Longitudinal change of energy expenditure, body composition and dietary habits in Progressive Supranuclear Palsy patients.

INTRODUCTION: Alterations in metabolic status, body composition, and food intake are present in all neurodegenerative diseases. Aim of this study was to detect the progression of these changes in Progressive Supranuclear Palsy (PSP). METHODS: We conducted a longitudinal study of 15 patients with PSP. The assessments were performed at baseline (T0) and after 7(IQR = 5) months of follow-up (T1). We collected anthropometric measures including body weight, height, body mass index and waist circumference, metabolic parameters through indirect calorimeters, body composition using bioimpedance analysis, and dietary habits with a validated questionnaire. PSP-rating scale (PSP-rs) was used to evaluate disease severity and dysphagia. RESULTS: The majority of patients (66.66%) presented PSP-Richardson Syndrome and 33.33% the other variant syndromes of the disease. At T1 there was a decrease in intake of total daily calories (p < 0.001), proteins (p < 0.001), fibers (p = 0.001), calcium (p = 0.008), iron (p < 0.001), zinc (0.034), vitamin E (p = 0.006) and folates (p = 0.038) compared to T0. No other changes were found. As for T1 data, no significant differences were shown according to disease phenotypes or the presence of clinically significant dysphagia for solids. CONCLUSIONS: Within a mid-term follow up, PSP patients presented reduced caloric and proteins intake regardless the presence of dysphagia. The PSP-rs is likely not adequate to assess dysphagia, which should be investigated by specific clinical scales or instrumental examinations. With the goal of maintaining adequate nutritional status, the administration of protein and vitamin supplements should be considered even in the absence of dysphagia evidenced by the rating scales.

Preclinical, phase I, and phase II investigational clinical trials for treatment of progressive supranuclear palsy.

INTRODUCTION: Our understanding of the pathological basis of progressive supranuclear palsy (PSP), as the most common atypical parkinsonian syndrome, has greatly increased in recent years and a number of disease-modifying therapies are under evaluation as a result of these advances. AREAS COVERED: In this review, we discuss disease-modifying therapeutic options which are currently under evaluation or have been evaluated in preclinical or clinical trials based on their targeted pathophysiologic process. The pathophysiologic mechanisms are broadly divided into three main categories: genetic mechanisms, abnormal post-translational modifications of tau protein, and transcellular tau spread. EXPERT OPINION: Once the best therapeutic approaches are identified, it is likely that some combination of interventions will need to be evaluated, but this will take time. It is critical to treat patients at early stages, and development of the Movement Disorder Society PSP diagnostic criteria is an important step in this direction. In addition, development of biological biomarkers such as tau PET and further refinement of tau ligands may help both diagnose early and measure disease progression. In the meantime, a comprehensive, personalized interdisciplinary approach to this disease is absolutely necessary.

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.

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.

Disrupted thalamocortical connectivity in PSP: a resting-state fMRI, DTI, and VBM study.

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 nucleus. 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.

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.

Improvement of balance after audio-biofeedback. A 6-week intervention study in patients with progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a neurodegenerative disease with no sufficient treatment options to date. The most devastating symptom is the loss of balance with consecutive falls. Based on the observation that postural control improved in patients with vestibular dysfunction after audio-biofeedback training, we tested the effects of this training in PSP patients. Eight PSP patients were included into an uncontrolled 6-week intervention trial. The focus of the training was the improvement of posture and dynamic balance by using audio-biofeedback. The device was well accepted. No adverse events occurred. A significant improvement in the Berg Balance Scale was observed (T2 vs. T1, p=0.016), which remained significant at the 4-week follow-up (T3 vs. T1, p=0.008). Significant improvement of the Parkinson's disease questionnaire was demonstrated. No significant changes were found in the Timed Up-and-Go Test, the Five Chair Rise Test, and in specific clinical scales. To our knowledge, the present study is the first to demonstrate that audio-biofeedback training with PSP patients is associated with improvements of balance and psychosocial aspects.

Sound naming in neurodegenerative disease.

