Atypical Progressive Supranuclear Palsy Research Articles

Late-life mood disorder as the initial presentation of progressive supranuclear palsy: A case series.

Progressive supranuclear palsy (PSP) is a rapidly progressive neurodegenerative disorder characterized by Parkinsonism, supranuclear ophthalmoplegia, postural instability, and cognitive impairment. This case series describes three patients initially diagnosed with late-life mood disorders (depression and bipolar disorder) who were later diagnosed with PSP because of the development of typical neurological symptoms. The diagnostic challenge of PSP is highlighted in this case report, particularly in the early stages, when characteristic symptoms may not be present. The importance of considering PSP in the differential diagnosis of late-life mood disorders, especially in the absence of response to standard antidepressant therapy, is also emphasized. The heterogeneity of PSP is described, with various subtypes and atypical variants presenting with different clinical features. The psychiatric symptoms of PSP include apathy, disinhibition, depression, and anxiety, whereas hallucinations and delusions are less frequent. Tau positron emission tomography imaging is discussed as a potential biomarker for atypical PSP. Early diagnosis and intervention are crucial for improved outcomes in PSP, necessitating further research to enhance the diagnostic and treatment strategies for PSP and other neurodegenerative diseases.

Rainwater Charitable Foundation criteria for the neuropathologic diagnosis of progressive supranuclear palsy

Neuropathologic criteria for progressive supranuclear palsy (PSP) proposed by a National Institute of Neurological Disorders and Stroke (NINDS) working group were published in 1994 and based on the presence of neurofibrillary tangles in basal ganglia and brainstem. These criteria did not stipulate detection methods or incorporate glial tau pathology. In this study, a group of 14 expert neuropathologists scored digital slides from 10 brain regions stained with hematoxylin and eosin (H&E) and phosphorylated tau (AT8) immunohistochemistry. The cases included 15 typical and atypical PSP cases and 10 other tauopathies. Blinded to clinical and neuropathological information, raters provided a categorical diagnosis (PSP or not-PSP) based upon provisional criteria that required neurofibrillary tangles or pretangles in two of three regions (substantia nigra, subthalamic nucleus, globus pallidus) and tufted astrocytes in one of two regions (peri-Rolandic cortices, putamen). The criteria showed high sensitivity (0.97) and specificity (0.91), as well as almost perfect inter-rater reliability for diagnosing PSP and differentiating it from other tauopathies (Fleiss kappa 0.826). Most cases (17/25) had 100% agreement across all 14 raters. The Rainwater Charitable Foundation criteria for the neuropathologic diagnosis of PSP feature a simplified diagnostic algorithm based on phosphorylated tau immunohistochemistry and incorporate tufted astrocytes as an essential diagnostic feature.

Four-repeat tauopathies and late-onset psychiatric disorders: Etiological relevance or incidental findings?

Argyrophilic grain disease (AGD), progressive supranuclear palsy (PSP) and corticobasal degeneration are four-repeat (4R) tauopathies that develop in the presenium or later. Whether these diseases are associated with the occurrence of late-onset psychiatric disorders remains unclear. To facilitate the accumulation of clinicopathological findings regarding this issue, we here present a selected series of 11 cases that clinically developed psychotic disorder (n=7; age at onset: 41-75 years), depressive disorder (n=1; 49 years), bipolar disorder (n=2; 32 and 37 years) and somatoform disorder (n=1; 88 years), and had at least one pathological hallmark of these tauopathies. The mean age at death was 74.3 years. No case showed dementia, at least in the early stage of the course. Nine cases had AGD. Granular fuzzy astrocytes in the amygdala were noted in all AGD cases and one non-AGD case. Two AGD cases had tufted astrocytes (TAs) in the amygdala but not in the frontal cortex and striatum. Three AGD and two non-AGD cases had TAs in the frontal cortex and/or striatum but not in the amygdala. One AGD case had a small number of astrocytic plaques in the frontal cortex, striatum and globus pallidus. Only one case was diagnosed as atypical PSP according to the NINDS-PSP neuropathological criteria. No case had high-level Alzheimer's disease pathology, Lewy body disease or limbic-predominant age-related TDP-43 encephalopathy. Two cases had mild neuronal loss in the hippocampus and substantia nigra, respectively. Clinicopathological studies focusing especially on early changes of 4R tauopathies, as well as the development of surrogate markers of these diseases, may be necessary for better understanding of the pathogenic backgrounds of late-onset psychiatric disorders.

