Skip Navigation
Skip to contents

JMD : Journal of Movement Disorders



Page Path
HOME > J Mov Disord > Volume 17(2); 2024 > Article
Original Article
Phenotypic Spectrum of Progressive Supranuclear Palsy: Clinical Study and Apolipoprotein E Effect
Amina Nasri1,2,3orcid, Ikram Sghaier1,3orcid, Anis Neji1, Alya Gharbi1,2,3orcid, Youssef Abida1,2,3orcid, Saloua Mrabet1,2,3orcid, Amina Gargouri1,2,3orcid, Mouna Ben Djebara1,2,3orcid, Imen Kacem1,2,3orcid, Riadh Gouider1,2,3corresp_iconorcid
Journal of Movement Disorders 2024;17(2):158-170.
Published online: January 30, 2024

1Department of Neurology, LR18SP03, Razi University Hospital, Tunis, Tunisia

2Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis, Tunisia

3Clinical Investigation Center (CIC) “Neurosciences and Mental Health”, Razi University Hospital, Tunis, Tunisia

Corresponding author: Riadh Gouider, MD Department of Neurology, Razi University Hospital, 1 rue des orangers Manouba, Tunis 2010, Tunisia / Tel: +216-70-162-243 / Fax: +216-71-601-300 / E-mail:
• Received: September 9, 2023   • Revised: December 8, 2023   • Accepted: January 30, 2024