Modern cognitive neuroscientific theories and empirical evidence suggest that brain structures involved in movement may be related to action-related semantic knowledge. To test this hypothesis, we examined the naming of environmental sounds in patients with corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), two neurodegenerative diseases associated with cognitive and motor deficits. Subjects were presented with 56 environmental sounds: 28 sounds were of objects that required manipulation when producing the sound, and 28 sounds were of objects that required no manipulation. Subjects were asked to provide the name of the object that produced the sound and also complete a sound-picture matching condition. Subjects included 33 individuals from four groups: CBD/PSP, Alzheimer disease, frontotemporal dementia, and normal controls. We hypothesized that CBD/PSP patients would exhibit impaired naming performance compared with controls, but the impairment would be most apparent when naming sounds associated with actions. We also explored neural correlates of naming environmental sounds using voxel-based morphometry (VBM) of brain MRI. As expected, CBD/PSP patients scored lower on environmental sounds naming (p<0.007) compared with the controls. In particular, the CBD/PSP patients scored the lowest when naming sounds of manipulable objects (p<0.05), but did not show deficits in naming sounds of non-manipulable objects. VBM analysis across all groups showed that performance in naming sounds of manipulable objects correlated with atrophy in the left pre-motor region, extending from area six to the middle and superior frontal gyrus. These results indicate an association between impairment in the retrieval of action-related names and the motor system, and suggest that difficulty in naming manipulable sounds may be related to atrophy in the pre-motor cortex. Our results support the hypothesis that retrieval of action-related semantic knowledge involves motor regions in the brain.

Development of a sensitive ELISA for quantification of three- and four-repeat tau isoforms in tauopathies.

Tau protein plays an important role in stabilising and assembling neuronal microtubules. Pathological changes in expression and aggregation of tau isoforms containing three (3R-tau) and four (4R-tau) microtubule-binding repeat domains are associated with several tauopathies. This paper describes novel sandwich ELISAs for quantification of 3R- and 4R-tau in brain. The assays are constructed using well-characterised isoform-specific antibodies (RD3 and RD4) as capture antibodies and an affinity-purified HRP-anti-tau peptide antibody and biotin-tyramide amplification for detection. For 3R-tau, we achieved a minimal detection limit in buffer of 460 pg mL(-1) and a recovery of 81.0% using 500 pg mL(-1) recombinant 3R-tau spiked in diluted brain homogenate. Mean intra- and inter-assay variation of the 3R-tau ELISA was 8.8 and 10.5%, respectively. For 4R-tau, the detection limit was 780 pg mL(-1) and the recovery of 5 ng mL(-1) spiked recombinant 4R-tau was 86.0% and the mean intra- and inter-assay variation was 10.4 and 15.6%, respectively. With these assays, we showed that in progressive supranuclear palsy (PSP) brains, 4R-tau is significantly increased in frontal cortex and caudate, the two regions that are usually associated with 4R-tau-dominant pathology. This increase was not observed in occipital lobe, a region that is spared of tau inclusions. No differences in 3R-tau levels were found between PSP and control brains in all regions tested. With this, we have for the first time developed ELISAs for quantification of 3R- and 4R-tau isoforms in pathological samples. These could prove useful in the pathological investigation and differential diagnosis of tauopathies.

Differentiation of PA from early PSP with different patterns of symptoms and CBF reduction.

OBJECTIVE: To clarify the features of pure akinesia (PA) and progressive supranuclear palsy (PSP) in the early stage of disease. METHODS: We investigated 15 PA and 41 PSP patients' clinical and radiologic features including head MRI, ethyl cysteinate dimmer-single photon emission-computed tomography (ECD-SPECT) and iodine-123 meta-iodobenzyl guanidine (123I-MIBG) myocardial scintigraphy. In ECD-SPECT study, cerebral blood flow (CBF) reduction was quantitatively expressed as Z-score, and that in the frontal lobe was evaluated. RESULTS: Many PSP patients claimed falls as the initial symptom but no PA patients did. Eye movement, as well as optokinetic nystagmus elicitation, was more frequently disturbed in PSP. Dementia, dysarthria and rigidity were also more frequent in PSP than in PA. Midbrain tegmentum atrophy in head MRI was more frequently observed in PSP. CBF in the frontal lobe, especially in the frontal eye field, was significantly lower in PSP than in PA. MIBG myocardial scintigraphy showed no difference between two groups. DISCUSSION: PA and PSP show distinct symptoms from the early stage, indicating that they are distinct disorders. The occurrence of falls and eye movement disturbance, as well as CBF reduction at the frontal eye field, is very important for distinguishing these disorders.