Association of Tripartite Motif Containing 11 rs564309 With Tau Pathology in Progressive Supranuclear Palsy.

Intronic variant rs564309 in tripartite motif containing 11 (TRIM11) is associated with clinical phenotypic differences in progressive supranuclear palsy (PSP), whereby the minor allele (A) is more common in atypical PSP than typical PSP (PSP-Richardson's syndrome). However, rs564309 has not been investigated relative to neuropathological outcomes. Evaluate the association of rs564309 with the neuropathologically assessed severity of tau pathology, as measured by semi-quantitative scores for neurofibrillary tangles, tufted astrocytes, neuropil threads, and oligodendroglial coiled bodies. 797 neuropathologically confirmed PSP cases were genotyped for TRIM11 rs564309 and assessed for tau pathology across 20 neuroanatomical regions. Tau pathology measures and age at death were examined for association with TRIM11 rs564309-A using multivariable linear regression models. TRIM11 rs564309-A was associated with increased neurofibrillary tangles pathology (P = 0.050), but was not significantly associated with age at death, neuropil threads, coiled bodies, or tufted astrocytes tau pathology scores. TRIM11 rs564309 may influence burden of neurofibrillary tangles tau pathology in PSP; further study is warranted. © 2020 International Parkinson and Movement Disorder Society.

Incipient progressive supranuclear palsy is more common than expected and may comprise clinicopathological subtypes: a forensic autopsy series.

We investigated 998 serial Japanese forensic autopsy cases (0-101years old, mean age 61.7±21.9), with no case selection, using immunohistochemistry to detect cases with progressive supranuclear palsy (PSP). Twenty-nine cases (mean age 82.3±7.2years, 11 males, 18 females) fulfilled the National Institute of Neuronal Disorders and Stroke (NINDS)-PSP pathological criteria (2.9% of all cases, 4.6% of cases over 60). All had neuronal and glial inclusions in the basal ganglia and brainstem. However, 13 cases had low tau pathology and were categorized as atypical PSP. In addition to PSP pathology, multiple types of astrocytic inclusions and comorbid proteinopathies, particularly a high prevalence of argyrophilic grain disease, were found. All cases had not been diagnosed with PSP and had preserved daily functioning prior to death. However, 14 (48.3%), 11 (37.9%), and 16 (55.2%) cases showed signs of dementia, depressive state, and gait disturbance, respectively. Sixteen accidental death cases (55.2%), including from falls and getting lost, and 11 suicide cases (37.9%) appear to have a relationship with incipient PSP pathology. Cluster analysis using the distribution and amount of 4-repeat-tau pathology classified the cases into three subgroups: Group 1 (10 cases) had typical PSP pathology and seven cases (70.0%) had dementia as the most frequent symptom; Group 2 (7 cases) had significantly higher frequency of gait disorder (6 cases, 85.7%), and less neocortical tau pathology than Group 1; Group 3 (12 cases) had relatively mild PSP pathology and high argyrophilic grain burdens. Granular-shaped astrocytes were the dominant astrocytic inclusion in all cases. We conclude that in forensic cases incipient PSP occurs with a higher prevalence than expected. If these findings can be extrapolated to other population-based cohorts, PSP may be more common than previously thought.

Progressive supranuclear palsy (PSP): Richardson syndrome and other PSP variants.

