Progressive Supranuclear Palsy: Pathology and Genetics

Abstract

Progressive supranuclear palsy (PSP) is an atypical Parkinsonian disorder associated with progressive axial rigidity, vertical gaze palsy, dysarthria and dysphagia. Neuropathologically, the subthalamic nucleus and brainstem, especially the midbrain tectum and the superior cerebellar peduncle, show atrophy. The substantia nigra shows loss of pigment corresponding to nigrostriatal dopaminergic degeneration. Microscopic findings include neuronal loss, gliosis and neurofibrillary tangles in basal ganglia, diencephalon and brainstem. Characteristic tau pathology is also found in glia. The major genetic risk factor for sporadic PSP is a common variant in the gene encoding microtubule‐associated protein tau (MAPT) and recent studies have suggested that this may result in the altered expression of specific tau protein isoforms. Imaging studies suggest that there may be sensitive and specific means to differentiate PSP from other parkinsonian disorders, but identification of a diagnostic biomarker is still elusive.

INTRODUCTION

Progressive supranuclear palsy (PSP) is an atypical Parkinsonian disorder associated with progressive axial rigidity, vertical gaze palsy, dysarthria and dysphagia that was first described by Steele, Richardson and Olszewski in 1964 (80). A frontal lobe syndrome and subcortical dementia are sometimes observed (8). Atypical cases may present with apraxia of speech (38), corticobasal syndrome (91) or spastic paraparesis (39). Some patients with pathologically confirmed PSP have a parkinsonian syndrome that is difficult to differentiate from idiopathic Parkinson’s disease, at least initially (95). Given these variants in clinical presentation, it is not surprising that the overall diagnostic accuracy rate for PSP is only 70%–75%(37). In a large autopsy series from the “Society for Progressive Supranuclear Palsy” brain bank at the Mayo Clinic, there are slightly more men than women with PSP (M : F—227:195). The average age at death for cases in the brain bank is 75 ± 8 years and the average disease duration is about 7 years. PSP is a sporadic condition, although about 15% of cases have a family history of neurologic disorders, including parkinsonism and dementia. Kindreds with autosomal‐dominantly inherited PSP have also been described (72).

PATHOLOGY

Macroscopic pathology.  The gross examination of the brain in PSP often reveals distinctive features. Most cases have mild frontal atrophy that may involve the pre‐central gyrus, but the overall brain weight (1170 ± 150 g) may be within normal limits. The midbrain, especially the tectum, and to a lesser extent the pons, show atrophy (Figure 1). The third ventricle and aqueduct of Sylvius may be dilated. The substantia nigra shows loss of pigment, while the locus ceruleus is often better preserved. The subthalamic nucleus is smaller than expected and may have a gray discoloration. The superior cerebellar peduncle and the hilus of the cerebellar dentate nucleus are usually atrophic (90) and have a gray discoloration due to myelinated fiber loss (Figure 2).

Figure 1.

Gross appearance of the brain in progressive supranuclear palsy shows mild frontal atrophy (A) with widening of sulcal spaces (arrows); on medial views (B) the most consistent finding is atrophy of the midbrain with flattening of the tectal plate (arrow).

Figure 2.

Gross appearance of the sectioned brain reveals atrophy of the subthalamic nucleus (arrows) in the diencephalon at the level of the mammillothalamic tract (A), loss of pigment in the substantia nigra (arrow) in the midbrain (B), and atrophy of the superior cerebellar peduncle (arrow) in the rostral pons (C).

Microscopic pathology.  Microscopic findings include neuronal loss, gliosis and neurofibrillary tangles (NFTs) affecting basal ganglia, diencephalon and brainstem. The nuclei most affected are the globus pallidus, subthalamic nucleus and substantia nigra. See Table 1 for distribution of pathology. The cerebral cortex is relatively spared, but lesions are common in the peri‐Rolandic region (30). The limbic lobe is preserved in PSP unless there is concurrent argyrophilic grain disease, which occurs in about 20% of cases (85).

Table 1.

Regional distribution of tau pathology by cell type in PSP.

