DTT for identification of neuronal tracts with subsequent measurement of FA and ADC is a useful diagnostic tool for demonstrating patterns of neuronal tract involvement in neurodegenerative disease. In selected tracts, FA and ADC values might act as surrogate markers for disease stage.
The aim of this study was to compare differences in morphological and functional changes in brain regions in individual patients with progressive supranuclear palsy (PSP) and correlate their Mini-Mental State Examination (MMSE) score with anatomy and function using magnetic resonance imaging (MRI) and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET).
Sixteen PSP patients and 20 age-matched healthy volunteers underwent FDG-PET and 3-dimensional MRI. Gray matter, white matter and metabolic activity were compared between patients and normal controls. In addition, possible correlations between the MMSE score and brain function/anatomy were examined.
The PSP group had reduced cerebral glucose metabolism, and lower gray and white matter volumes in the frontal lobes and midbrain compared with normal controls. In PSP subjects, the metabolic changes observed in the PET scans were greater than the loss in gray and white matter observed in the MRI scans. The MMSE scores were positively correlated with volume and FDG uptake in the frontal lobe.
FDG-PET is a more effective tool in the diagnosis of PSP than MRI. Atrophy and hypometabolism in the frontal lobe are as important as in the basal midbrain for differentiating PSP patients who primarily exhibit cognitive dysfunction from normal controls.
DARTEL; Gray matter; Hypometabolism; Magnetic resonance imaging; Progressive supranuclear palsy; Voxel-based morphometry; White matter
To study the neuropsychological pattern of striatonigral degeneration (SND), 14 consecutive patients with probable SND were submitted to an extensive battery of neuropsychological tests. Compared with controls the performance of patients with SND was impaired on category and phonemic fluency, frontal behaviours, trail making test A and B, and free recall of the Grober and Buschke test, but normal on the revised WAIS verbal scale, Raven 47 coloured progressive matrices, Wechsler memory scale, California verbal learning test, Wisconsin card sorting test, and the Stroop interference condition. The performance of patients with SND was also compared with that of 14 patients with Parkinson's disease and 14 patients with progressive supranuclear palsy (PSP) matched for age at onset, duration of disease, severity of intellectual deterioration, and depression. The results showed that the dysexecutive syndrome of SND is similar to that of Parkinson's disease and less severe than in PSP.
Objectives: To measure vertical and horizontal responses to optokinetic (OK) stimulation and investigate directional abnormalities of quick phases in progressive supranuclear palsy (PSP).
Methods: Saccades and OK nystagmus were studied in six PSP patients, five with Parkinson's disease (PD), and 10 controls. The OK stimulus subtended 72° horizontally, 60° vertically, consisted of black and white stripes, and moved at 10–50°/s.
Results: All PSP patients showed slowed voluntary vertical saccades and nystagmus quick phases compared with PD or controls. Small, paired, horizontal saccadic intrusions (SWJ) were more frequent and larger in PSP during fixation. Vertical saccades were transiently faster at the time of SWJ and horizontal saccades in PSP. During vertical OK nystagmus, small quick phases were often combined with horizontal SWJ in all subjects; in PSP the vector was closer to horizontal. Vertical OK slow phase gain was reduced in PSP but, in most PD patients, was similar to normals. The average position of gaze shifted in the direction of vertical OK stimulus in PSP patients with preserved slow phase responses but impaired quick phases.
Conclusions: Vertical OK responses in PSP show impaired slow phase responses, and quick phases that are slowed and combined with SWJ to produce an oblique vector. SWJ facilitate vertical saccades and quick phases in PSP, but it is unclear whether this is an adaptive process or a result of the disease. A large OK stimulus is useful to induce responses that can be quantitatively analysed in patients with limited voluntary range of vertical gaze.
Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterized by gait and postural disturbance, gaze palsy, apathy, decreased verbal fluency and dysexecutive symptoms, with some of these clinical features potentially having origins in degeneration of frontostriatal circuits and the mesencephalon. This hypothesis was investigated by manual segmentation of the caudate and putamen on MRI scans, using previously published protocols, in 15 subjects with PSP and 15 healthy age-matched controls. Midbrain atrophy was assessed by measurement of mid-sagittal area of the midbrain and pons. Shape analysis of the caudate and putamen was performed using spherical harmonics (SPHARM-PDM, University of North Carolina). The sagittal pons area/midbrain area ratio (P/M ratio) was significantly higher in the PSP group, consistent with previous findings. Significantly smaller striatal volumes were found in the PSP group – putamina were 10% smaller and caudate volumes were 17% smaller than in controls after controlling for age and intracranial volume. Shape analysis revealed significant shape deflation in PSP in the striatum, compared to controls; with regionally significant change relevant to frontostriatal and corticostriatal circuits in the caudate. Thus, in a clinically diagnosed and biomarker-confirmed cohort with early PSP, we demonstrate that neostriatal volume and shape are significantly reduced in vivo. The findings suggest a neostriatal and mesencephalic structural basis for the clinical features of PSP leading to frontostriatal and mesocortical-striatal circuit disruption.
Neostriatum; Caudate; Putamen; Mesencephalon; Magnetic Resonance Imaging
Objective: Bradykinesia is one of the clinical hallmarks of Parkinson’s disease (PD) and atypical Parkinsonian syndromes. Clinical ratings scales and technology-based assessments have been developed to measure bradykinesia. We review the different tools that exist for measurement of bradykinesia and analyze their reliability and applicability to PD and atypical Parkinsonian syndromes.
Methods: We summarize data on the factor structure of the two primary scales used to assess PD, the Unified Parkinson’s Disease Rating Scale (UPDRS) and Movement Disorder Society revision of the UPDRS, the MDS-UPDRS. We review how these scales have been used in atypical Parkinsonian syndromes, specifically Progressive Supranuclear Palsy (PSP). Finally, we report on the different technology-based tools being used to assess bradykinesia.
Results: The UPDRS is a useful measure of PD function and disability with six clinically distinct factors, three of which pertain to bradykinesia. The MDS-UPDRS has shown high internal consistency and correlation with the original UPDRS. Factor analysis of the UPDRS in PSP reveals five clinically distinct factors, two of which are independent bradykinesia factors. Thus the UPDRS and MDS-UPDRS are reliable and applicable scales for PD and the UPDRS can be used to assess bradykinesia in PSP. Technology-based tools for measuring bradykinesia include gyrosensors, Coordination Ability Test System, Brain Test, quantitative digitography, Motus motion analysis system, precision real-time image-based motion analysis, and the At-Home Testing Device. These tools have been compared to the UPDRS motor subscale and are effective in assessing bradykinesia.
Conclusion: The UPDRS and MDS-UPDRS are well-established measures of bradykinesia that are applicable and useful in PD. The UPDRS is also been shown to be applicable to PSP. Different technologies exist to measure bradykinesia, though further work is needed to validate these assessment tools and bring them to clinical practice.
bradykinesia; UPDRS; MDS-UPDRS; technology; Parkinson disease; PSP
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.
In order to better understand the similarities and differences in the motor behaviour of different groups of patients, their scores on the Motor Examination section of the Unified Parkinson's Disease Rating Scale (UPDRS) were analysed simultaneously. The three groups consisted, respectively, of patients with Parkinson's disease (PD) on medication, patients with Parkinson's disease withdrawn from anti-parkinsonian medication for at least 12 hours, and patients diagnosed with a specific Parkinsonism syndrome: Progressive Supranuclear Palsy (PSP).
A total of 669 consecutively sampled patients from three separate hospital-based clinics participated (294 PD on medication; 200 PD off medication: 175 PSP). The Motor Examination section of the UPDRS was administered by neurologists at the three participating clinics. The patient scores on each item were recorded. To assess similarities and differences among the components of the UPDRS in these samples, we performed simultaneous or multigroup factor analysis on the covariance matrices of the three groups. In addition, it was investigated whether a single model for the Motor Examination section of the UPDRS could be developed which would be valid for all three groups at the same time.
