Visual Hallucinations in Progressive Supranuclear Palsy

The classical presentation of sporadic Creutzfeldt-Jakob disease (sCJD) is rapid progressive dementia often associated with myoclonus and ataxia followed by death in less than a year from diagnosis. The few patients in the literature who presented with parkinsonism and who were suspected to have progressive supranuclear palsy (PSP) all ran a malignant course and most of them died within 3 years of diagnosis. We screened the Queen Square Brain Bank database and, among 213 patients with a clinical diagnosis of PSP, we found ten patients with 3 years or less disease duration, including one patient with CJD pathology. We report this patient and review other similar cases from the literature. Ten additional cases with similar presentation were identified in the literature. The mean disease duration was 24.2 months. The classical clinical, radiological and laboratory findings for sCJD were absent in the majority of these cases. Clinical presentation of these patients consists of: early falls, prominent dementia, early vertical supranuclear gaze palsy and symmetric akinetic syndrome. In the patients who were subtyped at post-mortem, all four represented the MM2 subtype of sCJD. A rapidly progressive course of PSP with early falls, cognitive impairments and vertical supranuclear gaze palsy should raise suspicion of underlying sCJD pathology regardless of absence of supportive findings on ancillary tests. This case and the literature support the notion that biochemical properties of the prion protein can influence the clinical presentation of sCJD.

Ziel/Aim Progressive supranuclear palsy (PSP) is a 4-repeat (4R) tauopathy and region-specific tau deposits establish the neuropathological diagnosis of “definite PSP” post mortem. Future interventional trials against tau in PSP would strongly benefit from biomarkers to validate the specific presence of the target before therapy initiation. The novel second generation tau-PET ligand 18F-PI2620 proved absent off-target binding to monoamine oxidases and high affinity to 3/4R tau in Alzheimer’s disease (AD). The aim of this multicenter-evaluation was to investigate 18F-PI2620 in patients with suspected 4R tau pathology in clinically diagnosed PSP.

Dysphagia is a frequent and early symptom in progressive supranuclear palsy (PSP) predisposing patients to aspiration pneumonia. Fiberoptic endoscopic evaluation of swallowing (FEES) has emerged as a valuable apparative tool for objective evaluation of neurogenic dysphagia. This is the first study using FEES to investigate the nature of swallowing impairment in PSP. Eighteen consecutive PSP patients (mean age 69.7 +/- 9.0 years) were included. The salient findings of FEES in PSP patients were compared with those of 15 patients with Parkinson's disease (PD). In 7 PSP patients, a standardized FEES protocol was performed to explore levodopa (L-dopa) responsiveness of dysphagia. Most frequent abnormalities detected by FEES were bolus leakage, delayed swallowing reflex, and residues in valleculae and piriformes. Aspiration events with at least one food consistency occurred in nearly 30% of PSP patients. Significant pharyngeal saliva pooling was observed in 4 PSP patients. We found no difference of salient endoscopic findings between PSP and PD patients. Endoscopic dysphagia severity in PSP correlated positively with disease duration, clinical disability, and cognitive impairment. No correlation was found with dysarthria severity. In early PSP patients, swallowing dysfunction was solely characterized by liquid leakage with the risk of predeglutitive aspiration during the oral phase of swallowing. Two PSP patients showed relevant improvement of swallowing function after L-dopa challenge. Chin tuck-maneuver, hard swallow, and modification of food consistency were identified as the most effective therapeutic interventions. In conclusion, FEES assessment can deliver important findings for the diagnosis and refined therapy of dysphagia in PSP patients.

Progressive supranuclear palsy (PSP) patients can show ventricular enlargement mimicking normal pressure hydrocephalus (NPH). The aim of this study was to distinguish PSP patients with marked ventricular dilatation (PSP-vd) from those with normal ventricular system and to evaluate the coexistence of NPH in PSP-vd patients. One hundred three probable PSP patients, 18 definite NPH patients, and 41 control subjects were enrolled in the study. Evans index (EI) > 0.32 associated with callosal angle (CA) < 100° was used to identify PSP-vd patients. Automated ventricular volumetry (AVV) and Magnetic Resonance Hydrocephalic Index (MRHI) were performed on T1-weighted MR images to evaluate the presence of NPH in PSP-vd patients. Twelve (11.6%) out of 103 PSP patients had both abnormal EI and CA values (PSP-vd). In two of these 12 patients, AVV and MRHI values suggested PSP + NPH. In the remaining 10 PSP-vd patients, AVV and MRHI values were higher than PSP patients with normal ventricular system and controls, but lower than PSP + NPH and NPH patients, suggesting a non-hydrocephalic ventricular enlargement. Our study provides evidence that the combination of EI and CA biomarkers allowed to identify PSP patients with marked ventricular dilatation mimicking NPH. Only a few of these patients had PSP + NPH. Recognition of these PSP patients with enlarged ventricles can positively impact the care of this disease, helping clinicians to identify patients with PSP + NPH who could benefit from shunt procedure and avoid surgery in those with enlarged ventricles without NPH.

