Tremor in progressive supranuclear palsy

IntroductionTremor is thought to be a rare feature of progressive supranuclear palsy (PSP).MethodsWe retrospectively reviewed the database of the CurePSP brain bank at Mayo Clinic Florida to retrieve all available clinical information for PSP patients. All patients underwent a standard neuropathological assessment and an immunohistochemical evaluation for tau and α-synuclein. DNA was genotyped for the MAPT H1/H2 haplotype.ResultsOf the 375 PSP patients identified, 344 had a documented presence or absence of tremor, which included 146 (42%) with tremor, including 29 (20%) with postural/action tremors, 16 (11%) with resting tremor, 7 (5%) with intention tremor, 20 (14%) with a combination of different types of tremor, and 74 (51%) patients who had tremor at some point during their illness, but details were unavailable. The tremor severity of 96% of the patients (54/55) who had this data was minimal to mild. The probability of observing a tremor during a neurological examination during the patient's illness was estimated to be ∼22%. PSP patients with postural/action tremors and PSP patients with resting tremor responded to carbidopa-levodopa therapy more frequently than PSP patients without tremor, although the therapy response was always transient. There were no significant differences in pathological findings between the tremor groups.ConclusionsTremor is an inconspicuous feature of PSP; however, 42% (146/344) of the PSP patients in our study presented some form of tremor. Because there is no curative therapy for PSP, carbidopa/levodopa therapy should be tried for patients with postural, action, and resting tremor.     

Orthostatic tremor in progressive supranuclear palsy.

Patients with orthostatic tremor (OT) can be classified as having "primary OT," with or without postural arm tremor but no other abnormal neurological features, or "OT plus." We describe a patient with OT, with postural tremor of the arms and restless legs syndrome (RLS), who developed features typical of progressive supranuclear palsy (PSP). PSP can be accompanied by OT.     

Cerebrospinal fluid analysis for Whipple's disease in patients with progressive supranuclear palsy.

The clinical picture of neurological involvement in Whipple's disease (WD) may resemble progressive supranuclear palsy (PSP). We looked for WD pathogen DNA in the cerebrospinal fluid of 9 patients with a clinical diagnosis of PSP. The analysis was negative for all samples, showing that WD is not commonly involved in the aetiopathogenesis of PSP.     

Characterizing behavioral and cognitive dysexecutive changes in progressive supranuclear palsy.

Frontal lobe dysfunction is a prominent feature of many neurological disorders. Early diagnosis may be enhanced by establishing a profile of cognitive, behavioral, and emotional change. Traditional psychometric assessment focuses on cognitive dysfunction and fails to identify behavioral changes, particularly those associated with orbitofrontal dysfunction. We examined progressive supranuclear palsy (PSP), a prototypical subcortical dementia with frontal features, using commonly available neuropsychological measures and a modification of the Katz Adjustment Scale-Relatives (KAS-R), an instrument first developed to assess dysexecutive changes in head-injured patients. Executive tests identified deficits in reasoning, planning, set shifting, verbal fluency, information processing speed, and response initiation. On the KAS-R, changes in apathy, social withdrawal, and independence were observed, with little change in belligerence, social irresponsibility, uncooperativeness, obstreperousness, anxiety, and depression. The results show the potential utility of this instrument in characterizing behavioral and emotional changes associated with frontal lobe dysfunction in neurodegenerative disease.     

Genetic variation at the tau locus and clinical syndromes associated with progressive supranuclear palsy.

A number of different clinical syndromes have been associated with progressive supranuclear (PSP) tau pathology. Previous reports have suggested that atypical clinical phenotypes of PSP occur in familial disease, and might be associated with mutations of MAPT. We examined the association of PSP-susceptibility tau haplotypes in pathologically diagnosed PSP, separated according to initial clinical features into classic PSP and atypical PSP groups (PSP-Parkinsonism, PSP-P). These patients were screened for mutations in exons 1 and 10 of MAPT. No mutations were found in 75 patients (21 PSP-P), and H1c was associated with both Richardson's syndrome and PSP-P compared with controls. Routine screening for MAPT mutations in atypical PSP is not recommended.     