A single six-dimensional factor solution was found that fitted all groups, although this was not straightforward due to differences between the tremor-at-rest variables. The factors were identified as Tremor-at-rest, Postural Tremor, Axial Dysfunctioning, Rigidity, Left Bradykinesia and Right Bradykinesia. The analysis also pointed to a somewhat lower lateralization in bradykinesia for PSP patients. The groups differed in intensity of motor impairment, especially with respect to Tremor-at-Rest, but the overall relationships between the variables were shared by the three groups. In addition, apart from the common factor structure evidence of differences in body part-specific and motor-specific variances was found.
From a clinical point of view, the analyses showed that using the Motor Examination section of the UPDRS is also appropriate for patients with PSP, because the correlational structure of the items is directly comparable to that of Parkinson's patients. Methodologically, the analysis of all groups together showed that it is possible to evaluate similarities and differences between factor structures in great detail.
Frontotemporal lobar degeneration (FTLD) often overlaps clinically with corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP), both of which have prominent eye movement abnormalities. To investigate the ability of oculomotor performance to differentiate between FTLD, Alzheimer's disease, CBS and PSP, saccades and smooth pursuit were measured in three FTLD subtypes, including 24 individuals with frontotemporal dementia (FTD), 19 with semantic dementia (SD) and six with progressive non-fluent aphasia (PA), as compared to 28 individuals with Alzheimer's disease, 15 with CBS, 10 with PSP and 27 control subjects. Different combinations of oculomotor abnormalities were identified in all clinical syndromes except for SD, which had oculomotor performance that was indistinguishable from age-matched controls. Only PSP patients displayed abnormalities in saccade velocity, whereas abnormalities in saccade gain were observed in PSP > CBS > Alzheimer's disease subjects. All patient groups except those with SD were impaired on the anti-saccade task, however only the FTLD subjects and not Alzheimer's disease, CBS or PSP groups, were able to spontaneously self-correct anti-saccade errors as well as controls. Receiver operating characteristic statistics demonstrated that oculomotor findings were superior to neuropsychological tests in differentiating PSP from other disorders, and comparable to neuropsychological tests in differentiating the other patient groups. These data suggest that oculomotor assessment may aid in the diagnosis of FTLD and related disorders.
oculomotor; frontotemporal lobar degeneration; corticobasal syndrome; progressive supranuclear palsy; Alzheimer's disease
The clinical and neuroanatomical correlates of specific apraxias in neurodegenerative disease are not well understood. Here we addressed this issue in progressive nonfluent aphasia (PNFA), a canonical subtype of frontotemporal lobar degeneration that has been consistently associated with apraxia of speech (AOS) and in some cases orofacial apraxia, limb apraxia and/or parkinsonism. Sixteen patients with PNFA according to current consensus criteria were studied. Three patients had a corticobasal syndrome (CBS) and two a progressive supranuclear palsy (PSP) syndrome. Speech, orofacial and limb praxis functions were assessed using the Apraxia Battery for Adults-2 and a voxel-based morphometry (VBM) analysis was conducted on brain MRI scans from the patient cohort in order to identify neuroanatomical correlates. All patients had AOS based on reduced diadochokinetic rate, 69% of cases had an abnormal orofacial apraxia score and 44% of cases (including the three CBS cases and one case with PSP) had an abnormal limb apraxia score. Severity of orofacial apraxia (but not AOS or limb apraxia) correlated with estimated clinical disease duration. The VBM analysis identified distinct neuroanatomical bases for each form of apraxia: the severity of AOS correlated with left posterior inferior frontal lobe atrophy; orofacial apraxia with left middle frontal, premotor and supplementary motor cortical atrophy; and limb apraxia with left inferior parietal lobe atrophy. Our findings show that apraxia of various kinds can be a clinical issue in PNFA and demonstrate that specific apraxias are clinically and anatomically dissociable within this population of patients.