Phenotypic heterogeneity of progressive supranuclear palsy (PSP) has been increasingly reported in the literature and can be the source of incorrect clinical diagnosis particularly in the early stages of the disease when the classically associated symptoms of early falls and supranuclear gaze palsy may not be apparent. In addition to Richardson syndrome (RS), several atypical clinical phenotypes have been described. Advances in genetic, neuroimaging, and biochemical/molecular technologies contribute to the identification of these clinical subtypes in the context of typical PSP pathological findings. Our goal is to review the phenomenology reported in the literature that is associated with confirmed histopathological changes consistent with a PSP diagnosis and to highlight the clinical spectrum of PSP. A systematic review of the literature in PubMed through July 2015 using MeSH terms and key words related to PSP was conducted. Articles describing PSP classifications, diagnostic criteria, and case reports were reviewed and summarized. Additional PSP phenotypes not seen in recent clinicopathological studies are included. These include primary lateral sclerosis, pallido-nigro-luysian degeneration, axonal dystrophy, and multiple system atrophy in the spectrum of atypical PSP variants beyond the traditionally classified PSP subtypes. This review is intended to help with the diagnostic challenges of atypical PSP variants. We believe that large multicenter clinicopathological studies will help expand our understanding of etiology and specific mechanisms of neurodegeneration and will aid in the appropriate interpretation of outcomes when conducting clinical and basic science research.

Morphological in vivo investigation of two main variants of progressive supranuclear palsy

Progressive supranuclear palsy (PSP) can occur with two main clinical presentations, classified as classical Richardson’s syndrome (PSP-RS) and as PSP-parkinsonism (PSP-P), the most common atypical PSP variant. The differential diagnosis between them is challenging, as well as from idiopathic Parkinson’s disease (PD). Therefore, we studied different neuroimaging markers, using both conventional and unconventional MRI methods to test their value in the diagnostic work up of PSP and PD patients. Ten PSP-RS, 10 PSP-P, 25 PD patients, and 24 healthy controls were studied. Neuroimiging investigations included MRI brainstem region of interest measurements, as well as voxel-based morphometry (VBM) analysis. The pons/midbrain and the MR parkinsonism index allowed to differentiate PSP-RS from PD with high sensitivity (90%, 100%), specificity (96%, 92%), and accuracy (94%, 97%). Only the pons/midbrain was found to distinguish PSP-P from PD, but with a lower diagnostic accuracy (sensitivity = 60%, specificity = 96%, accuracy = 86%). Compared to PSP-RS, PSP-P experienced a different pattern of both gray matter and white matter atrophy on VBM. Compared to PSP-RS, PSP-P experience a relatively less severe atrophy of infratentorial brain. The pons/midbrain looks as a promising measure in the differentiation of individual PSP-P from PD patients.

Atypical Progressive Supranuclear Palsy Manifesting as Pure Akinesia with Gait Freezing: A Pathologically Proven Case (P04.155)

Atypical Progressive Supranuclear Palsy Manifesting as Pure Akinesia with Gait Freezing: A Pathologically Proven Case (P04.155)

Progressive supranuclear palsy: clinicopathological concepts and diagnostic challenges

Progressive supranuclear palsy (PSP) is a clinical syndrome comprising supranuclear palsy, postural instability, and mild dementia. Neuropathologically, PSP is defined by the accumulation of neurofibrillary tangles. Since the first description of PSP in 1963, several distinct clinical syndromes have been described that are associated with PSP; this discovery challenges the traditional clinicopathological definition and complicates diagnosis in the absence of a reliable, disease-specific biomarker. We review the emerging nosology in this field and contrast the clinical and pathological characteristics of the different disease subgroups. These new insights emphasise that the pathological events and processes that lead to the accumulation of phosphorylated tau protein in the brain are best considered as dynamic processes that can develop at different rates, leading to different clinical phenomena. Moreover, for patients for whom the diagnosis is unclear, clinicians must continue to describe accurately the clinical picture of each individual, rather than label them with inaccurate diagnostic categories, such as atypical parkinsonism or PSP mimics. In this way, the development of the clinical features can be informative in assigning less common nosological categories that give clues to the underlying pathology and an understanding of the expected clinical course.