Although widely described in Parkinson's disease (PD), peripheral neuropathy (PNP) is scarcely reported in progressive supranuclear palsy (PSP). We aimed to compare the frequency, clinical and electrophysiologic characteristics of PNP in PSP and PD patients. This cross-sectional study included 23 PSP and 93 PD patients. Demographic data, Movement Disorders Society-Unified Parkinson's Disease Rating Scale-III (MDS-UPDRS-III), Hoehn-Yahr staging, Toronto Clinical Neuropathy Score, nerve conduction study (NCS), and sympathetic skin response (SSR) were recorded. Diagnosing isolated large fiber neuropathy required abnormal NCS. Isolated small fiber neuropathy required clinical findings of pinprick and thermal sensory loss and/or allodynia and/or hyperalgesia with/without impaired SSR, along with normal NCS. PNP was commoner in PSP than PD (65.2% vs. 50.5%, P = 0.21). While a comparable proportion in both groups had clinical neuropathy, NCS abnormalities predominated in PSP (65.2% vs. 39.8%, P = 0.03). All patients had distal symmetrical axonal polyneuropathy. A significantly higher proportion of PSP patients had large fiber involvement (65.21% vs. 39.78%, χ 2 = 4.82; P = 0.03) and mixed fiber PNP (60.9% vs. 33.3%, P = 0.01). PSP patients with neuropathy had a significantly shorter disease duration [median (interquartile range {IQR} = 2 (2-3) years vs. 6 (3-9) years, P < 0.001], higher MDS-UPDRS-III score [median (IQR) = 47 (36-54) vs. 34 (28-49), P = 0.049], higher Hoehn-Yahr stage [median (IQR) = 4 (2-5) vs. 3 (1-5), P < 0.001], and shorter duration of levodopa use [median (IQR) = 2 (1-2) years vs. 3.5 (2-5) years, P = 0.006]. NCS parameters were comparable between PSP and PD patients with neuropathy. While PNP in PSP was not associated with any of the clinical variables, a longer disease duration was independently associated with PNP in PD. PNP affected two-thirds of PSP patients and was more prevalent than PD. Both groups had distal symmetrical axonal polyneuropathy, with mixed fiber PNP predominating in PSP. A longer disease duration in PD was associated with PNP.

Deterioration of horizontal saccades in progressive supranuclear palsy

Background: Mentalizing and emotion recognition are impaired in behavioral variant frontotemporal dementia (bvFTD). It is not clear whether these abilities are disturbed in progressive supranuclear palsy (PSP). Objective: To investigate social cognition (SC) between bvFTD and PSP. The neural basis of SC in PSP and bvFTD groups were also investigated by neuroimaging. Methods: Data from the notification sheet were collected and patients were classified according to current clinical and pathological criteria. Results: Groups did not differ on age, schooling and sex. Compared to controls, bvFTD and PSP patients had reduced scores in all tests of SC. bvFTD and PSP did not differ on measures of SC. PSP and bvFTD had cerebral atrophy in critical regions for SC. The cortical correlates of emotion recognition overlapped in bvFTD and PSP, correlating with frontal medial cortex, insula and limbic structures. PSP and bvFTD patients also displayed similar patterns of brain correlations (anterior temporal lobes) for social norms. The neural correlates of mentalizing were associated with frontal and temporal poles bilaterally, in both bvFTD and PSP. Conclusion:PSP patients exhibit impairment in mentalizing. PSP and bvFTD share clinical, cognitive and neuroimaging features.

Typically, progressive supranuclear palsy (PSP) is clinically characterized by slow vertical saccades or supranuclear gaze palsy, levodopa-resistant parkinsonism with predominant axial symptoms, and cognitive executive impairment. Over the past decades, various PSP phenotypes, including PSP with predominant parkinsonism, PSP with corticobasal syndrome, PSP with progressive gait freezing, and PSP with predominant frontal dysfunction, have been identified from pathologically confirmed cases. Expanding knowledge led to new diagnostic criteria for PSP that with increased disease awareness led to increased PSP prevalence estimates. The identification of environmental and modifiable risk factors creates an opportunity to intervene and delay the onset of PSP or slow disease progression. To date, despite the increasing number of publications assessing risk factors for PSP, few articles have focused on environmental and lifestyle risk factors for this disorder. In this article, we reviewed the literature investigating the relationship between PSP and several environmental and other modifiable lifestyle risk factors. In our review, we found that exposures to toxins related to diet, metals, well water, and hypertension were associated with increased PSP risk. In contrast, higher education and statins may be protective. Further case-control studies are encouraged to determine the exact role of these factors in the etiopathogenesis of PSP, which in turn would inform strategies to prevent and reduce the burden of PSP.