Progressive nonfluent aphasia; Primary progressive aphasia; Frontotemporal dementia; Frontotemporal lobar degeneration
The aim of the study was to determine the usefulness of diffusion tensor tractography (DTT) in parkinsonian disorders using a recently developed method for normalization of diffusion data and tract size along white matter tracts. Furthermore, the use of DTT in selected white matter tracts for differential diagnosis was assessed.
We quantified global and regional diffusion parameters in major white matter tracts in patients with multiple system atrophy (MSA), progressive nuclear palsy (PSP), idiopathic Parkinson’s disease (IPD) and healthy controls). Diffusion tensor imaging data sets with whole brain coverage were acquired at 3 T using 48 diffusion encoding directions and a voxel size of 2×2×2 mm3. DTT of the corpus callosum (CC), cingulum (CG), corticospinal tract (CST) and middle cerebellar peduncles (MCP) was performed using multiple regions of interest. Regional evaluation comprised projection of fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and the apparent area coefficient (AAC) onto a calculated mean tract and extraction of their values along each structure.
There were significant changes of global DTT parameters in the CST (MSA and PSP), CC (PSP) and CG (PSP). Consistent tract-specific variations in DTT parameters could be seen along each tract in the different patient groups and controls. Regional analysis demonstrated significant changes in the anterior CC (MD, RD and FA), CST (MD) and CG (AAC) of patients with PSP compared to controls. Increased MD in CC and CST, as well as decreased AAC in CG, was correlated with a diagnosis of PSP compared to IPD.
DTT can be used for demonstrating disease-specific regional white matter changes in parkinsonian disorders. The anterior portion of the CC was identified as a promising region for detection of neurodegenerative changes in patients with PSP, as well as for differential diagnosis between PSP and IPD.
of executive function is frequent in Parkinson's disease (PD),
striatonigral degeneration-type multisystem atrophy (SND), and
progressive supranuclear palsy (PSP); sometimes frank dementia is also
present. However, the progression of cognitive decline has not been
adequately studied. The objectives were to delineate the progression of
cognitive impairment in these parkinsonisms and to elucidate
patients with SND and 21 with PSP, referred consecutively, and 18 patients with PD matched for severity of parkinsonism were compared on
a comprehensive battery of cognitive tests and motor invalidity scales.
A mean of 21 months later (range 18-24 months) the patients were
called for retesting.
RESULTS—Only 12 patients with PD (66.6%), 14 with SND (60.8%), and 11 with PSP
(52.4%) were retested; those who dropped out refused, had died, or
were too disabled. The patients with PSP performed worse than patients
with PD or SND in the short tale, verbal fluency, visual search, and
Benton tests at first evaluation. Overall cognitive performance was
similar in the PD and SND groups except that the SND group did
significantly worse on the verbal fluency test. Between group
comparison of changes in scores from first to second evaluation showed
that patients with PSP deteriorated significantly in the Nelson test
compared with patients with PD or SND, and that patients with PSP or
SND declined significantly on the visual search test compared with
patients with PD. There was no difference between the groups for motor
decline. Two patients with PSP were demented (DSM IV criteria) at first
evaluation and six at second evaluation; no patients with PD or SND
were demented at either evaluation.
greater decline of patients with PSP in attention, set shifting, and
categorisation abilities is probably related to the conspicuous frontal
deafferentation associated with direct premotor and prefrontal
involvement, and to dysfunction of the midbrain ascending activating
system, known to occur in PSP.
We aimed to describe cases with incidental neuropathological findings of progressive supranuclear palsy (PSP) from the Banner Sun Health Research Institute Brain and Body Donation Program.
We performed a retrospective review of 277 subjects with longitudinal motor and neuropsychological assessments who came to autopsy. The mean Gallyas-positive PSP features grading for subjects with possible incidental neuropathological PSP was compared to those of subjects with clinically manifest disease.