Copyright © 2024 The Korean Movement Disorder Society

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

  • 69 Download
  • Objective
    Progressive supranuclear palsy (PSP) is a rare neurodegenerative disorder encompassing several phenotypes with various motor and cognitive deficits. We aimed to study motor and cognitive characteristics across PSP phenotypes and to assess the influence of apolipoprotein E (APOE) gene variants on PSP phenotypic expression.
  • Methods
    In this 20-year cross-sectional study, we retrospectively reviewed the charts of all patients classified as PSP patients and recategorized them according to phenotype using the Movement Disorder Society criteria (2017). Phenotypes were divided into three subgroups, Richardson’s syndrome (PSP-RS), PSP-cortical (PSP with predominant frontal presentation [PSP-F] + PSP with predominant speech/language disorder [PSP-SL] + PSP with predominant corticobasal syndrome [PSP-CBS]) and PSP-subcortical (PSP with predominant parkinsonism [PSP-P] + PSP with progressive gait freezing [PSP-PGF] + PSP with predominant postural instability [PSP-PI] + PSP with predominant ocular motor dysfunction [PSP-OM] + PSP with cerebellar ataxia [PSP-C] + PSP with primary lateral sclerosis [PSP-PLS]), based on clinical presentation during the first 3 years after symptom onset, which defines the early disease stage. Clinical and neuropsychological assessment data were collected. Genotyping of APOE was performed using restriction fragment length polymorphism polymerase chain reaction and verified by Sanger sequencing.
  • Results
    We included 112 PSP patients comprising 10 phenotypes classified into 48 PSP-RS, 34 PSP-cortical (PSP-CBS, 17.6%; PSP-F, 9.4%; PSP-SL, 8.2%) and 30 PSP-subcortical (PSP-P, 11.6%; PSP-PI, 8%; PSP-OM, 2.7%; PSP-PGF, 1.8%; PSP-C, 1.8%; PSP-PLS, 0.9%) subgroups. PSP-RS patients were older at disease onset (p = 0.009) and had more akinetic-rigid and levodopa-resistant parkinsonism (p = 0.006), while PSP-cortical patients had more tremors and asymmetric and/or levodopa-responsive parkinsonism (p = 0.025). Cognitive domains were significantly less altered in the PSP-subcortical subgroup. Overall, PSP-APOEε4 carriers developed parkinsonism earlier (p = 0.038), had earlier oculomotor dysfunction (p = 0.052) and had more altered cognitive profiles. The APOEε4 allele was also associated with a younger age of parkinsonism onset in the PSP-RS phenotype group (p = 0.026).
  • Conclusion
    This study demonstrated the wide phenotypic spectrum of PSP among Tunisians. Disease onset and akinetic-rigid and levodopa-resistant parkinsonism were the hallmarks of the PSP-RS phenotype, while milder cognitive impairment was characteristic of the PSP-subcortical subgroup. The APOEε4 allele was associated with earlier parkinsonism and oculomotor dysfunction and seemed to play a role in defining a more altered cognitive profile in PSP patients.
Progressive supranuclear palsy (PSP) is a rare neurodegenerative disorder defined as a neuropathological entity linked to abnormal tau protein accumulation. Classically, PSP is characterized by clinical manifestations, including early postural instability, vertical supranuclear gaze palsy, cognitive decline, pseudobulbar palsy, levodopa-resistant bradykinesia and axial rigidity [1]. Despite the emphasis of earlier reports on motor signs, cognitive decline is henceforth considered a major manifestation of PSP, with a fronto-executive deficit being a core feature [2]. In fact, the classical presentation of PSP, which was initially reported and is now termed PSP-Richardson’s syndrome (PSP-RS), appears to be one of many clinical expressions on a large spectrum. Indeed, in 2017, the Movement Disorder Society (MDS) acknowledged several atypical phenotypes beyond PSP-RS according to the predominant clinical features, including various motor and cognitive deficits [3].
Unfortunately, the factors underlying the clinical expressions and heterogeneity of PSP remain unclear. Several studies have shown that these phenotypic differences are primarily due to the heterogeneity of the distribution of 4-repeat tau pathologies [4]. Genetic factors seem to be implicated in PSP etiopathogenesis considering the reported cases of familial PSP and the role of the microtubule-associated protein tau (MAPT) H1 haplotype in PSP [5]. Furthermore, the role of the apolipoprotein E (APOE) gene as a risk factor for other late-life tauopathies, such as Alzheimer’s disease [6], supports its probable implication as a genetic contributor to PSP phenotypic variability [7].
To date, few cohort studies have attempted to describe the distribution of PSP phenotypes according to the updated MDS classification [7] and to characterize the motor and neuropsychological aspects across these phenotypes. Moreover, to the best of our knowledge, no studies have assessed the impact of APOE on these different phenotypes. Hence, we investigated motor and cognitive features across PSP phenotypes through our Tunisian cohort and evaluated the influence of APOE gene variants on the phenotypic expression of PSP.
Study subjects
A cross-sectional retrospective study was carried out in the Department of Neurology at Razi University Hospital over a period of 20 years (from January 2003 to December 2022). We retrospectively reviewed the charts of all patients classified as PSP from our atypical parkinsonian syndrome database and reviewed their demographic data and clinical motor and cognitive assessments. All patients underwent neurological examination performed by a movement disorder specialist and systematic brain imaging. We excluded all patients with parkinsonism of other origins, notably hydrocephalus or vascular parkinsonism.
Demographic data and clinical assessment
Demographic, motor and neuropsychological data were collected at the first examination using standardized case reports. The demographic data included age, sex, family history, age of onset (defined as the age when the patient first had motor or cognitive symptoms presumably attributable to PSP), and age of diagnosis (defined as the age when the diagnosis was retained in our department). Motor signs included akinesia, rigidity, falls, dysarthria, dysphagia, gait difficulties, oculomotor dysfunction and other movement disorders. Response to levodopa was defined according to the Brain Bank Annual Assessment. The Unified Parkinson’s Disease Rating Scale (UPDRS) section III was used to rate the severity of extrapyramidal symptoms. The parkinsonian motor phenotypes were classified into three subgroups, tremor dominant (TD), postural instability gait disorder (PIGD) and indeterminate phenotypes, according to published formulas used for Parkinson’s disease (PD) [8].
Clinical and neuropsychological assessment
The neuropsychological assessment included the 30-item Mini-Mental State Examination (MMSE) to assess overall cognitive efficiency at the first consultation [9]. The Frontal Assessment Battery (FAB) was used to evaluate executive function [10]. Episodic memory was assessed with the Free and Cued Selective Reminding Test of Grober and Buschke [11]. Visuospatial functions were evaluated by the Clock-Drawing Test. The Montreal-Toulouse Language Assessment Battery was used to explore language impairment [12]. Other domains evaluated by neuropsychological assessment included attention, apraxia, agnosia, judgment and reasoning. The Beck Depression Inventory was used to assess mood disturbance and detect depression in patients aged < 65 years [13], and the Geriatric Depression Scale14 was used in patients aged > 65 years. The Neuropsychiatric Inventory (NPI) was used to assess both the frequency and severity of behavioral abnormalities. The presence of dementia or major cognitive impairment (CI) was established based on cognitive examination, neuropsychiatric assessment and functional autonomy assessed by the Katz Index of Independence in Activities of Daily Living and the Lawton Instrumental Activities of Daily Living scale to assess functional capacity.
Based on the clinical presentation during the first 3 years after symptom onset, which defines the early disease stage, we applied retrospective recategorization to the phenotypes of patients with a clinical diagnosis of PSP using the MDS criteria for PSP (2017) [3]. We included patients with probable, possible, or suggestive PSP. For the latter, only patients with suggestive PSP who ultimately (beyond the first 3 years of disease onset) developed probable or possible PSP, according to the 2017 diagnostic criteria, were included.
We identified 10 phenotypes: PSP-RS, PSP with predominant parkinsonism (PSP-P), PSP with predominant corticobasal syndrome (PSP-CBS), PSP with predominant frontal presentation (PSP-F), PSP with predominant postural instability (PSP-PI), PSP with predominant speech/language disorder (PSP-SL), PSP with progressive gait freezing (PSP-PGF), PSP with predominant ocular motor dysfunction (PSP-OM), PSP with cerebellar ataxia (PSP-C), and PSP with primary lateral sclerosis (PSP-PLS). The latter two corresponded to phenotypes that were mentioned but not included in the MDS 2017 classification since the patients developed typical PSP signs later in the disease course. When describing PSP phenotypes, patients may fulfill more than one criterion at a time. Accordingly, the Multiple Allocations eXtinction (MAX) criteria reported in 2019 were applied to allow identification of the dominant phenotype [15]. Furthermore, we regrouped our patients as previously described into three subgroups: PSPRS, PSP-cortical (PSP-F + PSP-SL + PSP-CBS), and PSP-subcortical (PSP-P + PSP-PGF + PSP-PI + PSP-OM + PSP-C + PSPPLS) [16,17].
APOE genotyping