Region		Neurons	Astrocytes	Oligodendroglia
Cortex	Temporal	0.8	0.8	0.2
	Motor	1.8	2.6	2.1
Basal ganglia	Caudate nucleus	2.0	2.7	1.6
	Globus pallidus	2.1	0.8	2.3
Diencephalon	Hypothalamus	2.6	0.2	0.4
	Basal nucleus	2.8	0.4	0.7
	Ventral thalamus	1.9	1.6	2.4
	Subthalamic nucleus	2.6	1.3	2.4
	Thalamic fasciculus		0.04	2.6
Midbrain	Tectum	1.5	2.0	2.4
	Oculomotor nucleus	2.2	0.2	0.6
	Red nucleus	1.9	1.6	2.5
	Substantia nigra	2.4	0.6	1.4
Pons	Locus ceruleus	2.8	0.02	0.2
	Tegmentum	2.0	0.2	1.9
	Base	2.7	0.1	1.0
Medulla	Tegmentum	2.6	0.2	1.5
	Inferior olive	1.7	0.1	1.0
Cerebellum	Dentate nucleus	2.0	0.1	0.8
	White matter		0.03	2.2

Average score of 97 cases of PSP; scored on 0–3 point scale for each region and lesion type; darker shading corresponds to more severely affected region. For neurons both pretangles and NFT are scored together; for astrocytes, tufted astrocytes are scored; and for oligodendroglia, coiled bodies are scored.

The striatum and thalamus often have some degree of neuronal loss and gliosis, especially in the ventral anterior and lateral thalamic nuclei. The basal nucleus of Meynert usually has mild cell loss (82). Affected brainstem regions include the superior colliculus, periaqueductal gray matter, oculomotor nuclei, locus ceruleus, pontine nuclei, pontine tegmentum, vestibular nuclei, medullary tegmentum and inferior olives. Cholinergic nuclei in the brainstem appear to be particularly susceptible (94). The cerebellar dentate nucleus is frequently affected and may show grumose degeneration, a type of neuronal degeneration associated with clusters of degenerating presynaptic terminals around dentate neurons (35). The dentatorubrothalamic pathway consistently shows fiber loss. The cerebellar cortex is preserved, but there may be mild Purkinje cell loss and scattered axonal torpedoes. The spinal cord is often affected, with neuronal inclusions in anterior and posterior horns and the intermediolateral cell column 43, 44).

Silver stains (eg, Gallyas stain) or immunostaining for tau reveal NFTs in residual neurons in the basal ganglia, diencephalon, brainstem and spinal cord (Figure 3). In addition to NFTs, special stains demonstrate argyrophilic, tau‐positive inclusions in both astrocytes and oligodendrocytes. Tufted astrocytes are increasingly recognized as a characteristic feature of PSP (56), where they are commonly found in motor cortex and striatum (51). They differ from astrocytic lesions in other neurodegenerative disorders 45, 46). Oligodendroglial changes appear as argyrophilic and tau‐positive perinuclear fibers (3), so‐called “coiled bodies”(9), and are often accompanied by thread‐like processes in white matter, especially in diencephalon and cerebellar white matter.

Figure 3.

The major histologic lesions in progressive supranuclear palsy (PSP) are visible with tau immunohistochemistry (A,C,E) or silver stain (Gallyas) (B,D,F). Neurofibrillary tangles (A,B) often have a globose appearance. Tufted astrocytes (C,D) are relatively specific for PSP. Oligodendroglial coiled bodies (E,F) are characteristic, but can also be found in other disorders.

Neuroinflammation in PSP.  Neuroinflammation occurs in both PSP and the related tauopathy, corticobasal degeneration (CBD), but there are differences in the distribution of microgliosis that to a large extent parallel the tau pathology (35). Activated microglia are abundant in nuclei that show NFTs and neuronal loss, such as the substantia nigra, subthalamic nucleus and globus pallidus, but they are also prominent in certain fiber tracts (eg, dentatorubrothalamic tract), where there is no significant tau pathology. This suggests that degeneration in PSP is linked to tau pathology in a complicated, and sometimes indirect, way.

Electron microscopy.  NFTs in PSP are composed of straight filaments with a diameter of 15 nm that are composed of tau protein 10, 21, 83) (Figure 4). The abnormal filaments in glial cells are also straight and made of tau 3, 56).

Figure 4.

Electron microscopy of neurofibrillary tangle in progressive supranuclear palsy (A) shows a globose tangled mass of filaments that displaces cytosolic elements. The filaments at higher magnification (B) are mostly straight (bars = 1 µm).