Attention and cognition in bradykinetic-rigid syndromes: an event-related potential study.

Bradykinetic-rigid syndromes are often accompanied by cognitive impairment. Because prominent motor involvement in these disorders may interfere with neuropsychological testing, we used event-related potentials (ERPs) for the assessment of cognition and attention in 41 patients with various bradykinetic-rigid syndromes of less than 5 years duration: idiopathic Parkinson's disease corticobasal degeneration, Steele-Richardson-Olszewski syndrome (SRO), and multiple system atrophy. Patients were compared with matched normals. ERP abnormalities in the auditory "oddball" paradigm were found only in corticobasal degeneration and SRO. ERP abnormalities in selective attention tasks were present in all patient groups, changes in SRO being the most prevalent. Abnormalities in corticobasal degeneration were present under "less-attention-demanding" conditions and suggested involvement of posterior parts of the brain. Multiple system atrophy and idiopathic Parkinson's disease patient groups had minimal ERP abnormalities. However, reaction times in MSA were longer in all paradigms. The results of the study support the view that bradykinetic-rigid syndromes involve some attentional deficits, but also have distinct reaction time and ERP characteristics, which may be helpful in differential diagnosis.

A new splicing variant for human tyrosine hydroxylase in the adrenal medulla.

It has been reported that several mRNA isoforms of tyrosine 3-monooxygenase (tyrosine hydroxylase; TH) occur only in primates. New TH isoforms produced by skipping of exon 3 in the adrenal medulla of patients with progressive supranuclear palsy (PSP) have recently been reported, J. Neurochem. 67 (1996) 19. Here, we looked for the presence of new TH isoforms in control brains and adrenal medulla and in brains from patients with PSP. We found a novel type of TH mRNA in the adrenal medulla from one of the control subjects. The mRNA lacked exon 4, resulting in a premature stop codon at amino acid 147. This result suggests the importance of alternative splicing in the regulation of TH activity.

Parálisis supranuclear progresiva / Progressive supranuclear palsy

La parálisis supranuclear progresiva (PSP), también llamada síndrome de Steele-Richardson-Olszewski, es uno de los síndromes parkinsionanos atípicos más frecuentes. Es una afección degenerativa de causa desconocida caracterizada por atrofia del tegmentum protuberancial y mesencéfalo, decoloración de la sustancia nigra y relativo respeto de la corteza cerebral. Existe un consenso sobre la dificultad para llegar al diagnóstico de certeza tanto clínico como patológico. Ha habido casos de PSP clínica cuyas autopsias no confirmaron el diagnóstico, y autopsias con hallazgos diagnósticos de PSP que fueron interpretados clínicamente como otros padecimientos o síndromes degenerativos. En Latinoamérica no existen estadísticas epidemiológicas sobre esta entidad nosológica y en Chile no se ha publicado ningún caso hasta la fecha. El objetivo del presente reporte es la presentación de seis casos que cumplen con los criterios diagnósticos establecidos por el National Institute of Neurological Disorders and Stroke and The Society for PSP (NINDS-SPSP) en 1996. Se concluye, a partir del presente trabajo que la PSP no es excepcional en nuestro medio y que debe considerarse entre los diagnósticos diferenciales de los síndromes parkinsonianos

Executive function in Parkinson's disease and subcortical disorders.

Changes in cognitive function that accompany the progression of subcortical disorders such as Parkinson's disease are often overlooked in the early stages because of a "context of discovery" that accompanies the diagnostic progress. This article discusses the nature of that context, a subcortical cognitive profile, and the contribution of executive function failure to that profile. The utility of using brief assessments of executive function and other measures, such as a brief screen for apathy, are shown with Parkinson's disease patients. Several suggestions are provided for means by which clinicians can help patients, caregivers, and families adjust to patients' impairments in executive function.

Effects of a startling acoustic stimulus on reaction time in different parkinsonian syndromes.