Peripheral venous blood was collected from available participants in EDTA-containing tubes. Genomic DNA was prepared with a QIAamp® DNA Blood Mini Kit according to the manufacturer’s instructions (Qiagen GmbH, Hilden, Germany). Genotyping of APOE was performed using restriction fragment length polymorphism polymerase chain reaction. APOE genotypes were determined by scoring for a unique combination of fragment sizes. The genotype was then verified using Sanger sequencing.
Database and statistical analysis
We described demographic and clinical characteristics as well as APOE genetic frequencies and then assessed the relationships between the clinical variables and APOE genotype in the total cohort and compared them across subgroups. Continuous variables are expressed as the mean ± standard deviation. Fisher’s exact probability test for frequency tables was used for statistical analysis. Differences in the proportions were analyzed by the chi-square test and Fisher’s exact test. Multivariate logistic regression was used to model outcome variables according to APOE ε4 mutation status. A value of p < 0.05 was considered to indicate statistical significance. The Spearman rank correlation test was used to evaluate correlations. Corrections for multiple comparisons were performed with a Bonferroni correction. All statistical procedures and figures were generated with R software for Windows (version 4.1.1; R Foundation for Statistical Computing, Vienna, Austria) using the “multinom,” “SNPassoc,” “Hmisc,” “corrplot” and “ggplot” packages.
The study was approved by the Razi University Hospital Ethics Committee under ID number 012003. All subjects conformed to the principles outlined in the Declaration of Helsinki and were informed about the purposes of the study. All the patients included in this study provided written consent (patients themselves or their parents or caregivers) at the first consultation.
Phenotype distribution and demographic findings
We included 112 patients who met the criteria for 42 probable (37.50%), 34 possible (30.35%) or 36 suggestive of PSP (32.14%). We included only patients with suggestive PSP who ultimately (beyond the first 3 years) developed probable or possible PSP according to the 2017 diagnostic criteria. After applying the MAX criteria, all patients were determined to have only one predominant phenotype, which was considered for the study. Forty-eight patients met the criteria for the PSP-RS subgroup (42.85%), 34 patients (30.35%) met the criteria for the PSP-cortical subgroup, and 30 (26.78%) met the criteria for the PSP-subcortical subgroup. The cortical phenotypes included 17 PSP-CBSs (15.2%), 10 PSP-Fs (8.9%) and 7 PSP-SLs (6.2%). The PSP subcortical phenotypes included 13 PSP-Ps (11.6%), 9 PSP-PIs (8%), 3 PSPOMs (2.7%), 2 PSP-PGFs (1.8%), 2 PSP-C (1.8%) and 1 PSP-PLS (0.9%).
A male predominance was noted in our total cohort, with a sex ratio equal to 1.38, without a significant difference between PSP subgroups. Additionally, the PSP subgroups were similar in terms of age, education and disease duration. The mean age at disease onset was 60.82 years, and the age at disease onset was lower for the subcortical subtype and higher for PSP-RS (p= 0.004) (Table 1).
Motor and neuropsychological findings across PSP subgroups
The detailed motor and neuropsychological characteristics of the total study population and across subgroups are detailed in Tables 1 and 2, respectively.
PSP-RS patients had more akinetic-rigid and levodopa-resistant parkinsonism (p = 0.006), while PSP-cortical patients had more tremors and asymmetric and/or levodopa-responsive parkinsonism (p = 0.025).
CI was found in 98 PSP patients (87.5%). Overall, the PSPsubcortical subgroup seemed to be significantly less cognitively affected (Table 2 and Figure 1A).
The clinical profiles of the three PSP subgroups (RS, cortical, and subcortical) and comparisons of clinical features between the patients with the typical and atypical PSP phenotypes are depicted in Figure 1B and 2.
The evaluation of correlations between clinical variables in each subgroup revealed various associations (Figure 3). Concerning the subcortical strata, we found a significant inverse correlation between memory impairment and the occurrence of freezing of gait (p = 0.048, r = -0.45) as well as oculomotor dysfunction and memory impairment (p = 0.013, r = -0.46).
For the cortical subgroup, a correlation was detected between freezing and the initial FAB score (p = 0.048, r = 0.42), while an association was detected between frequent falls and oculomotor dysfunction (p = 0.047, r = 0.34). Regarding the PSP-RS phenotype, we found a correlation between oculomotor dysfunction and dystonia (p = 0.05, r = 0.29) and between oculomotor dysfunction and dysarthria (p = 0.047, r = 0.29). Moreover, we noted another correlation between freezing and memory impairment (p = 0.026, r = -0.10) (Figure 3).
APOE genotype and its impact on the clinical profile across PSP subgroups
The APOE genotype had different frequencies across PSP subtypes. Approximately 6.31% of PSP patients were carriers of the homozygous form of APOE ε4/ε4, and 40.0% of PSP patients carried one copy of the APOE ε4 allele. Accordingly, significant differences were noted in the genotype distributions across the PSP subgroups (p = 0.025) (Table 3).
Analysis of the associations of APOE ε4 with the whole cohort and the other variables revealed an association between APOE ε4 and the age of parkinsonism onset (p = 0.019). Indeed, all PSP-RS patients in the subcortical and cortical subgroups with APOE ε4 developed parkinsonian syndrome at an earlier age than the noncarriers (63.61 years and 62 years vs. 66.64 years and 66 years).
A stratified investigation of the impact of APOE ε4 on motor profiles across PSP subgroups revealed earlier onset parkinsonism in ε4 mutation carriers (p = 0.011), as did tremor and tremor at onset (p = 0.027 and p=0.022, respectively). Earlier repeated falls were associated with APOE ε4 carriage status (p = 0.038). Freezing was significantly associated with ε4 carriage (p = 0.047). Additionally, a marginal association was noted between oculomotor dysfunction and APOE ε4 (p = 0.052) (Table 1).
Our results adjusted for APOE ε4 carriage among PSP subtypes, according to the cognitive profile, revealed new associations in terms of memory impairment (p = 0.025), with a higher frequency of cases with memory impairment at onset (p = 0.019) and earlier stages (p = 0.008). Additionally, APOE ε4 carriers had a hippocampal profile of memory impairment (p = 0.049). Interestingly, APOE adjustment revealed new associations with early language impairment (p = 0.003). We also reported more frequent mood and behavior disorders (p = 0.038) in the PSPcortical subgroup with the APOE ε4 allele (67.64%) (Table 2).
The analysis of correlations among different motor and nonmotor parameters in each PSP subgroup according to APOE ε4 carriage status revealed an inverse correlation between the ε4 allele and freezing in the PSP-RS subgroup (p = 0.032) (Figure 3A). In addition, the APOE ε4 allele was associated with tremor (p = 0.047) in the PSP-cortical subgroup (Figure 3C) and with a significant correlation between APOE and dysarthria (p = 0.035) and freezing (p = 0.05) in the PSP-subcortical subgroup (Figure 3D).
Analysis of the clinical profiles of PSP patients according to APOE ε4 carriage revealed differences in graph shape (Figure 1C). In fact, compared with that of noncarriers, carriers of the APOE ε4 allele presented the most frequent predominance of cognitive dysfunction (Figure 1C).
In the present study, we provided one of the first and largest cohort studies comparing clinical motor and neuropsychological characteristics across PSP phenotypes and subtypes diagnosed according to the MDS criteria with the exploration of the impact of APOE on expression [18,19]. Only a few studies have been conducted in Africa to explore the clinical features of PSP in African patients [7], and even fewer have explored the genetic aspects of the disease [20]. The present study is the first to explore the phenotypic spectrum of PSP among Tunisian and North-African patients and one of the few studies that has examined PSP phenotypes across populations, which is shown in Table 4. Notably, we based our phenotyping process on disease presentation during the first three years of the disease, when diagnosis might be the most challenging. Indeed, PSP subtypes tend to change over time in an individual patient, and most patients eventually fulfill the criteria for PSP-RS [17].
Our cohort included a large variety of phenotypes. The typical PSP-RS was the most common PSP phenotype (42.85%), which was in line with the findings of previous studies (24% to 69%), followed by PSP-CBS, PSP-P, PSP-F, PSP-PI, and PSP-SL. The rarest ones were PSP-C and PSP-PLS. Unlike in previous studies, the PSP-CBS phenotypes were more frequent than the PSP-P phenotypes among our cohort. The reasons for this discrepancy might be the lack of pathologically confirmed diagnoses in our series and the different levels of diagnostic certainty across studies. In fact, the highest incidence of the PSP-CBS phenotype was found in studies without neuropathological evidence, and the lowest was found in pathologically confirmed diagnoses [3,19]. Due to the lack of studies comparing cortical and subcortical presentations, we calculated the rates of presentation from available reports. In our cohort, the PSP-cortical and subcortical strata were more closely related (30.35% vs. 26.78%), in contrast to previous reports in which PSP-cortical subgroups tended to be less common (22% vs. 44%). Our findings may be due to the higher PSP-CBS and PSP-SL rates and the lower PSP-P rate compared to those reported in the literature [3,19].