There were 5 cases with histopathological findings suggestive of PSP, but no parkinsonism, dementia or movement disorder during life. Cognitive evaluation revealed 4 of the 5 cases to be cognitively normal; one case had amnestic mild cognitive impairment (MCI) in her last year of life. The mean age at death of the 5 cases was 88.9 years (range 80-94). All 5 individuals had histopathologic microscopic findings suggestive of PSP. Mean Gallyas-positive PSP features grading was significantly lower in subjects with possible incidental neuropathological PSP than subjects with clinical PSP, particularly in the subthalamic nucleus.
We present 5 patients with histopathological findings suggestive of PSP, without clinical PSP, dementia or parkinsonism during life. These incidental neuropathological PSP findings may represent the early or pre-symptomatic stage of PSP. The mean Gallyas-positive PSP features grading was significantly lower in possible incidental PSP than in clinical PSP, thus suggesting that a threshold of pathological burden needs to be reached within the typically affected areas in PSP before clinical signs and symptoms appear.
progressive supranuclear palsy; PSP; incidental; autopsy; parkinsonism; neuropathology
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 with PSP using voxel based morphometry (VBM).
Methods: VBM is an observer unbiased volumetry which allows the investigation of the entire brain. An optimised protocol for normalisation, segmentation, and correction for volume changes in preprocessing was used. Grey matter, white matter, and cerebrospinal fluid (CSF) partitions in 12 patients with probable PSP were compared with 12 healthy controls matched for age and sex.
Results: In PSP patients, the following cortical areas were decreased in volume (pcorr<0.05): the prefrontal cortex, predominantly the medial frontal gyri and a cluster in the left lateral middle frontal gyrus; the insular region including the frontal opercula; both supplementary motor areas; and the left medio-temporal area (V5). White matter comparisons revealed a volume reduction in both frontotemporal regions and the mesencephalon. Analysis of the CSF compartment showed no significant regional changes between the groups.
Conclusions: Frontal atrophy in PSP predominantly involves mesio-frontal targets of striatal projections. This atrophy pattern probably accounts for cardinal PSP associated behavioural deficits.
MAPT mutations are associated with disorders within the frontotemporal lobar degeneration spectrum. The usual presenting syndrome is behavioural variant frontotemporal dementia, although some patients present with parkinsonism. In a number of these cases the dominant clinical features have been consistent with a progressive supranuclear palsy (PSP) syndrome.
To describe a family with an autosomal dominant PSP syndrome with a novel L284R mutation in the MAPT gene.
A retrospective case review and genetic analysis of the MAPT gene. A literature review of PSP syndromes associated with mutations in the MAPT gene.
Multiple members of family DRC292 across different generations had a PSP syndrome with 1 member of the family being found to have a novel L284R mutation in the MAPT gene. Behavioural features were also prominent in most cases. A PSP syndrome is only a rare finding associated with MAPT mutations and many of these cases have atypical clinical features.
Although rare, MAPT mutations should be considered when there is an autosomal dominant family history of a PSP syndrome, particularly of young onset and with prominent behavioural features.
Frontotemporal dementia; Progressive supranuclear palsy; Tau
The current study sought to describe the functional profiles of patients with early-stage progressive supranuclear palsy (PSP) in a large prospective, multisite study.
Using data from 202 individuals meeting criteria for clinically definite or probable PSP, 3 functional scales were examined. Functional scores were then compared to measures of motor, cognition, and psychiatric symptoms.
Functional disability was high in early-stage PSP, with 100% of patients having less than perfect scores on all functional scales. Whereas functional scores tended not to be related to cognition or psychiatric symptoms, they were strongly related to motoric ratings.
Both clinically and in research settings, the definition of functional intactness/impairment has important implications. Future studies should examine if functional impairment is this high in PSP or if new scales of functional abilities need to be developed for this condition.
Progressive supranuclear palsy (PSP) and parkinsonian variant of multiple system atrophy (MSA-P) are clinically difficult to differentiate from idiopathic Parkinson's disease (PD), particularly in the early stages of the disease. Previous reports indicated that the olfactory function is relatively intact or slightly reduced in patients with PSP and MSA-P, suggesting that the odor stick identification test for Japanese (OSIT-J), which is a short and simple noninvasive test that is potentially useful clinically for detecting early-stage PD in Japan, may be useful in the differential diagnosis of early-stage PD from MSA-P and PSP. There is no information on the sensitivity and specificity of OSIT-J in the diagnosis of parkinsonian syndromes such as PSP and MSA-P.