Atypical progressive supranuclear palsy underlying progressive apraxia of speech and nonfluent aphasia

Progressive supranuclear palsy (PSP) is a clinicopathological entity typically presenting as an akinetic rigid syndrome with early falls, axial rigidity, vertical supranuclear gaze palsy and levodopa resistance. Pathological features consist of tau deposition in neuronal and glial cells located mainly in subcortical and brainstem structures. Rare cases with the pathological diagnosis of atypical PSP have been described in which neocortical tau deposition is more widespread than what is usually seen in typical PSP. Progressive nonfluent aphasia (PNFA) is a syndrome characterized by spontaneous nonfluent speech and early preserved comprehension of language. Apraxia of speech (AOS) is a motor speech disorder that may be a feature of PNFA. We report the clinical and pathological findings of four cases that presented with features most consistent with PNFA predominated by AOS. Pathological features in these four cases included the typical features of PSP subcortically and in brainstem structures, but combined with tau-positive neuronal and glial pathology in the neocortex. Comprehensive semiquantitative analyses of tau burden including neurofibrillary tangles and pretangles, coiled bodies, tufted astrocytes and threads were undertaken in the four cases of atypical PSP and compared to 10 cases of typical PSP. Semiquantitative analysis demonstrated that in atypical PSP, the pathology shifts from subcortical grey and brainstem regions, commonly affected in typical PSP, towards neocortical regions. This shift in pathology accounts for the presentation of PNFA and AOS observed in our patients, as well as the lack of classic features of PSP. These cases demonstrate that atypical PSP can present as AOS and PNFA without the classic features of PSP. Supported by grants AG 16574 and AG 07216 from the National Institute on Aging, and the Society for Progressive Supranuclear Palsy brain bank. We extend our appreciation to the patients and families for participating in research on aging and dementia. We appreciate the generous donation of antibodies for our studies from Dr. Peter Davies, Albert Einstein College of Medicine, Bronx, NY. Case 4 has already been published. This study was presented at the 9th International Conference on Alzheimer’s Disease and Related Disorders, July 17–22, 2004 in Philadelphia, Pennsylvania, USA.

Characteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson's syndrome and PSP-parkinsonism

The clinical diagnosis of progressive supranuclear palsy (PSP) relies on the identification of characteristic signs and symptoms. A proportion of pathologically diagnosed cases do not develop these classic features, prove difficult to diagnose during life and are considered as atypical PSP. The aim of this study was to examine the apparent clinical dichotomy between typical and atypical PSP, and to compare the biochemical and genetic characteristics of these groups. In 103 consecutive cases of pathologically confirmed PSP, we have identified two clinical phenotypes by factor analysis which we have named Richardson's syndrome (RS) and PSP-parkinsonism (PSP-P). Cases of RS syndrome made up 54% of all cases, and were characterized by the early onset of postural instability and falls, supranuclear vertical gaze palsy and cognitive dysfunction. A second group of 33 (32%) were characterized by asymmetric onset, tremor, a moderate initial therapeutic response to levodopa and were frequently confused with Parkinson's disease (PSP-P). Fourteen cases (14%) could not be separated according to these criteria. In RS, two-thirds of cases were men, whereas the sex distribution in PSP-P was even. Disease duration in RS was significantly shorter (5.9 versus 9.1 years, P < 0.001) and age at death earlier (72.1 versus 75.5 years, P = 0.01) than in PSP-P. The isoform composition of insoluble tangle-tau isolated from the basal pons also differed significantly. In RS, the mean four-repeat:three-repeat tau ratio was 2.84 and in PSP-P it was 1.63 (P < 0.003). The effect of the H1,H1 PSP susceptibility genotype appeared stronger in RS than in PSP-P (odds ratio 13.2 versus 4.5). The difference in genotype frequencies between the clinical subgroups was not significant. There were no differences in apolipoprotein E genotypes. The classic clinical description of PSP, which includes supranuclear gaze palsy, early falls and dementia, does not adequately describe one-third of cases in this series of pathologically confirmed cases. We propose that PSP-P represents a second discrete clinical phenotype that needs to be clinically distinguished from classical PSP (RS). The different tau isoform deposition in the basal pons suggests that this may ultimately prove to be a discrete nosological entity.