Consistent with the findings of previous reports, no significant differences were noted among the three PSP subgroups according to sex (p = 0.321) [21,22] or age of parkinsonism onset (p = 0.522). Interestingly, the mean age of disease onset was younger in the PSP-subcortical subtype (58.51 years vs. 62.23 years in PSP-RS). Consequently, the age of diagnosis was significantly higher in the PSP-RS subgroup than in the other subgroups (p = 0.017). Our findings contradict those of other studies that outlined the later age of onset in the subcortical PSP. Those studies explained this feature by the more benign clinical trajectory with less CI delaying the perception of disease onset and the age at first consultation [17,23]. Our results may be explained by the fact that parkinsonian motor features that are prominent in PSP-P and PSP-PGF phenotypes (consisting of the subcortical subgroup of PSP) may be more obvious and earlier detected than more subtle cognitive features.
As expected, akinetic-rigid, predominantly axial, and levodopa-resistant parkinsonism was found in two-thirds of the PSP patients and was significantly more frequent in the RS vs. atypical phenotypes, contrary to tremor-associated and/or asymmetric and/or levodopa-responsive parkinsonism (p = 0.025), which was a major characteristic of the PSP-P22 and PSP-CBS phenotypes. Even if tremors were present, almost no PSP patients had a TD form of parkinsonism according to the UPDRS-III assessment, and the PIGD phenotype prevailed across all PSP subgroups (Table 2) [24].
In addition to motor symptoms, patients with PSP commonly exhibit cognitive and behavioral disorders [2,3]. Compared to the former cohorts, which included individuals with CI and dementia, our patients had higher rates of both items (57% vs. 87.5% with CI and 33% vs. 45.5% with dementia) [25] and lower mean MMSE scores (21.63 vs. 26) [14]. The cognitive pattern according to altered domains in all subgroups confirmed the prevailing fronto-executive deficits as a core feature of the PSP cognitive profile. Notably, it was observed that 35.7% of patients in our series were PSP patients with a hippocampal profile of memory disorders. However, memory impairment was not a predominant feature to be considered an exclusion criterion according to the 2017 MDS criteria [3], and all patients with a hippocampal profile developed features of PSP, notably vertical gaze palsy. In addition, recent observations revealed either an Alzheimer disease copathology in PSP patients or a distinct subregional distribution of tau pathology in the hippocampus in PSP patients, suggesting that there may be an AD-independent pathogenic process involved in the hippocampus [26-28].
However, when comparing the subgroups in our cohort, all cognitive domains were significantly less impaired in the subcortical subgroup, particularly for executive functions (p = 0.001). In fact, these findings suggest that subcortical phenotypes are mainly motor and cortical phenotypes that are predominantly cognitive. Although few cohort studies have compared PSP phenotypes in the literature, few have clinically compared PSP-RS, PSP-cortical and PSP-subcortical subgroups, revealing either more CI in the cortical subgroup [29] or no significant differences in cognitive scores [30]. Additionally, a recent study revealed cognitive and behavioral differences in PSP phenotypes, with more semantic verbal fluency in PSP-RS and PSP-CBS patients and more ideomotor apraxia in PSP-CBS patients [19].
Next, we investigated the correlations of different clinical parameters in each subgroup independently (Figure 3). Among the subcortical strata, we found mutual associations between oculomotor dysfunction, memory impairment and freezing of gait at disease onset. This result may be explained by considering the prevailing role of the frontal lobe in the PSP-subcortical subgroup at early stages of the disease in terms of oculomotoricity, gait control and the frontal component of memory functioning. The role of the frontal lobe in the cortical PSP subgroup may emerge later in the disease course, as we also found significant associations between the FAB score and freezing during the disease course [31].
Despite the well-established pathological heterogeneity of PSP, its correlation with PSP phenotypes remains elusive. In fact, the regional variations in the type of tau lesions or differences in tau load may explain the clinical variety of PSP [4,27]. Pathologically, APOE ε4 may lead to increased Aβ aggregation and decreased clearance of Aβ from the brain [32]. However, the influence of APOE isoforms on tau pathology is unclear. Although tau is a cytoplasmic protein, it has been reported that tau protein is also found in the extracellular space [33]. In fact, intracellular tau aggregates are in equilibrium with extracellular tau, whose aggregation might mediate the spread of pathological species of tau between cells. Since APOE may be present in the cytoplasm, it could form a complex with tau and modulate its metabolism in the brain [34]. Thus, APOE can also modulate tau aggregation and related pathologies [34]. Furthermore, it is hypothesized that the potentially different complex-forming properties of tau and APOE isoforms (ε3, ε2, and ε4) might affect tau metabolism to variable degrees. Overall, these findings may lead us to speculate that one of the possible mechanisms by which APOE could have an impact on PSP phenotypes is through the modulation of Tau metabolism, aggregation and distribution. Additionally, genome-wide association studies have shown a strong correlation between APOE and cerebrospinal fluid tau and phosphorylated tau (p-tau) [35].
The impact of APOE on the phenotypic diversity of PSP has not yet been adequately investigated, apart from one study that confirmed similar frequencies of APOE genotypes in PSP-RS and PSP-P [22]. Accordingly, we aimed to evaluate the effect of APOE ε4 on PSP phenotypes. Overall, a significant association was detected between the APOE genotype distribution and PSP subgroup (p = 0.025). Furthermore, significant differences in demographic, motor and nonmotor variables were detected between APOE ε4 carriers and noncarriers. In fact, earlier age of parkinsonism onset was significantly associated with APOE ε4 carriage (p = 0.019). Indeed, it has been reported that patients with PD and carriers of APOE ε4 have a significantly earlier onset of parkinsonism [36,37]. Early tremor at onset was less common among patients who were carriers of the APOE risk allele (p = 0.031).
Concerning the cognitive profile, the study of APOE ε4 compared to non-APOE ε4 revealed significant differences, with APOE ε4 carriers presenting more marked cognitive dysfunction. Indeed, carriers of the risk allele developed earlier memory impairment (p = 0.049). We noted a significant impact of APOE ε4 on attention, executive functions, and apraxia but not agnosia among the PSP subgroups. In fact, the associations found previously continued to be significant regardless of APOE ε4 carrier status adjustment.
Nonetheless, we reported the emergence of a new significant association between memory deficits and disease onset by adjusting for APOE ε4 status (p = 0.019). These findings agree with previous results in which APOE ε4 was associated with a faster rate of memory decline [38]. At the cellular level, this could be due to a possible APOE ε4 association with enhanced tau deposition in medial-temporal regions [31]. Additionally, an association between APOE status and early language impairment was reported (p = 0.003). In fact, noncarriers of the ε4 allele developed language impairment earlier than allele carriers did. These findings might be explained by previous observations that revealed that patients with the APOE risk allele exhibited more brain atrophy in the medial temporal lobe than noncarriers, while the nonε4 patients exhibited more brain atrophy in the frontal and parietal lobes than the other patients [39,40].
The initial NPI was associated with APOE ε4 carriage (p = 0.038). This finding was in line with the findings of other studies suggesting a link between the mutant APOE allele ε4 and the risk of depressive symptoms in patients with dementia, probably due to reduced amygdala volume [41].
A correlation analysis of the total PSP cohort revealed a positive association between APOE and attention disorders (p = 0.032, r = 0.24). A major possibility for the APOE-attention link is the alteration of cholinergic transmission associated with the cortical areas that are important for attentional operations [42]. However, the correlation between APOE and PSP severity changed with stratification.
The findings of our study have to be considered in light of several limitations. Due to its nature, our retrospective study relies on the use of charts; occasionally, the charts were not designed to collect adequate information for research. This fact could inevitably lead to missing data but without substantially impacting the PSP subtyping process. Additionally, despite the large cohort of PSP patients included in the present study, the different subgroups were restricted. Finally, the limited APOE genotype data and the lack of neuropathological confirmation could be major limitations.
This study demonstrated the wide phenotypic spectrum of PSP among Tunisians. Disease onset and akinetic-rigid and levodopa-resistant parkinsonism were the hallmarks of the PSPRS phenotype, while milder CI was characteristic of the PSPsubcortical subgroup. The APOEε4 allele seemed to play a role in defining a more altered cognitive profile in PSP patients. This effect mainly concerned executive function, memory, attention and apraxia. Our study may enrich the scientific literature on PSP North African patients. Further studies could also help to elucidate the interplay between APOE genotyping and other potential ethnic and genetic singularities of PSP in these regions.