Modeling trajectories of regional volume loss in progressive supranuclear palsy

Progressive supranuclear palsy is a neurodegenerative disease with progressive brain atrophy over time. It is unknown which specific brain regions decline over time, whether regional volume loss occurs in a linear fashion, and whether regional atrophy correlates with clinical decline over time in progressive supranuclear palsy. Twenty‐eight subjects meeting probable progressive supranuclear palsy criteria were prospectively recruited and completed 96 MRI scans over 2 years. Mixed‐effect models were utilized to determine which regions had significant atrophy over time and whether decline was linear or nonlinear. We assessed 13 regions across the brain, as well as whole‐brain and ventricular volume. Regional trajectories were also correlated with change in clinical measures of executive function and gait and ocular motor impairment. A linear decline was observed in all frontal and temporal regions, the superior parietal lobe, the thalamus, the caudate nuclei, and the midbrain, as well as in the whole brain. Ventricular expansion was also linear. Nonlinear decline was observed for the caudal middle frontal lobe and globus pallidus. Rates of change in the superior frontal lobe, thalamus, and midbrain were beyond those expected in normal aging. Decline in frontal lobe volume and the midbrain area correlated best to decline in clinical measures. In progressive supranuclear palsy, atrophy is occurring in multiple brain regions, particularly in those that have previously been implicated in the disease. Decline is mainly linear but can be nonlinear for some regions. The frontal lobe and midbrain seem to be playing the most significant roles in the progressive worsening of clinical signs in progressive supranuclear palsy. © 2013 Movement Disorder Society     

Further extension of the H1 haplotype associated with progressive supranuclear palsy.

The recent finding of disequilibrium among several polymorphisms along the tau gene and the strong association of one of the two haplotypes formed by these polymorphisms (H1) with progressive supranuclear palsy (PSP) suggests that a single allele in or near the tau gene at 17q21 is responsible for increased risk in most of the PSP cases. We sought to determine whether mutations in the tau gene are responsible for the disease in 45 sporadic PSP patients. Furthermore, we analyzed some markers located in the common region of linkage (D17S800-D17S791), associated with some cases of familial frontotemporal dementia (FTDP-17), and the SNPs rs1816 and rs937 close to the tau gene, to determine their possible association with sporadic PSP. We did not find pathogenic mutations in exons 9, 10, 12, or 13 of the tau gene, indicating that tau mutations in both the splice-site region of the exon 10 and in the microtubule-binding region of tau gene are not a cause of PSP in this study group. We found significant overrepresentation of the haplotypes H1, extended up to the promoter of the tau gene (H1P), in PSP patients as compared with controls. In addition, a significant overrepresentation of the D17S810 2/2 and 3/2 genotypes, of the SNP rs1816 A/A, and of the SNP rs937 delG/delG genotypes was detected in PSP, further extending the haplotype described previously. These results are consistent with the hypothesis that a change either in the 5' or in the 3' flanking regions of the tau gene, or even other genes contained in the H1E haplotype, could increase the genetic susceptibility to PSP.     

Progressive supranuclear palsy: phenotypic sex differences in a clinical cohort.

We examined sex-based differences in phenotypic expression among a consecutive clinical series of 121 individuals diagnosed with probable progressive supranuclear palsy (PSP). For both men (44%) and women (56%), the age at symptomatic onset (66.2 and 68.5 years, respectively) and disease duration (4.6 and 4.3 years, respectively) were similar. The overwhelming majority of sex-based comparisons showed no significant difference on a variety of demographic, historical, and clinical characteristics, as well as measures of disease progression. The only differences observed were that men had significantly worse tremor as measured by the Unified Parkinson's Disease Rating Scale tremor subscore (0.9 for men and 0.3 for women, P<0.01) and men had a significantly higher mean body mass index (BMI; 28.2 for men and 25.1 for women, P=0.01), although these differences were not significant after Bonferroni correction. In general, the disease phenotype was similar between men and women, suggesting that sex may have little or no influence on the development, expression, or progression of the PSP phenotype.     

Diffusion-weighted magnetic resonance imaging differentiates Parkinsonian variant of multiple-system atrophy from progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) and the parkinsonian variant of multiple-system atrophy (MSA-P) may present with a similar phenotype. Magnetic resonance diffusion-weighted imaging (DWI) has been shown to be a sensitive discriminator of MSA-P from Parkinson's disease (PD). We studied 20 PSP, 11 MSA-P, 12 PD patients and 7 healthy controls in order to investigate whether regional apparent diffusion coefficients (rADCs) help distinguish PSP and MSA-P; whether rADCs are correlated with clinical disease severity scores; and the relationship between brainstem and cerebellar volumes and rADCs in PSP and MSA-P. The Unified Parkinson's Disease Rating Scale, Hoehn and Yahr score, Mini Mental State Examination, and frontal assessment battery were recorded in all patients. Regional ADCs were measured in the middle cerebellar peduncle (MCP), caudal and rostral pons, midbrain, decussating fibers of the superior cerebellar peduncle, thalamus, putamen, globus pallidus, caudate nucleus, corpus callosum, frontal and parietal white matter, as well as the centrum semiovale. In MSA-P, rADCs in the MCP and rostral pons were significantly greater than in PSP (P < 0.001 and 0.009) and PD (P < 0.001 and = 0.002). Stepwise logistic regression revealed that the MCP rADC distinguishes MSA-P from PSP with a sensitivity of 91% and a specificity of 84%. Increased brainstem rADCs were associated with motor deficit in MSA-P and PSP. Increased rADCs in the pons and MCP were associated with smaller pontine and cerebellar volumes in MSA-P. rADCs distinguish MSA-P from PSP. These have a clinical correlate and are associated with reduced brainstem and cerebellar volumes.     