Effects on splicing and protein function of three mutations in codon N296 of tau in vitro

Three Mutations were recently reported in the same codon (N296) in exon 10 of the tau gene. Two of these mutations, N296N and N296H, lead to a clinical syndrome similar to autosomal dominant fronto-temporal dementia with Parkinsonism linked to chromosome 17. In contrast the third mutation, delN296, gives rise to atypical progressive supranuclear palsy in individuals homozygous for the mutation, but in heterozygous individuals this mutation is incompletely penetrant and associated with a phenotype similar to idiopathic Parkinson's disease. Functional assays were employed to determine the effects of these mutations on alternative splicing of exon 10, on microtubule assembly and self-aggregation of recombinant tau protein. We demonstrate that these mutations exhibit a spectrum of potentially pathogenic changes in tau function, and provide insight into the possible cause of the incompletely penetrant phenotype of the delN296 mutation.

Familial atypical progressive supranuclear palsy associated with homozigosity for the delN296 mutation in the tau gene.

Heterozygous missense and splice-site mutations in the tau gene have been previously identified in familial frontotemporal dementia with autosomal dominant inheritance. Here we report a Spanish kindred in which two brothers born from a third-degree consanguineous marriage were both affected with atypical progressive supranuclear palsy. A homozygous deletion at codon 296 (delN296) was identified in one of the affected siblings. Among the heterozygous carriers, two members with probable Parkinson's disease were identified, but none of heterozygotes developed atypical parkinsonism. The delN296 mutation lies in the sequence corresponding to the second tubulin-binding repeat of tau protein and affects one asparagine residue absolutely conserved in other species. This finding indicates that homozygous mutations in the tau gene may also cause hereditary tauopathies.

Longitudinal ocular motor study in corticobasal degeneration and progressive supranuclear palsy.

To evaluate the usefulness of ocular motor information in the early diagnosis of corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). Seven PSP patients, six CBD patients, and three atypical CBD patients were followed longitudinally with repeated electrooculographic (EOG) recordings, at 6-month intervals, to search for features that could confirm or modify the diagnosis. Visually guided saccades and antisaccades were studied. Data from clinical evaluations were independently collected. PSP patients had decreased saccade velocity throughout the disease course. Patients with probable CBD showed preserved saccade velocity but important increased saccade latency ipsilateral to the apraxia side. Similar to patients with PSP, those with atypical CBD features exhibited clinically evident abnormalities of vertical saccades and early slowing of horizontal saccade velocity, but no increase in saccade latency or early square-wave jerks. When clinical "telltale signs" appeared and the clinical diagnosis was reviewed independent of EOG recording, the three patients with atypical CBD features were diagnosed as having PSP although new or overlapping syndromes cannot be excluded. Consecutive EOG recordings help diagnose atypical CBD and PSP disorders earlier.

Possible relation of atypical parkinsonism in the French West Indies with consumption of tropical plants: a case-control study

In Europe and North America, Parkinson's disease is the major form of parkinsonism; less than 4% of cases are progressive supranuclear palsy (PSP) and about 20% are atypical parkinsonism. The distribution of these subgroups is different in the French West Indies. We aimed to define the clinical and demographic specificity of these disorders in Guadeloupe and to investigate a postulated link with consumption of herbal tea and fruits from the Annonaceae family (Annona muricata and Annona squamosa), which contain neurotoxic benzyltetrahydroisoquinoline alkaloids. Between September, 1996, and August, 1998, 87 consecutive patients with parkinsonism were referred to the single neurological department in Guadeloupe. After detailed clinical, neurophysiological, cognitive, and neuroradiological assessment, they were classified by generally accepted criteria as having Parkinson's disease, PSP, or atypical parkinsonism. We compared the amount of tropical fruits and herbal tea consumed by the various parkinsonian subgroups and by frequency-matched controls (patients with benign symptoms and no neurodegenerative disease). Of the 87 patients, 22 had Parkinson's disease, 31 had PSP, 30 had atypical parkinsonism, and four had atypical parkinsonism associated with motor neuron disease, 44 of the patients with PSP or atypical parkinsonism were male. The patients with atypical parkinsonism had symmetrical rigidity and bradykinesia, and no levodopa peak-dose dyskinesias. Patients with PSP differed from those with atypical parkinsonism because they had supranuclear vertical down-gaze palsy, severe gait and balance problems, and frontal-lobe syndrome. 29 patients with PSP reported regular consumption of pawpaw fruit, and 26 drank herbal tea. 30 patients with atypical parkinsonism reported regular consumption of pawpaw fruit, and 24 drank herbal tea. Both of these groups consumed significantly more fruit and herbal tea than patients with Parkinson's disease (fruit: odds ratio 23.6; herbal tea: 28.2); and controls (fruit: 20.7; herbal tea: 6.48). Our study confirms the over-representation of atypical parkinsonism and PSP in patients with parkinsonism in the French West Indies. Chronic exposure to neurotoxic alkaloids could be an important aetiological factor because these compounds induce parkinsonism in animals. A larger epidemiological study, to clarify the link between these fruits with atypical parkinsonism and PSP, is proposed.