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement


Author contributions

Conceptualization: Riadh Gouider. Data curation: Amina Nasri, Ikram Sghaier, Anis Neji, Alya Gharbi, Youssef Abida, Saloua Mrabet. Formal analysis: Ikram Sghaier. Funding acquisition: Riadh Gouider. Investigation: Amina Nasri, Anis Neji, Saloua Mrabet, Alya Gharbi, Imen Kacem, Mouna Ben Djebara, Youssef Abida. Methodology: Riadh Gouider, Amina Nasri, Mouna Ben Djebara, Imen Kacem. Project administration: Riadh Gouider. Resources: Riadh Gouider. Software: Ikram Sghaier. Supervision: Riadh Gouider, Mouna Ben Djebara, Amina Gargouri. Validation: Riadh Gouider. Visualization: Riadh Gouider, Imen Kacem, Mouna Ben Djebara. Writing—original draft: Amina Nasri, Ikram Sghaier. Writing—review & editing: Amina Nasri, Ikram Sghaier, Imen Kacem, Alya Gharbi, Mouna Ben Djebara, Amina Gargouri.

We thank all subjects who gave their consent and participated in the present study.
Figure 1.
Neuropsychological and clinical profiles of PSP according to subtype (A, B) and APOE carrier status (C). Radar charts comparing the percentages of PSP-RS, PSP-cortical, and PSP-subcortical patients with neuropsychological findings (A) and Movement Disorder Society PSP diagnostic criteria clinical features (B) and APOEε4 carrier vs. noncarrier Movement Disorder Society PSP diagnostic criteria clinical features (C). PSP-RS, PSP-Richardson’s syndrome; PSP, progressive supranuclear palsy.
Figure 2.
Clinical profile of PSP patients with typical and atypical phenotypes. Radar charts comparing the percentages of PSP-RS (typical phenotype) and PSP atypical phenotype patients according to the clinical features of the Movement Disorder Society PSP diagnostic criteria. PSP-RS, PSP-Richardson’s syndrome; PSP, progressive supranuclear palsy.
Figure 3.
Correlation between clinical variables among PSP subgroups. A: Total cohort. B: PSP-RS. C: PSP-cortical. D: PSP-subcortical. PSP, progressive supranuclear palsy; PSP-RS, progressive supranuclear palsy-Richardson’s syndrome; PSP-cortical, progressive supranuclear palsy-cortical; PSP-subcortical, progressive supranuclear palsy-subcortical.
Table 1.
Demographic and motor characteristics of total study cohort and across PSP subgroups
Variables Total cohort (n = 112) Typical form
Atypical forms
p value1 p value2
PSP-RS (n = 48) PSP-cortical (n = 34) PSP-subcortical (n = 30)
Demographic variables
 Sex, male/female 65/47 26/16 21/13 15/15 0.321 0.024*
 Sex-ratio 1.38 1.62 1.61 1.00 0.321 0.024*
 Age of onset (yr) 60.82 ± 7.92 62.23 ± 7.69 60.23 ± 8.60 58.51 ± 6.90 0.009* 0.003*
 Age of parkinsonism onset (yr) 62.59 ± 7.67 62.72 ± 8.03 61.80 ± 7.70 60.71 ± 6.69 0.522* 0.019*
 Age of diagnosis (yr) 65.87 ± 7.89 67.77 ± 9.53 66.45 ± 7.60 62.25 ± 7.58 0.018* 0.004*
Family history of neurodegenerative diseases
 Dementia 24 (21.43) 11 (22.91) 8 (23.52) 5 (16.67) 0.767 0.763
 Parkinsonism 19 (16.96) 7 (14.53) 5 (14.70) 7 (23.33) 0.765 0.705
 Psychiatric disorders 5 (4.46) 2 (4.16) 2 (8.90) 1 (3.34) 0.928 0.808
Motor signs
 Parkinsonism 112 (100) 48 (100) 34 (100) 30 (100) - 0.474
  Parkinsonism at onset 62 (55.36) 28 (58.34) 16 (47.05) 19 (63.34) 0.679 0.052
  Appearance of parkinsonism within 3 years 98 (87.50) 48 (100) 31 (91.17) 30 (100) 0.053 0.011*
  Akinetic-rigid, predominantly axial, and levodopa resistant parkinsonism 56 (50.00) 24 (85.68) 13 (41.90) 14 (53.67) 0.025* -
  Parkinsonism, with tremor and/or asymmetric and/or levodopa responsive 34 (30.35) 4 (11.76) 18 (52.92) 12 (35.29) 0.025* -
  UPDRS-III 40.81 ± 15.61 40.22 ± 14.52 43.97 ± 16.30 37.80 ± 16.31 0.691 0.221
  PIGD form 101 (90.17) 44 (93.68) 31 (91.17) 26 (86.67) 0.081 0.031*
  Tremor dominant form 1 (0.89) 0 (0.00) 0 (0.00) 1 (3.33) 0.081 0.031*
  Intermediate 9 (8.04) 3 (6.40) 3 (8.82) 3 (10.00) 0.081 0.031*
 Tremor 45 (40.18) 17 (36.17) 13 (38.23) 15 (50.00) 0.384 0.027*
  Tremor at onset 15 (13.39) 4 (8.51) 5 (14.70) 6 (20.00) 0.255 0.022*
  Occurrence of tremor within 3 years 39 (34.82) 15 (31.90) 11 (32.35) 13 (43.33) 0.415 0.034*
 Falls 94 (83.92) 41 (87.23) 27 (79.41) 26 (86.67) 0.557 0.068
  Repeated unprovoked falls at onset 44 (39.28) 18 (38.30) 14 (41.17) 12 (40.00) 0.704 0.056
  Occurrence of repeated unprovoked falls within 3 years 83 (74.10) 37 (78.70) 23 (67.64) 23 (76.67) 0.568 0.038*
 Freezing of gait 19 (16.96) 8 (17.02) 4 (11.76) 7 (23.34) 0.686 0.053
  Freezing of gait at onset 4 (3.57) 2 (4.26) 0 (0.00) 2 (6.67) 0.796 0.047*
  Occurrence of freezing of gait within 3 years 12 (10.71) 6 (12.70) 2 (5.88) 4 (16.67) 0.645 0.031*
 Oculomotor signs vertical supranuclear gaze palsy 109 (97.32) 48 (100) 34 (100) 27 (90.00) 0.705 0.052
  Vertical supranuclear gaze palsy (O1) within 3 years 86 (76.78) 38 (79.16) 27 (79.41) 21 (70.00) 0.704 0.729
  Slow velocity of vertical saccades and frequent macro square wave jerks or eyelid opening apraxia (O2 and O3) within 3 years 23 (20.53) 10 (20.83) 7 (20.58) 6 (20.00) 0.395 0.485
 Dysphagia 72 (64.28) 30 (62.50) 26 (76.47) 15 (50.00) 0.295 0.450
  Swallowing problem at onset 4 (3.57) 2 (4.26) 1 (2.94) 1 (3.34) 0.780 0.750
  Occurrence of swallowing problem within 3 years 47 (41.97) 21 (43.75) 20 (58.82) 9 (30.00) 0.575 0.583
 Spastic dysarthria 67 (59.82) 23 (47.91) 25 (73.52) 18 (60.00) 0.453 0.539
  Spastic dysarthria at onset 12 (10.71) 6 (12.50) 4 (11.76) 2 (6.67) 0.407 0.548
  Occurrence of spastic dysarthria within 3 years 44 (39.28) 15 (31.25) 20 (58.82) 9 (30.00) 0.969 0.812
Other motor disorders
 Dystonia 68 (60.71) 23 (48.91) 25 (73.52) 18 (60.00) 0.435 0.580
 Myoclonic jerk 19 (16.96) 6 (12.70) 10 (29.41) 3 (10.00) 0.705 0.730
 Cerebellar syndrome 4 (3.57) 0 (0.00) 0 (0.00) 4 (13.34) 0.068 0.075
 Pyramidal signs 43 (38.39) 15 (31.25) 15(44.12) 13 (43.34) 0.300 0.488

Values are presented as mean ± standard deviation or n (%).

p value1; is the result of comparison of each variable included in the table between the three subgroups (PSP-RS, PSP-subcortical, and PSP-cortical).

p value2; is the result of comparison of each variable included in the table between the three subgroups taking into account the status of APOE ε4 (carrier or not-carriers).

* p value < 0.05.

PSP, progressive supranuclear palsy; PSP-RS, progressive supranuclear palsy-Richardson; PSP-cortical, progressive supranuclear palsy-cortical; PSP-subcortical, progressive supranuclear palsy-subcortical; UPDRS, Unified Parkinson’s disease Rating Scale; PIGD, postural instability and gait difficulties.