Biochemistry.  Biochemical studies show differences between filamentous tau from Alzheimer’s disease (AD) and that from PSP and CBD (10). In AD, detergent‐insoluble tau migrates as three major bands (68, 64 and 60 kDa) on western blots, while in PSP and CBD it migrates as two major bands (68 and 64 kDa) (Figure 5). The 68 and 64 kDa bands of PSP and CBD comprise hyperphosphorylated tau isoforms with four microtubule‐binding repeats (see below). Their contribution to PSP pathology has been confirmed by immunohistochemistry using specific antibodies (50).

Figure 5.

Western blot of detergent insoluble tau proteins in Alzheimer’s disease (AD), corticobasal degeneration (CBD) and two cases of progressive supranuclear palsy (PSP). Note that PSP and CBD have two prominent bands (arrowheads) at 64‐kDa and 68‐kDa, while AD has three major bands (arrowheads) at 60‐kDa, 64‐kDa and 68‐kDa. There is a minor higher molecular weight species in AD, CBD and PSP, as well as variable lower molecular weight species due to protein degradation.

Studies of neurotransmitters reveal loss of striatal dopamine in PSP, as expected for a Parkinsonian disorder (32), as well as deficits in cholinergic markers and basal forebrain cholinergic neurons, but usually not as marked as in AD 36, 82, 94). Other transmitter systems, such as serotonin and gamma‐aminobutyric acid, are affected less consistently (48).

Differential diagnosis.  The major pathologic processes that are clinically mistaken for PSP include multiple system atrophy (MSA), Lewy body disease (LBD) and CBD (37). Neither MSA nor LBD present differential diagnostic difficulties, as they are associated with alpha‐synuclein‐immunoreactive neuronal and glial lesions rather than tau‐immunoreactive deposits. CBD, on the other hand, can present diagnostic difficulties. Table 2 summarizes differential diagnostic features of PSP, CBD and argyrophilic grain disease.

Table 2.

Differential diagnosis of 4R tauopathies. NFT = neurofibrillary tangle.

Feature	Corticobasal degeneration	Progressive supranuclear palsy	Argyrophilic grain disease
Gross appearance	Circumscribed atrophy, parasagittal superior frontal and parietal gyri	Premotor and frontal atrophy	No atrophy or mild medial temporal atrophy
Cortex	Superficial spongiosis and gliosis, with rarefaction of white matter	Minimal or no histopathology	None
Ballooned neurons	Abundant in affected cortices	None or sparse, limbic lobe	Sparse, limbic lobe
Tau immunoreactive neuronal lesions	Pleomorphic skein‐like inclusions, pretangles, and sparse NFTs	Globose NFTs, pretangles	Pretangles and grains
Threads and thread‐like lesions	Numerous, gray and white matter cortical and striatal	Numerous in diencephalon and brainstem tectum and tegmentum	Minimal, medial temporal lobe
Glial pathology	Astrocytic plaques, coiled bodies	Tufted astrocytes, coiled bodies	Coiled bodies, tau‐positive ramified astrocytes
Subthalamic nucleus	Variable gliosis and pretangles, but minimal neuronal loss	Marked neuronal loss and gliosis with neuronal and glial tau pathology	Minimal or no pathology
Substantia nigra	Marked neuronal loss and gliosis	Marked neuronal loss and gliosis	None
Brainstem	Minimal or no neuronal loss, but pretangles and threads are present in certain nuclei (eg, locus ceruleus)	Variable neuronal loss (eg, red nucleus) and many pretangles and threads	None
Cerebellum	Minimal tau pathology, mostly in dentate nucleus; dentate grumose degeneration is uncommon	Tau pathology in dentate nucleus and white matter; dentate grumose degeneration is common	None

Clinically, both PSP and CBD give rise to extrapyramidal signs similar to Parkinson’s disease, but neither condition is responsive to levodopa therapy. Motor abnormalities in PSP are usually symmetrical, while asymmetry is the hallmark of CBD. Focal cortical signs, such as apraxia and aphasia, are common in CBD, but rare in PSP. Frontal dementia is more common in CBD than in PSP (7).