Lesion of the dorsorostral midbrain sparing the nigrostriatal tract mimics axial rigidity seen in progressive supranuclear palsy.

We report on a patient with a residual dorsorostral midbrain lesion after resection of a pineal gland tumor. In addition to severe vertical gaze palsy, this patient exhibited other neurological features closely resembling progressive supranuclear palsy. Normal dopamine transporter single-photon emission computed tomography imaging excluded significant dopamine deficiency. We suggest that dorsorostral midbrain pathology rather than dopamine deficiency due to degeneration of nigrostriatal dopaminergic neurons or basal ganglia nuclei might be responsible for axial rigidity in extension.     

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.     

In vivo demonstration of microstructural brain pathology in progressive supranuclear palsy: A DTI study using TBSS

We investigated DTI changes, potentially indicating alterations of microstructure and brain tissue integrity in 13 patients with probable progressive supranuclear palsy (PSP, Richardson syndrome) at stage III or less and 10 age‐matched controls using a whole brain analysis of diffusion tensor imaging (DTI) data. DTI images were analyzed using tract‐based spatial statistics, a hypothesis‐free technique. Fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD) were determined. In patients with PSP, significant increases in FA (P < 0.0001), an unspecific measure of microstructural tissue integrity, were found in the cerebellum and in the superior cerebellar peduncle bilaterally, in the fornix, the body of the corpus callosum and the olfactory region, when compared with age‐matched healthy controls. Further, regional reductions in AD (P < 0.0001), an indicator of altered axonal integrity, were observed in the pons, the right substantia nigra and the cerebellar white matter bilaterally. Significant increases in RD (P < 0.0001), a potential measure of altered myelin integrity, occurred bilaterally in the superior cerebellar peduncle, the cerebellar white matter, the vermis of the cerebellum, the fornix, the body of the corpus callosum, and the olfactory region. RD values in the superior cerebellar peduncle discriminated patients with PSP and controls with high sensitivity (0.92) and specificity (1.0). The findings are supported by neuropathological studies. Our data suggest the usefulness of this clinically available new technique as a possible tool for differential diagnosis. © 2010 Movement Disorder Society     

Diagnostic potential of automated tractography in progressive supranuclear palsy variants

BackgroundMicrostructural white matter integrity captured by diffusion-tensor imaging (DTI) is significantly more affected in progressive supranuclear palsy-Richardson's syndrome (PSP-RS) compared to PSP-parkinsonism (PSP–P).ObjectivesTo characterize the microstructural integrity of large fascicular bundles using standardized probabilistic tractography and combine it with previously established DTI- and volumetric measures of subcortical brain structures in order to evaluate its diagnostic properties for the differentiation of PSP- RS, PSP-P and Parkinson's disease (PD).MethodsDTI metrics as well as volumes of subcortical brain regions, acquired by 3T MRI of patients with PSP-RS (n = 15), PSP-P (n = 13), and a mean disease duration of 2.7 ± 1.8 years, were quantified by probabilistic tractography as well as a validated infratentorial atlas and compared to PD (n = 18) and healthy controls (n = 20). Classification accuracy of MRI measures was tested by consecutive linear discriminant analyses.ResultsDTI metrics of the anterior thalamic radiation, the corticospinal tract, the superior longitudinal fasciculus, the bundles of the corpus callosum and cingulate, the dentatorubrothalamic tract as well as volumes of the dorsal midbrain, globus pallidus and thalamus were significantly altered in PSP-RS and to a lesser extent in PSP-P compared to PD and healthy controls. Linear discriminant analysis identified DTI metrics of the dentatorubrothalamic tract and the anterior thalamic radiation as well as the volume of the dorsal midbrain to classify correctly 91.3% of PSP-RS, PSP-P and PD patients.ConclusionsObserver-independent investigations of microstructural integrity of major fiber bundles improved existing MRI processing strategies to differentiate PSP-P from PSP-RS and PD, in their early disease stages.