These include, among others, two forms of atypical Parkinsonism, multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). This study aimed to assess the potential role of C9orf72 repeat expansions among Serbian patients diagnosed with MSA and PSP. Genomic DNA of 44 MSA patients, 73 PSP patients, and 96 controls was extracted from peripheral blood, and normal C9orf72 alleles were analyzed by standard quantitative fluorescence polymerase chain reaction (QF-PCR) and fragment analysis. Subsequently, for all samples presenting a single allele, repeat-primed PCR was performed with two different sets of primers to avoid a false-negative result. Thirty repeats were used as a pathogenic cut-off and 20-29 repeats for the intermediate alleles. No pathological C9orf72 expansions were detected in the MSA and PSP patients nor the control subjects. In the MSA group, the most common was the allele with 2 repeats, and the largest repeat number was 14. Among PSP patients, the most common allele also had 2 repeats, while the largest detected repeat size within the normal range was 17. Also, we identified one PSP patient that had an intermediate size allele (25 repeats). We did not find correlation between the number of repeats and disease onset, age at the time of examination, or disease duration in MSA or PSP patients. Regarding family history, in PSP the sum of both allele repeats numbers was higher in patients with positive family history than in sporadic cases. The results presented in this study are the first systematic assessment of C9orf72 allele sizes among patients diagnosed with MSA and PSP in the Serbian population. Although the potential role of intermediate C9orf72 repeats in neurodegenerative disorders is still to be elucidated, our results support the current knowledge that C9orf72 repeat expansions are not associated with MSA and PSP.

Background: Most magnetic resonance imaging (MRI) studies of progressive supranuclear palsy (PSP) are cross-sectional and lack post mortem confirmation of the diagnosis. MRI features described previously in PSP correspond to...

Progressive supranuclear palsy (PSP) is a rare neurodegenerative tauopathy characterized by early postural instability and vertical gaze palsy. Mitochondrial dysfunctions have been increasingly implicated in the pathogenesis of neurodegenerative disorders, including PSP. We investigated mitochondrial DNA copy number (mtDNA-CN) alterations in the peripheral blood of PSP patients, assessing its potential as a biomarker for disease onset and progression. We measured mtDNA-CN in a cohort of clinically diagnosed PSP patients and age-matched healthy controls using quantitative real-time PCR. We evaluated differences across clinical phenotypes and age groups. PSP patients exhibited a significant reduction in ND3-CN compared to healthy controls (p < 0.0001). This depletion remained consistent across age groups, suggesting that mitochondrial impairment in PSP is independent of physiological aging. Although not statistically significant, ND3-CN levels were lower in PSP-parkinsonism (PSP-P) patients compared to those with Richardson's syndrome (PSP-RS). Interestingly, in PSP-RS patients, ND3-CN levels tended to increase with age, potentially reflecting an age-related compensatory mitochondrial response to chronic neuroinflammation. Our findings support the involvement of mitochondrial dysfunction in PSP pathogenesis, suggesting that peripheral mtDNA-CN may serve as a non-invasive biomarker for disease monitoring. Further studies in larger cohorts are warranted to validate its prognostic potential in different PSP phenotypes.

Progressive supranuclear palsy: Neuropathology, clinical presentation, diagnostic challenges, management, and emerging therapies

Progressive supranuclear palsy (PSP) is typically manifested by vertical supranuclear gaze palsy, frequent falls early in the disease course, axial rigidity and poor response to levodopa. Prominent anterograde memory dysfunction with subsequent impairment in other cognitive domains is characteristic of Alzheimer’s disease (AD). No clear clinical syndrome has been identified in argyrophilic grain disease (AGD). Frontotemporal dementia (FTD) is characterized by apathy, emotional blunting, disinhibition, and impairment in executive functioning despite relatively preserved memory and visuospatial abilities. Cognitive deficits are known to occur in PSP; however, overt clinical FTD without parkinsonism or supranuclear gaze palsy associated with PSP pathology has rarely been documented. We report an elderly patient with the typical clinical, neuropsychometric, and neuroimaging features of FTD who had autopsy findings most consistent with PSP plus AGD and AD in limbic structures. We suggest that PSP with or without coexisting AD and AGD be included in the differential diagnosis of patients presenting with FTD.

Omics profile of iPSC-derived astrocytes from Progressive Supranuclear Palsy (PSP) patients

Corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) share pathologic features, and cortical and subcortical signs. Apraxia is frequently described in CBD and sometimes in PSP; however, it is difficult to distinguish ideomotor from limb-kinetic apraxia, and apraxia frequency is unclear. The authors set out to clarify the nature and frequency of apraxia in these diseases. The authors compared probable CBD and PSP patients, matched for motor disability, to healthy age-matched controls on cognitive tests and the De Renzi ideomotor apraxia test. Cognitive impairment was similar, but more CBD (70.8%) than PSP (36%) patients had apraxia. CBD patients committed more apraxic errors of awkwardness and were more compromised on simple gestures; PSP patients committed more sequence errors. While progressive supranuclear palsy (PSP) patients had ideomotor apraxia, the peculiar gesture compromise in corticobasal degeneration (CBD) suggests that limb-kinetic apraxia is dominant. In both illnesses, the movement production system of Roy and Square appears compromised: in CBD defective control of muscle activation seems likely, producing clumsy movements; in PSP, control of motor program activation appears defective, resulting in sequence errors and perseverations. The De Renzi test can reliably estimate apraxia frequency and may be used to distinguish limb-kinetic from ideomotor apraxia.