Pathologically, both PSP and CBD are associated with neuronal and glial filamentous lesions composed of hyperphosphorylated four‐repeat tau protein. The morphologies of the lesions differ (20). In CBD only a minority of the neuronal lesions consists of well‐formed NFTs. Most lesions are pleomorphic filamentous inclusions. Nerve cells can also display diffuse granular cytoplasmic tau immunoreactivity that is non‐argyrophilic, consistent with so‐called “pretangles”. In contrast, globose and argyrophilic NFTs are more common in PSP.

The astrocytic lesions are also different. In CBD the characteristic lesion is the so‐called astrocytic plaque (25), which is characterized by clusters of short and irregular tau‐immunoreactive cell processes around the unstained cell body. In contrast, the tufted astrocyte of PSP has tau‐immunoreactive cell processes that extend to the stained cell body. The most characteristic lesions of CBD are thread‐like tau‐immunoreactive processes in both gray and white matter of cerebrum, diencephalon and rostral brainstem (23). In CBD there are usually only a few oligodendroglial coiled bodies. They are more numerous in PSP, especially in areas vulnerable to thread‐like pathology. Thread‐like processes in PSP have a different distribution from those in CBD, being sparse in cerebrum, but dense in diencephalon and brainstem, as well as in cerebellar white matter (26). Both diseases affect the cerebellar dentate nucleus, with grumose degeneration being much more common in PSP (34) than in CBD (71).

Another characteristic feature of CBD are the swollen, achromatic, or ballooned neurons (71). They correspond to swollen pyramidal cells, in affected cortical areas (eg, superior frontal gyrus), that are immunoreactive for neurofilaments and alpha‐B‐crystallin 22, 42). They are not typical of PSP; however, when present, it is usually in the setting of concurrent argyrophilic grain disease (84).

GENETICS

The tau gene (MAPT).  PSP and CBD are considered non‐familial or sporadic tauopathies, although rare multiplex kindreds have been described. A genetic basis for familial clustering has been demonstrated in a Spanish family with autosomal‐dominant PSP that is linked to chromosome 1q31 72, 73, 97) and in families with causal mutations in the microtubule‐associated protein tau gene (MAPT) (68). In addition, numerous studies have identified common genetic variability in MAPT as a major risk factor for PSP.

MAPT is located on the long arm of chromosome 17 (17q21.1) and consists of a non‐coding exon 0 followed by 14 coding or alternatively spliced exons 1, 68). In humans, MAPT exons 2, 3, 4A, 6, 8 and 10 undergo tissue‐specific and developmentally regulated alternative mRNA splicing. In brain, MAPT exons 4A, 6 and 8 are not usually transcribed; however, alternative splicing of MAPT exons 2, 3 and 10 gives rise to six major tau isoforms composed of 352–441 amino acids 1, 29). Binding to microtubules occurs through the C‐terminal half, where tau contains four imperfect repeats that are encoded by exons 9–12, with alternative mRNA splicing of exon 10 giving rise to classes of tau isoforms with either three (3R) or four (4R) repeats (29). In vitro studies have shown that 4R tau binds more strongly to microtubules than 3R tau (61). The isoform composition in brain is developmentally regulated, with only 3R tau being expressed in fetal brain and similar levels of 3R and 4R tau being found in adult human brain (29). In neurodegenerative disorders, the isoform composition of pathologic tau varies in predictable ways. Neurofibrillary pathology in Alzheimer’s disease is composed of hyperphosphorylated of 3R and 4R tau, while Pick bodies of Pick’s disease contain predominantly hyperphosphorylated 3R tau (10). The family of 4R tauopathies includes PSP and CBD, as well as the age‐related medial temporal lobe tauopathy, argyrophilic grain disease (86).

Frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP‐17) may be associated with mutations in MAPT 33, 66, 77). To date, 39 different pathogenic mutations have been reported in 115 families worldwide (68). In some families, affected individuals have clinical and pathologic features that overlap with those of PSP and CBD 11, 13, 19, 54, 62, 67, 74, 76, 78, 79). At least three MAPT mutations have been shown to cause a pathologically confirmed PSP phenotype: R5L in exon 1, ΔN296 in exon 10 and G303V in exon 10 67, 74, 76, 79).