Table 2.
Neuropsychological characteristics of total study cohort and across PSP subgroups
Variables Total cohort (n = 112) Typical form
Atypical forms
p value1 p value2
PSP-RS (n = 48) PSP-cortical (n = 34) PSP-subcortical (n = 30)
Global cognitive status
 Mini-Mental State Examination (MMSE) 21.63 ± 6.83 20.46 ± 7.83 20.38 ± 6.35 24.73 ± 4.39 0.018 0.022
 Cognitive impairment (CI)* 98 (87.50) 40 (83.34) 31 (100) 27 (90.00) 0.091 0.013
 Mild CI* 30 (26.78) 6 (12.50) 13 (38.24) 11 (36.67) 0.017 0.061
 Moderate CI* 21 (18.75) 11 (22.92) 7 (20.59) 3 (10.00) 0.017 0.061
 Severe CI* 17 (15.17) 7 (14.58) 9 (26.47) 1 (3.34) 0.017 0.061
 Dementia 51 (45.53) 20 (41.67) 23 (67.65) 8 (26.67) < 0.001 0.031
Memory 93 (83.04) 39 (81.25) 31 (91.17) 23 (76.67) 0.003 0.025
 Onset 17 (15.17) 7 (14.59) 8 (23.53) 2 (7.67) 0.195 0.019
 Early 69 (61.60) 31 (64.59) 23 (67.65) 15 (50.00) 0.197 0.008
 Hippocampal profile 40 (35.71) 16 (33.34) 15 (44.12) 9 (30.00) 0.522 0.049
 Immediate recall 21.83 ± 13.80 13.54 ± 10.04 19.92 ± 12.35 28.53 ± 13.30 0.001 0.019
 Delayed recall 7.10 ± 4.75 5.08 ± 4.27 6.22 ± 5.45 9.12 ± 4.11 0.016 0.217
Attention 87 (77.68) 39 (81.25) 27 (79.42) 21 (70.00) 0.002 0.029
Executive impairment 80 (71.43) 35 (72.91) 29 (85.29) 16 (53.33) 0.001 0.031
 Frontal Assessment Battery (FAB) 10.27 ± 5.07 9.38 ± 5.22 8.78 ± 4.34 13.12 ± 4.40 < 0.001 0.026
 Similarities 36 (32.14) 18 (37.50) 12 (35.29) 6 (20.00) 0.007 0.041
 Lexical fluency 61 (54.46) 30 (62.50) 17 (50.00) 14 (46.67) 0.024 0.063
 Motor series (Luria test) 49 (43.75) 26 (54.16) 15 (44.12) 8 (26.67) < 0.001 0.022
 Conflicting instruction 55 (49.11) 28 (58.34) 16 (47.05) 11 (36.67) 0.005 0.051
 Go-No Go 59 (52.68) 32 (66.67) 17 (50.00) 10 (33.34) < 0.001 0.009
 Prehension behavioral 1 (0.89) 0 (0.00) 1 (2.94) 0 (0.00) 0.971 0.225
 Frontal cognitive/behavioral presentation 42 (50.00) 19 (67.90) 18 (52.94) 5 (20.00) 0.001
Apraxia (Ideational, ideomotor, limb-kinetic apraxia) 69 (61.61) 30 (62.50) 27 (79.41) 12 (40.00) < 0.001 0.001
Visual agnosia 4 (3.57) 0 (0.00) 4 (11.76) 0 (0.00) 0.030 0.062
Prosopagnosia 7 (6.25) 0 (0.00) 6 (17.64) 1 (3.34) 0.005 0.061
Judgment 22 (19.64) 20 (41.67) 16 (47.05) 4 (13.34) < 0.001 0.051
Reasoning 41 (36.61) 21 (41.75) 15 (44.12) 5 (16.67) < 0.001 0.037
Visuospatial dysfunction 53 (47.32) 21 (41.75) 21 (61.76) 11 (36.67) 0.005 0.163
Language 74 (66.07) 31 (64.59) 29 (85.29) 14 (46.67) 0.009 0.025
 Non fluent/agrammatic variant of primary progressive aphasia or progressive apraxia of speech 23 (20.53) 7 (25.00) 14 (41.17) 2 (8.00) 0.008
 Language impairment at onset 13 (11.61) 4 (8.34) 7 (20.58) 2 (6.67) 0.680 0.051
 Early language impairment 54 (48.21) 24 (50.00) 21 (61.76) 9 (30.00) 0.511 0.003
Mood and behavior (NPI) 67 (42.22) 25 (52.09) 23 (67.64) 19 (63.34) 0.534 0.038
 At onset 26 (23.21) 7 (14.59) 13 (38.23) 6 (20.00) 0.033 0.043
 Early 57 (50.89) 22 (45.84) 19 (55.89) 16 (53.34) 0.740 0.037
 Delirium 21 (18.75) 10 (20.84) 6 (17.65) 5 (16.67) 0.819 0.075
 Visual hallucinations 16 (14.29) 6 (12.50) 9 (26.47) 1 (3.34) 0.073 0.072
 Agitation 16 (14.29) 6 (12.50) 6 (17.64) 4 (13.34) 0.577 0.095
 Anxiety 31 (27.68) 16 (33.34) 9 (26.47) 6 (20.00) 0.854 0.091
 Apathy 33 (29.46) 11 (22.92) 12 (35.29) 10 (33.34) 0.515 0.065
 Disinhibition 22 (19.64) 8 (16.67) 9 (26.47) 5 (16.67) 0.375 0.145
 Aberrant motor behavior 12 (10.71) 5 (10.41) 6 (17.64) 1 (3.34) 0.017 0.217
 Appetite 20 (17.86) 5 (10.41) 7 (20.59) 8 (26.67) 0.454 0.084
 Sleep 61 (54.46) 24 (50.00) 21 (61.76) 16 (53.34) 0.344 0.115
 Depression 63 (56.25) 25 (52.09) 21 (61.76) 17 (56.67) 0.411 0.157
 Euphoria 2 (1.79) 0 (0.00) 2 (5.88) 0 (0.00) 0.126 0.216
 Irritability 38 (33.93) 9 (18.75) 17 (50.00) 12 (40.00) 0.015 0.200
Mood disorder
 Geriatric Depression Scale (GDS) 13.85 ± 6.50 12.35 ± 6.54 12.82 ± 4.91 19.14 ± 5.49 0.093 0.209
 Beck’s Depression Inventory (BDI) 19.86 ± 8.62 - 24.85 ± 6.50 16.75 ± 9.11 0.129 0.433

p value1; is the result of calculation of each variable included in the table between the three subgroups (PSP-RS, PSP-subcortical, and PSP-cortical).

p value2; is the result of calculation of each variable included in the table between the 3 subgroups taking into account the status of APOE ε4 (carrier or not-carriers).

* stratification according to MMSE score;

p value < 0.05.

PSP, progressive supranuclear palsy; PSP-RS, progressive supranuclear palsy-Richardson; PSP-cortical, progressive supranuclear palsy-cortical; PSP-subcortical, progressive supranuclear palsy-subcortical; NPI, neuropsychiatric Inventory.

Table 3.
APOE allele and genotype distribution across PSP subgroups
APOE genotypes Total cohort (n = 95) Typical PSP
Atypical PSP
p value OR (95% CI)
PSP-RS (n = 42) Cortical–PSP (n = 30) Subcortical-PSP (n = 23)
Non-ɛ4* 51 (53.68) 18 (42.85) 17 (56.67) 15 (65.21) 0.025 0.62 (0.45–0.86)
ɛ4 44 (46.31) 24 (57.15) 13 (43.34) 8 (34.78)
ɛ3/ɛ3 42 (44.21) 14 (33.34) 15 (50.00) 13 (56.52) 0.055 -
ɛ3/ɛ4 38 (40.00) 20 (47.61) 10 (33.34) 8 (34.78)
ɛ4/ɛ4 6 (6.31) 4 (9.72) 3 (10.00) 0 (0.00)
ɛ3/ɛ2 9 (9.45) 4 (9.72) 2 (6.67) 2 (8.69)

Values are presented as n (%).

* non-ɛ4 group including cases carriers of ɛ3/ɛ3 and ɛ3/ɛ2 genotypes;

ɛ4 group including cases carriers of ɛ3/ɛ4 and ɛ4/ɛ4 genotypes;

p value < 0.05.

APOE, Apolipoprotein E; PSP, progressive supranuclear palsy; PSP-RS, progressive supranuclear palsy-Richardson’s syndrome; OR, odds ratio; CI, confidence interval.