BACKGROUND: The functional assessment of the startle circuit is usually done by analyzing the acoustic startle response (ASR). However, a startling acoustic stimulus (SAS) also induces changes in the excitability of neural structures that can be demonstrated by studying the SAS-induced change in the behavior of certain neurophysiologic responses. OBJECTIVE: To examine the effects induced by an SAS on voluntary reaction time in patients with parkinsonian syndromes (StartReact effect) and to compare the results with those obtained in a group of age-matched healthy volunteers. METHODS: Twelve patients with idiopathic PD (IPD), seven patients with progressive supranuclear palsy (PSP), seven patients with multisystem atrophy (MSA), and seven healthy age-matched control volunteers performed a simple visual reaction time task and received SAS together with the "go" signal in random trials. RESULTS: Baseline reaction time was significantly slower in PSP patients than in control subjects and MSA patients. The SAS induced a significant shortening of the reaction time in control subjects and in patients with IPD and MSA, but not in patients with PSP. The percentage of reaction time shortening with regard to the baseline values also differed significantly between PSP patients and the other groups of subjects. The StartReact effect was consistent throughout the experiment and showed reduced habituation with repeated testing. CONCLUSIONS: The results are consistent with an abnormal function of the startle circuit in patients with PSP and agree with previous studies using the ASR. The reduced habituation of the StartReact effect favors its clinical applicability in the assessment of differences between patients with parkinsonian syndromes.

[A case report of Weber's syndrome associated with supranuclear vertical gaze palsy caused by the ipsilateral thalamomesencephalic lesion].

We report a rare case showing Weber's syndrome associated with supranuclear vertical gaze palsy caused by the ipsilateral lesion of the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF), which is regarded as the supranuclear control center of vertical gaze. To date, no literature concerning Weber's syndrome associated with the ipsilateral riMLF lesion was documented. The patient was a 53-year-old female, who suddenly developed unconsciousness and left-sided weakness. Neurological findings on admission revealed right third nerve palsy, severe supranuclear vertical gaze palsy, almost complete convergence palsy, left hemiparesis and hyperreflexia with positive Babinski's sign on the left side. There was no sign of pupillary disturbance or no abnormality of the horizontal movements of the left eye. The vestibulo-ocular reflex of the left eye was preserved. There was no sensory disturbance. Cranial MRI had the advantages in demonstrating unilateral ischemic lesions at the cerebral peduncle and the thalamomesencephalic junction involving the unilateral riMLF on the right side. Recent reports have demonstrated that supranuclear vertical gaze palsy is caused by the unilateral riMLF lesion. We confirm that the unilateral riMLF lesion causes supranuclear vertical gaze palsy in our case and that cranial MRI has the advantages in demonstrating the specific lesion.

Mapping of event-related potentials to auditory and visual odd-ball paradigms in patients affected by different forms of dementia.

The paper reports the results of recordings and maps of event-related potentials (ERPs) in patients with Alzheimer's disease (AD), progressive supranuclear palsy (PSP) and in subjects affected by dementia in multiple sclerosis (MS). ERPs were recorded from 19 scalp electrode derivations using both visual and acoustic paradigms. In 43% of AD patients, ERPs were normal; in 20%, although present, ERP components were delayed, while in the other 37% none of the N2 and P3 peaks could be recorded, because of abnormal topography of potentials on the scalp. In patients with PSP, the normal ERP sequence was not identified. In patients with MS delayed ERPs (50%), abnormal topography of ERPs (30%) and absence of ERPs (20%) were observed. The follow-up of AD patients showed a progressive alteration of ERPs. ERP topography alterations were observed in AD, PSP and MS patients with poorest cognitive performances.

Mapping of event-related potentials to auditory and visual odd-ball paradigms.

This paper reports the results of recordings and maps of event-related potentials (ERPs) obtained in normal subjects, patients with Alzheimer's disease (AD), progressive supranuclear palsy, confusional states, and in subjects with homonymous hemianopsia. ERPs were recorded from 19 scalp electrode derivations using both visual and acoustic paradigms. In normal subjects, the topographical distribution of all ERP components is described in detail. In 45% of AD patients, ERPs were normal; in 35%, although present, ERP components were delayed, while in the other 20% the N2 and P3 peaks could not be recorded. In patients with progressive supranuclear palsy, the normal ERP sequence was not identified. Our findings in normals and in hemianopic patients suggest that the early modulation of stimulus-related potentials could be located in primary associative areas, and that N2, P3a, P3b, SW should have different origins.