Before it was known that MAPT mutations lead to neurodegeneration in FTDP‐17, Conrad et al had reported that common genetic variability in MAPT could lead to increased risk for PSP 15, 16). The initial association study was performed with a dinucleotide repeat polymorphism in intron 9 of MAPT, presenting with four polymorphic alleles, two of which, A0 and A3, are common. Significant overrepresentation of the A0 allele was observed in PSP patients compared with controls, a finding replicated in at least four independent PSP populations 6, 31, 53, 59). More recently, it was recognized that MAPT is located in a complex genomic region that is surrounded by three highly homologous low‐copy repeats 17, 81). About 3 million years ago, these low‐copy repeats appear to have induced a 900 kb genetically balanced inversion that resulted in a high degree of linkage disequilibrium in the MAPT genomic region, producing the two extended MAPT haplotypes H1 and H2 (4). The A0 allele of the dinucleotide repeat in intron 9 is inherited as part of the H1 haplotype, resulting in a consistent association of PSP with the extended H1 haplotype in all analyzed Caucasian populations (4). In other populations, for example the Japanese, virtually all individuals are homozygous for the H1 haplotype 16, 24).

The sequence of tau protein is the same on the H1 and H2 backgrounds, suggesting that the association of MAPT with PSP relates to differences in tau expression levels, in alternative mRNA splicing, or in a combination of both. As H1 is common in the general population, it is expected that subtle genetic differences on this haplotype, rather than the haplotype per se, are responsible for the increased PSP risk.

Using high‐density association studies with a panel of H1‐specific tagging single nucleotide polymorphisms (SNPs), it was shown that the PSP risk could be explained in part by one of two major ancestral H1 haplotypes, named H1b by Rademakers et al (69) and H1c by Pittman et al (65). Analyses in young PSP patients localized the H1b/c risk to a 22 kb regulatory region in MAPT intron 0, defined by one SNP (rs242557) located in a highly conserved sequence element (69). In vitro assays of gene expression have indicated that this conserved region is indeed transcriptionally active, with both alleles of rs242557 differentially influencing expression. The functional relevance of the H1b/c haplotype defined by the “A” allele of rs242557 has been confirmed by extensive reporter gene analyses, which have shown that H1b/c increases levels of all MAPT transcripts and, in particular, those encoding 4R tau (55). A recent study focusing on allele‐specific gene expression in H1/H2 heterozygous neuronal cell cultures and post‐mortem human brain tissue has reported that the level of MAPT expression from H1 and H2 was not significantly different, but that about 1.5‐fold more 4R tau‐containing transcripts were expressed from H1 (12). The implication of these genetic studies is that the risk for PSP may be associated with lifelong higher levels of 4R tau expression in the nervous system.

Other genes.  One of the most common genetic causes of Parkinson’s disease is mutations in a gene on chromosome 12, LRRK2 60, 98). While most individuals with LRRK2 mutations have typical Lewy body Parkinson’s disease, there are individuals in some kindreds that have primarily a tau pathology 70, 96, 98). The lesions in these cases bear resemblance to those found in PSP, but they differ in the density and distribution. Consistent with these observations is the fact that mutations have not been found in LRRK2 in a large series of pathologically confirmed PSP (75).

Recently, the genetic basis for a major form of frontotemporal lobar degeneration associated with ubiquitin‐immunoreactive neuronal inclusions has been discovered 5, 18). Progranulin (PRGN), the mutant gene, is located close to MAPT on chromosome 17 5, 18, 27). Interestingly, while the most common clinical presentation of PGRN mutation carriers is frontal lobe dementia with progressive language failure, more than half of the pathologically confirmed cases had Parkinsonism and several cases came to autopsy with an initial clinical diagnosis of PSP (41). The pathology is distinctly different from PSP and is associated with cortical, limbic and striatal degeneration with neuronal cytoplasmic and intranuclear inclusions. NFTs and astrocytic lesions are not detected. To date, no case of PSP has been shown to be associated with a PGRN mutation.

Mixed pathology.  Given the advanced age of many patients with PSP, it is not surprising that they should have some degree of Alzheimer‐type pathology. In most cases this is minor, but rare individuals have sufficient senile plaques and NFTs to warrant a diagnosis of concurrent AD. The risk factors for AD in the setting of PSP are advanced age, female sex and carrier status of apolipoprotein E4 (89).