Table 4.
Distribution of PSP phenotypes and main findings for previous studies using the MDS 2017 criteria
Study Country Phenotypes of PSP
Main findings
Gültekın, 2017 [43] Turkey 7 (38.8) 3 (16.7) 0 (0.0) 4 (22.3) 0 (0.0) 0 (0.0) 0 (0.0) 2 (11.2) 2 (11.2) 0 (0.0) 18 Five different subtypes had predominant characteristics. PSP- RS was found to be the most common subtype.
Pellicano et al., 2017 [44] Italy 14 (56.0) 11 (44.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 25 Early phonological verbal fluency deficit identifies patients with PSP-RS whereas apathy supports the diagnosis of PSP-P
Picillo et al., 2019 [19] Italy 23 (46.9) 11 (22.4) 0 (0.0) 4 (8.2) 7 (14.3) 0 (0.0) 0 (0.0) 4 (8.2) 0 (0.0) 0 (0.0) 49 PSP-RS and PSP-CBS presented a similar burden of disease. The only cognitive testing differentiating the phenotypes were semantic fluency and ideomotor apraxia. The majority of cohort was either affected by dementia or presented normal cognition. PSP-RS presented the highest rate of dementia. The only marker of PSP non-RS phenotype was better performance in visuo-spatial testing, implying worse visuo-spatial abilities in PSP-RS
Whitwell et al., 2019 [45] United State 6 (27.3) 15 (68.2) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (4.5) 0 (0.0) 0 (0.0) 22 Symptoms typical of PSP commonly develop in patients presenting with a progressive speech/language disorder. Older age appears to be an important prognostic factor.
Jabbari et al., 2020 [16] United Kingdom 52 (51.5) 13 (12.8) 0 (0.0) 6 (5.9) 19 (18.8) 1 (0.9) 0 (0.0) 10 (9.9) 0 (0.0) 0 (0.0) 101 The PSP-subcortical group was distinguished from PSP-cortical and PSP-RS groups by cortical volumetric magnetic resonance imaging measures. Cognitive profile, serum NF-L level, and TRIM11rs564309 genotype. Midbrain atrophy was a common feature of all PSP groups.
Chaithra et al., 2020 [30] India 53 (76.8) 16 (23.2) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 69 The most prevalent non-motor symptoms (NMSs) in patients with PSP were in the domains of sleep/fatigue, mood/cognition, and sexual function. The least prevalent NMSs were in the domains of cardiovascular including falls, and perceptual problems/hallucinations. Patients with PSP-RS reported a higher severity of drooling, altered smell/taste, depression and a higher prevalence of sexual dysfunction.
Mahale et al., 2021 [24] India 241 (72.1) 45 (13.5) 2 (0.6) 14 (4.2) 17 (5.1) 0 (0.0) 0 (0.0) 14 (4.2) 1 (0.3) 0 (0.0) 334 PSP-RS was the commonest and PSP-OM was the rarest. PSP-P had a better prognosis than all other subtypes of PSP
Guasp et al., 2021 [18] Spain 15 (36.6) 13 (31.7) 3 (7.3) 4 (9.7) 5 (12.2) 0 (0.0) 0 (0.0) 0 (0.0) 1 (2.4) 0 (0.0) 41 PSP-subcortical phenotypes appear to have longer survival than PSP-RS and cortical phenotypes.
Picillo et al., 2021 [46] Italy 10 (52.6) 5 (26.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 4 (21.1) 0 (0.0) 0 (0.0) 19 PSP-RS presented worse cognitive functions. PSP-RS presents greater gait dynamic instability since the earliest stages than other phenotypes.
Current Study Tunisia 48 (42.8) 13 (11.6) 9 (8.0) 10 (8.9) 17 (15.2) 3 (2.7) 7 (6.2) 2 (1.8) 1 (0.9) 2 (1.8) 112 Later disease onset and akinetic-rigid and levodopa resistant parkinsonism were the hallmarks of PSP-RS. Milder cognitive impairment was characteristic of PSP-subcortical subgroup. APOEε4 allele may had an influence on PSP clinical features.

Values are presented as n or n (%).

PSP, progressive supranuclear palsy; MDS, Movement Disorder Society; RS, PSP with Richardson’s syndrome; P, PSP with predominant parkinsonism; PI, PSP with predominant postural instability; F, PSP with predominant frontal presentation; CBS, PSP with predominant corticobasal syndrome; OM, PSP with predominant ocular motor dysfunction; SL, PSP with predominant speech/language disorder; PGF, PSP with progressive gait freezing; PSL, PSP with primary lateral sclerosis; C, PSP with cerebellar ataxia.