We assessed the olfactory function using the OSIT-J test in 94 Japanese patients with idiopathic PD, 15 with MSA-P, 7 with PSP, and 29 age-matched control subjects.
The mean ± SD score of OSIT-J in patients with PD (4.4 ± 2.9) was significantly lower than in patients with MSA-P (8.7 ± 2.2, P < 0.0001), PSP (7.6 ± 2.2, P < 0.0057), and control subjects (10.5 ± 1.3, P < 0.0001). The area under the curve (AUC) of receiver operating characteristic (ROC) to discriminate PD from normal control using OSIT-J scores was 0.97 (95% confidence interval, 0.95-1.00), from MSA-P 0.87 (0.80-0.95), and from PSP 0.81 (0.66-0.96).
The OSIT-J is a potentially useful clinical test not only for detection of olfactory deficit in PD but also for differentiating PD from MSA-P and PSP.
Parkinson's disease (PD) and the atypical parkinsonian syndromes multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) are movement disorders associated with degeneration of the central nervous system. Degeneration of the retina has not been systematically compared in these diseases.
This cross-sectional study used spectral-domain optical coherence tomography with manual segmentation to measure the peripapillar nerve fiber layer, the macular thickness, and the thickness of all retinal layers in foveal scans of 40 patients with PD, 19 with MSA, 10 with CBS, 15 with PSP, and 35 age- and sex-matched controls.
The mean paramacular thickness and volume were reduced in PSP while the mean RNFL did not differ significantly between groups. In PSP patients, the complex of retinal ganglion cell- and inner plexiform layer and the outer nuclear layer was reduced. In PD, the inner nuclear layer was thicker than in controls, MSA and PSP. Using the ratio between the outer nuclear layer and the outer plexiform layer with a cut-off at 3.1 and the additional constraint that the inner nuclear layer be under 46 µm, we were able to differentiate PSP from PD in our patient sample with a sensitivity of 96% and a specificity of 70%.
Different parkinsonian syndromes are associated with distinct changes in retinal morphology. These findings may serve to facilitate the differential diagnosis of parkinsonian syndromes and give insight into the degenerative processes of patients with atypical parkinsonian syndromes.
OBJECTIVE--To analyse the natural history of progressive supranuclear palsy (PSP or Steele-Richardson-Olszewski syndrome) and clinical predictors of survival in 24 patients with PSP confirmed by necropsy, who fulfilled the NINDS criteria for a neuropathological diagnosis of typical PSP. METHODS--Patients were selected from the research and clinical files of seven medical centres involving tertiary centres of Austria, England, France, and the United States. Clinical features were analysed in detail. The patients' mean age at onset of PSP was 63 (range 45-73) years. RESULTS--The most frequent clinical features (occurring in at least 75% of the patients) were early postural instability and falls, vertical supranuclear palsy, akinetic-rigid predominant parkinsonian disorder characterised by symmetric bradykinesia and axial rigidity unrelieved by levodopa, pseudobulbar palsy, and frontal release signs. Occasionally, segmental dystonia or myoclonus were described, but neither aphasia nor alien limb syndrome was reported. Fractures occurred in 25% of the patients but were unrelated to the severity of the gait or to the presence of falls. Median survival time was 5.6 (range 2-16.6) years. Onset of falls during the first year, early dysphagia, and incontinence predicted a shorter survival time. Age at onset, sex, early onset of dementia, vertical supranuclear palsy, or axial rigidity had no effect on prognosis of survival. Pneumonia was the most common immediate cause of death. PSP was most often clinically misdiagnosed as Parkinson's disease. Errors in diagnosis suggest that PSP is underdiagnosed. CONCLUSION--Progressive onset of early postural instability with falls or supranuclear vertical palsy in the fifth decade, should suggest the diagnosis of PSP. Onset of falls during the first year are emphasised, as they could lead to an early diagnosis and influence the prognosis of patients with PSP. Whether appropriate treatment of the dysphagia could prolong the survival of PSP patients needs to be explored.