Lewy bodies are also detected in some cases of PSP, but in a distribution that is similar to that in incidental LBD or Parkinson’s disease. The frequency of Lewy bodies in PSP is about 10%, which is similar to the frequency in normal elderly controls 88, 92).

The environmental risk factors for PSP are unknown (49), but some studies have suggested that hypertension may be more frequent in PSP (28). However, other studies have failed to confirm this association (14). There is also no significant increase in the frequency of arteriosclerotic small vessel disease or lacunar infarcts in PSP compared with controls, which might be expected if hypertension was a risk factor for PSP.

Argyrophilic grain disease, like PSP and CBD, is a 4R tauopathy (86). It is a pathologic process in which tau accumulates in dendrites of pyramidal neurons as grain‐like structures. The lesions are concentrated in the medial temporal lobe. Ballooned neurons in argyrophilic grain disease are found in limbic areas, including the amygdala, entorhinal cortex, cingulate gyrus and claustrum (87). These are areas where ballooned neurons are also detected in PSP and almost all cases of PSP with ballooned neurons have a medial temporal lobe 4R tauopathy similar to argyrophilic grain disease.

Atypical cases.  While dementia occurs in some patients with PSP, it is usually relatively mild and characterized by a subcortical frontal‐executive syndrome, featuring cognitive slowing, poor memory retrieval and poor planning and organization. On the other hand, some patients have prominent cortical signs and features suggestive of a frontal lobe syndrome. The frontal lobe degeneration syndromes include frontal lobe dementia with prominent personality changes (apathy or disinhibition) (8), progressive language failure (progressive aphasia or semantic dementia) (38) and progressive asymmetrical rigidity and apraxia (corticobasal syndrome) (91). Some cases with autopsy‐proven PSP‐type pathology have each of these syndromes. As a general rule, when PSP presents with one of these syndromes, the cortical pathology extends beyond the peri‐Rolandic cortices to frontal, parietal or peri‐Sylvian areas. Morphologically, however, the lesions are similar to those in typical PSP.

Motor neuron degeneration is unusual in PSP, but some patients have been described to have long tract signs (eg, hyperreflexia, Babinski signs and clonus). Less common are cases with features suggestive of primary lateral sclerosis (39). These patients present diagnostic difficulties and are often considered to have frontal lobe degeneration with motor neuron disease or CBD. At autopsy, they have pathology similar to typical PSP, but more marked neuronal loss and gliosis in motor cortex, including loss of Betz cells (38). There is also degeneration of the corticospinal tract that can be traced from motor cortex to lower brainstem regions. Most of these cases have less pathology in the subthalamic nucleus and substantia nigra than typical cases of PSP. Histologically, the neuronal and glial lesions are similar to those in PSP, but some cases have peculiar globular inclusions in oligodendroglial cells.

At autopsy, the pathology of PSP is often found to underlie the clinical syndrome of pure akinesia 47, 52), which is characterized by bradykinesia with gait freezing. These patients do usually not suffer early falls or eye movement abnormalities. Thus, several cardinal clinical features of PSP are not met. Pathological changes are often milder and more concentrated in brainstem and diencephalon, with fewer changes in cortex and striatum.

Recently, Williams et al have drawn attention to the fact that some patients with PSP can present with an asymmetrical extrapyramidal syndrome with tremor and a positive response to levodopa therapy. They referred to this syndrome as PSP‐P (95). Most of these patients developed eventually the clinical features of PSP, but early in the disease their symptoms resembled those of Parkinson’s disease. The term Richardson’s syndrome was proposed to refer to the more typical PSP syndrome (95). The pathology of PSP‐P is virtually indistinguishable from that of PSP, except that cortex and striatum are less severely affected.

Biomarkers in PSP.  A definitive cerebrospinal fluid biomarker for PSP remains elusive. Several studies have measured CSF tau protein and found it to be variably increased in PSP, but not more than in AD or CBD 2, 57, 93). Thus, it cannot be used to differentiate PSP from these disorders.

Structural imaging holds promise for differentiating PSP from other parkinsonian disorders. In particular, indices of brainstem pathology, such as atrophy of the superior cerebellar peduncle (90), are present consistently and differ from the changes observed in idiopathic Parkinson’s disease and MSA 58, 63). Longitudinal measures also show a more marked cortical and brainstem atrophy in PSP, particularly of the midbrain, than in normal controls 40, 64).