  • 1. Litvan I, Agid Y, Calne D, Campbell G, Dubois B, Duvoisin RC, et al. Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP international workshop. Neurology 1996;47:1–9.ArticlePubMed
  • 2. Gerstenecker A, Mast B, Duff K, Ferman TJ, Litvan I; ENGENE-PSP Study Group. Executive dysfunction is the primary cognitive impairment in progressive supranuclear palsy. Arch Clin Neuropsychol 2013;28:104–113.ArticlePubMed
  • 3. Höglinger GU, Respondek G, Stamelou M, Kurz C, Josephs KA, Lang AE, et al. Clinical diagnosis of progressive supranuclear palsy: the movement disorder society criteria. Mov Disord 2017;32:853–864.PMC
  • 4. Dickson DW, Ahmed Z, Algom AA, Tsuboi Y, Josephs KA. Neuropathology of variants of progressive supranuclear palsy. Curr Opin Neurol 2010;23:394–400.ArticlePubMed
  • 5. Stamelou M, Respondek G, Giagkou N, Whitwell JL, Kovacs GG, Höglinger GU. Evolving concepts in progressive supranuclear palsy and other 4-repeat tauopathies. Nat Rev Neurol 2021;17:601–620.ArticlePubMedPDF
  • 6. Mayeux R, Saunders AM, Shea S, Mirra S, Evans D, Roses AD, et al. Utility of the apolipoprotein E genotype in the diagnosis of Alzheimer’s disease. N Engl J Med 1998;338:506–511.ArticlePubMed
  • 7. Nasri A, Ben Djebara M, Sghaier I, Mrabet S, Zidi S, Gargouri A, et al. Atypical parkinsonian syndromes in a North African tertiary referral center. Brain Behav 2021;11:e01924.ArticlePubMedPDF
  • 8. Jankovic J, McDermott M, Carter J, Gauthier S, Goetz C, Golbe L, et al. Variable expression of Parkinson’s disease: a base-line analysis of the DATATOP cohort. Neurology 1990;40:1529–1534.ArticlePubMed
  • 9. Ben Jemaa S, Attia Romdhane N, Bahri-Mrabet A, Jendli A, Le Gall D, Bellaj T. An Arabic version of the cognitive subscale of the Alzheimer’s disease assessment scale (ADAS-Cog): reliability, validity, and normative data. J Alzheimers Dis 2017;60:11–21.ArticlePubMed
  • 10. Dubois B, Slachevsky A, Litvan I, Pillon B. The FAB: a frontal assessment battery at bedside. Neurology 2000;55:1621–1626.ArticlePubMed
  • 11. Grober E, Buschke H. Genuine memory deficits in dementia. Dev Neuropsychol 1987;3:13–36.Article
  • 12. Nespoulous JL. [Protocole Montréal-Toulouse d’examen linguistique de l’aphasie MT 86: Module standard initial: M 1 ß]. Isbergues: Ortho Édition; 1992:French.
  • 13. Upton J. Beck depression inventory (BDI). In: Gellman MD, Turner JR, editors. Encyclopedia of behavioral medicine. New York: Springer; 2013:178–179.
  • 14. Yesavage JA, Brink TL, Rose TL, Lum O, Huang V, Adey M, et al. Development and validation of a geriatric depression screening scale: a preliminary report. J Psychiatr Res 1982;17:37–49.ArticlePubMed
  • 15. Grimm MJ, Respondek G, Stamelou M, Arzberger T, Ferguson L, Gelpi E, et al. How to apply the movement disorder society criteria for diagnosis of progressive supranuclear palsy. Mov Disord 2019;34:1228–1232.ArticlePubMedPMCPDF
  • 16. Jabbari E, Holland N, Chelban V, Jones PS, Lamb R, Rawlinson C, et al. Diagnosis across the spectrum of progressive supranuclear palsy and corticobasal syndrome. JAMA Neurol 2020;77:377–387.PubMed
  • 17. Jabbari E, Woodside J, Tan MMX, Pavese N, Bandmann O, Ghosh BCP, et al. The genetic and clinico-pathological profile of early-onset progressive supranuclear palsy. Mov Disord 2019;34:1307–1314.ArticlePubMedPMCPDF
  • 18. Guasp M, Molina-Porcel L, Painous C, Caballol N, Camara A, Perez-Soriano A, et al. Association of PSP phenotypes with survival: a brain-bank study. Parkinsonism Relat Disord 2021;84:77–81.ArticlePubMed
  • 19. Picillo M, Cuoco S, Tepedino MF, Cappiello A, Volpe G, Erro R, et al. Motor, cognitive and behavioral differences in MDS PSP phenotypes. J Neurol 2019;266:1727–1735.ArticlePubMedPDF
  • 20. Nasri A, Sghaier I, Gharbi A, Mrabet S, Ben Djebara M, Gargouri A, et al. Role of apolipoprotein E in the clinical profile of atypical parkinsonian syndromes. Alzheimer Dis Assoc Disord 2022;36:36–43.ArticlePubMed
  • 21. Respondek G, Stamelou M, Kurz C, Ferguson LW, Rajput A, Chiu WZ, et al. The phenotypic spectrum of progressive supranuclear palsy: a retrospective multicenter study of 100 definite cases. Mov Disord 2014;29:1758–1766.ArticlePubMedPDF
  • 22. Williams DR, de Silva R, Paviour DC, Pittman A, Watt HC, Kilford L, et al. Characteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson’s syndrome and PSPparkinsonism. Brain 2005;128(Pt 6):1247–1258.ArticlePubMed
  • 23. O’Sullivan SS, Massey LA, Williams DR, Silveira-Moriyama L, Kempster PA, Holton JL, et al. Clinical outcomes of progressive supranuclear palsy and multiple system atrophy. Brain 2008;131(Pt 5):1362–1372.ArticlePubMed
  • 24. Mahale RR, Krishnan S, Divya KP, Jisha VT, Kishore A. Subtypes of PSP and prognosis: a retrospective analysis. Ann Indian Acad Neurol 2021;24:56–62.ArticlePubMedPMC
  • 25. Brown RG, Lacomblez L, Landwehrmeyer BG, Bak T, Uttner I, Dubois B, et al. Cognitive impairment in patients with multiple system atrophy and progressive supranuclear palsy. Brain 2010;133(Pt 8):2382–2393.ArticlePubMed
  • 26. Gerstenecker A. The neuropsychology (broadly conceived) of multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration. Arch Clin Neuropsychol 2017;32:861–875.ArticlePubMed
  • 27. Kovacs GG, Lukic MJ, Irwin DJ, Arzberger T, Respondek G, Lee EB, et al. Distribution patterns of tau pathology in progressive supranuclear palsy. Acta Neuropathol 2020;140:99–119.ArticlePubMedPDF
  • 28. Nogami A, Yamazaki M, Saito Y, Hatsuta H, Sakiyama Y, Takao M, et al. Early stage of progressive supranuclear palsy: a neuropathological study of 324 consecutive autopsy cases. J Nippon Med Sch 2015;82:266–273.ArticlePubMed
  • 29. Jabbari E, Holland N, Chelban V, Jones PS, Lamb R, Rawlinson C, et al. Diagnosis across the spectrum of progressive supranuclear palsy and corticobasal syndrome. JAMA Neurol 2020;77:377–387.PubMed
  • 30. Chaithra SP, Prasad S, Holla VV, Stezin A, Kamble N, Yadav R, et al. The non-motor symptom profile of progressive supranuclear palsy. J Mov Disord 2020;13:118–126.ArticlePubMedPMCPDF
  • 31. Cho H, Choi JY, Hwang MS, Lee JH, Kim YJ, Lee HM, et al. Tau PET in Alzheimer disease and mild cognitive impairment. Neurology 2016;87:375–383.ArticlePubMed
  • 32. Liu CC, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 2013;9:106–118.ArticlePubMedPMCPDF
  • 33. Riddell DR, Zhou H, Atchison K, Warwick HK, Atkinson PJ, Jefferson J, et al. Impact of apolipoprotein E (ApoE) polymorphism on brain ApoE levels. J Neurosci 2008;28:11445–11453.ArticlePubMedPMC
  • 34. Brecht WJ, Harris FM, Chang S, Tesseur I, Yu GQ, Xu Q, et al. Neuronspecific apolipoprotein E4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice. J Neurosci 2004;24:2527–2534.ArticlePubMedPMC
  • 35. Deming Y, Li Z, Kapoor M, Harari O, Del-Aguila JL, Black K, et al. Genome-wide association study identifies four novel loci associated with Alzheimer’s endophenotypes and disease modifiers. Acta Neuropathol 2017;133:839–856.ArticlePubMedPMCPDF
  • 36. Li YJ, Hauser MA, Scott WK, Martin ER, Booze MW, Qin XJ, et al. Apolipoprotein E controls the risk and age at onset of Parkinson disease. Neurology 2004;62:2005–2009.ArticlePubMed
  • 37. Zareparsi S, Camicioli R, Sexton G, Bird T, Swanson P, Kaye J, et al. Age at onset of Parkinson disease and apolipoprotein E genotypes. Am J Med Genet 2002;107:156–161.ArticlePubMed
  • 38. Rawle MJ, Davis D, Bendayan R, Wong A, Kuh D, Richards M. Apolipoprotein-E (Apoe) ε4 and cognitive decline over the adult life course. Transl Psychiatry 2018;8:18.ArticlePMCPDF
  • 39. Emrani S, Arain HA, DeMarshall C, Nuriel T. APOE4 is associated with cognitive and pathological heterogeneity in patients with Alzheimer’s disease: a systematic review. Alzheimers Res Ther 2020;12:141.ArticlePubMedPDF
  • 40. Stevens M, van Duijn CM, de Knijff P, van Broeckhoven C, Heutink P, Oostra BA, et al. Apolipoprotein E gene and sporadic frontal lobe dementia. Neurology 1997;48:1526–1529.Article
  • 41. Cacabelos R, Rodríguez B, Carrera C, Beyer K, Lao JI, Sellers MA. Behavioral changes associated with different apolipoprotein E genotypes in dementia. Alzheimer Dis Assoc Disord 1997;11(Suppl 4):S27–S34.
  • 42. Parasuraman R, Greenwood PM, Sunderland T. The apolipoprotein E gene, attention, and brain function. Neuropsychology 2002;16:254–274.ArticlePubMedPMC
  • 43. Gültekın M. Phenotypic variants of patients with progressive supranuclear palsy. Noro Psikiyatr Ars 2017;57:61–64.PubMedPMC
  • 44. Pellicano C, Assogna F, Cellupica N, Piras F, Pierantozzi M, Stefani A, et al. Neuropsychiatric and cognitive profile of early Richardson’s syndrome, progressive supranuclear palsy-parkinsonism and Parkinson’s disease. Parkinsonism Relat Disord 2017;45:50–56.ArticlePubMed
  • 45. Whitwell JL, Stevens CA, Duffy JR, Clark HM, Machulda MM, Strand EA, et al. An evaluation of the progressive supranuclear palsy speech/language variant. Mov Disord Clin Pract 2019;6:452–461.ArticlePubMedPMCPDF
  • 46. Picillo M, Ricciardi C, Tepedino MF, Abate F, Cuoco S, Carotenuto I, et al. Gait analysis in progressive supranuclear palsy phenotypes. Front Neurol 2021;12:674495.ArticlePubMedPMC

Figure & Data



    Citations to this article as recorded by  

      Comments on this article

      Add a comment

      JMD : Journal of Movement Disorders Twitter