Rare mutations in the gene encoding for tau (MAPT, microtubule-associated protein tau) cause frontotemporal dementia-spectrum (FTD-s) disorders, including FTD, progressive supranuclear palsy (PSP) and corticobasal syndrome, and a common extended haplotype spanning across the MAPT locus is associated with increased risk of PSP and Parkinson's disease. We identified a rare tau variant (p.A152T) in a patient with a clinical diagnosis of PSP and assessed its frequency in multiple independent series of patients with neurodegenerative conditions and controls, in a total of 15 369 subjects.
Tau p.A152T significantly increases the risk for both FTD-s (n = 2139, OR = 3.0, CI: 1.6–5.6, P = 0.0005) and Alzheimer's disease (AD) (n = 3345, OR = 2.3, CI: 1.3–4.2, P = 0.004) compared with 9047 controls. Functionally, p.A152T (i) decreases the binding of tau to microtubules and therefore promotes microtubule assembly less efficiently; and (ii) reduces the tendency to form abnormal fibers. However, there is a pronounced increase in the formation of tau oligomers. Importantly, these findings suggest that other regions of the tau protein may be crucial in regulating normal function, as the p.A152 residue is distal to the domains considered responsible for microtubule interactions or aggregation. These data provide both the first genetic evidence and functional studies supporting the role of MAPT p.A152T as a rare risk factor for both FTD-s and AD and the concept that rare variants can increase the risk for relatively common, complex neurodegenerative diseases, but since no clear significance threshold for rare genetic variation has been established, some caution is warranted until the findings are further replicated.
To evaluate a standardised MRI acquisition protocol and a new image rating scale for disease severity in patients with progressive supranuclear palsy (PSP) and multiple systems atrophy (MSA) in a large multicentre study.
The MRI protocol consisted of two-dimensional sagittal and axial T1, axial PD, and axial and coronal T2 weighted acquisitions. The 32 item ordinal scale evaluated abnormalities within the basal ganglia and posterior fossa, blind to diagnosis. Among 760 patients in the study population (PSP=362, MSA=398), 627 had per protocol images (PSP=297, MSA=330). Intra-rater (n=60) and inter-rater (n=555) reliability were assessed through Cohen's statistic, and scale structure through principal component analysis (PCA) (n=441). Internal consistency and reliability were checked. Discriminant and predictive validity of extracted factors and total scores were tested for disease severity as per clinical diagnosis.
Intra-rater and inter-rater reliability were acceptable for 25 (78%) of the items scored (≥0.41). PCA revealed four meaningful clusters of covarying parameters (factor (F) F1: brainstem and cerebellum; F2: midbrain; F3: putamen; F4: other basal ganglia) with good to excellent internal consistency (Cronbach α 0.75–0.93) and moderate to excellent reliability (intraclass coefficient: F1: 0.92; F2: 0.79; F3: 0.71; F4: 0.49). The total score significantly discriminated for disease severity or diagnosis; factorial scores differentially discriminated for disease severity according to diagnosis (PSP: F1–F2; MSA: F2–F3). The total score was significantly related to survival in PSP (p<0.0007) or MSA (p<0.0005), indicating good predictive validity.
The scale is suitable for use in the context of multicentre studies and can reliably and consistently measure MRI abnormalities in PSP and MSA.
Clinical Trial Registration Number
The study protocol was filed in the open clinical trial registry (http://www.clinicaltrials.gov) with ID No NCT00211224.
The aim of this study was to compare the patterns of grey and white matter atrophy on MRI in autopsy confirmed PSP and 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.
Progressive supranuclear palsy; corticobasal degeneration; magnetic resonance imaging; pathology; white matter; grey matter; dementia; parkinsonism; extrapyramidal