Astrocytic plaques and tufts of abnormal fibers do not coexist in corticobasal degeneration and progressive supranuclear palsy.

Corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) are characterized by their unique clinical features and neuronal pathology. Although astrocytic plaques and tufts of abnormal fibers have been suggested to be specific histopathologic markers, recent studies have revealed significant clinicopathologic overlap between CBD and PSP. Based on the distinctive camera lucida profile of astrocytic inclusions on Gallyas-Braak silver staining, we found that astrocytic plaques and tufts of abnormal fibers did not coexist in the same patient among 30 cases of clinically diagnosed CBD, PSP and atypical Parkinson's disease. Using Tau immunohistochemistry it was difficult to verify the absence of tufts of abnormal fibers. A morphometric analysis revealed that the two groups classified by the presence or absence of astrocytic plaques and tufts of abnormal fibers exhibited significant differences in the density of ballooned neurons and neurofibrillary tangles and degeneration of the subcortical nuclei. Assessment using the NINDS neuropathologic criteria revealed that the cases with astrocytic plaques and tufts of abnormal fibers closely correspond to CBD and typical PSP, respectively. In addition, the cases lacking either of these two astrocytic inclusions had atypical PSP according to the NINDS criteria, and were associated with novel tau-positive astrocytes (spiny astrocytes). We thus conclude that astrocytic plaques and tufts of abnormal fibers are highly characteristic structures for CBD and typical PSP, respectively. We emphasize the importance of strict differentiation between different astrocytic inclusions not only for diagnosis, but also for further studies for elucidation of their role in the disease mechanisms of CBD and PSP.

Preliminary NINDS neuropathologic criteria for Steele‐Richardson‐Olszewski syndrome (progressive supranuclear palsy)

We present the preliminary neuropathologic criteria for progressive supranuclear palsy (PSP) as proposed at a workshop held at the National Institutes of Health, Bethesda, MD, April 24 and 25, 1993. The criteria distinguish typical, atypical, and combined PSP. A semiquantitative distribution of neurofibrillary tangles is the basis for the diagnosis of PSP. A high density of neurofibrillary tangles and neuropil threads in the basal ganglia and brain-stem is crucial for the diagnosis of typical PSP. Tau-positive astrocytes or their processes in areas of involvement help to confirm the diagnosis. Atypical cases of PSP are variants in which the severity or distribution of abnormalities deviates from the typical pattern. Criteria excluding the diagnosis of typical and atypical PSP are large or numerous infarcts, marked diffuse or focal atrophy, Lewy bodies, changes diagnostic of Alzheimer's disease, oligodendroglial argyrophilic inclusions, Pick bodies, diffuse spongiosis, and prion protein-positive amyloid plaques. The diagnosis of combined PSP is proposed when other neurologic disorders exist concomitantly with PSP.

Progressive supranuclear palsy with action myoclonus, seizures.

A case of atypical progressive supranuclear palsy is presented that differs from the classical description of the disorder. The patient was a 50 year old woman who had a neurologic disturbance that progressed over eight years and that was studied clinically and pathologically. The case differs from classical progressive supranuclear palsy in that action myoclonus, seizures, and a late eye-movement disorder were present, while rigidity and dementia were relatively absent. An additional difference is that the most prominent pathologic findings were in the midbrain, dentate nuclei, and cerebral cortex. If the case is properly classified, it is unique in its clinical presentation and in the distribution of lesions.