Sci. Aging Knowl. Environ., 28 July 2004
Vol. 2004, Issue 30, p. dn1
[DOI: 10.1126/sageke.2004.30.dn1]

NEURODEGENERATIVE DISEASE CASE STUDIES

Progressive Supranuclear Palsy

Michael Pourfar, and Jean-Paul Vonsattel

Michael Pourfar is at the Center for Parkinson's Disease and Other Movement Disorders, Columbia University Medical Center, New York, NY 10032, USA. Jean-Paul Vonsattel is a professor of Pathology and director of the New York Brain Bank, Taub Institute of Pathology, Columbia University Medical Center, New York, NY 10032, USA. E-mail: M.Pourfar{at}neuro.columbia.edu (M.P.)

http://sageke.sciencemag.org/cgi/content/full/2004/30/dn1

Key Words: tauopathy

Abstract: In this case study, we describe the symptoms, neurological examination, clinical course, and neuropathology of a patient with progressive supranuclear palsy (PSP). PSP is a relatively uncommon neurodegenerative disorder with many features similar to those of Parkinson's disease. It is characterized by slow motor function, ocular movement abnormalities, dystonia, and cognitive disabilities. PSP is largely a sporadic disorder caused by accumulation of the protein tau in diverse regions of the central nervous system. It is thus classified as one of several tauopathies. The exact cause of the disease remains unknown, and treatment is often limited. The following case provides a framework to explore the manifestations of PSP, as well as the progress made in understanding the nature of this challenging disorder.

Introduction Back to Top

M. L. was 65 years old in 1989 when he first noticed a resting tremor of his left hand. The following year, he was diagnosed with Parkinson's disease (PD) and started on treatment with carbidopa/levodopa, which resulted in an 80 to 90% improvement in his tremor. Soon thereafter, he noted a change in his speech, which he described as softer and slurred. He found that his general activities of daily living, such as writing and tending to chores, were becoming more laborious. By 1995, he began to experience frequent falls. Some were attributed to knee pain but others occurred as a result of freezing of his gait. Most falls were backward or sideways and occurred without warning. Two recent falls, both backward, occurred while tying his shoes and while urinating. In addition, his speech continued to worsen, becoming slower, slurred, and increasingly hoarse. Despite an increase in his carbidopa/levodopa dosage, his voice and gait continued to deteriorate. By 1995, he was dependent on a walker. Later that year, he first complained of difficulty with his memory. It was at this time that he was first evaluated at our Movement Disorder Center.

Medical History Back to Top

M. L.'s past medical history was significant only for a melanoma on the left leg that was resected along with his inguinal lymph nodes in 1960. There was no history of movement disorders in the family. He was married with seven children, all of whom were healthy, save for one son with schizophrenia. M. L. was a past smoker with moderate continued alcohol use. He was a retired bond trader. He had no known history of unusual chemical or toxic exposures.

Neurological Examination Back to Top

His examination at that time was notable for occasional abnormal eye movements called square wave jerks, decreased facial expression, slurred and low-volume speech (hypophonia), mild slowness of movements (bradykinesia)--particularly on the right side of his body--and slight dystonia in the right hand. In addition, he demonstrated difficulty in rising from a chair, a stooped posture, and a wide-based gait with decreased bilateral arm swing. When pulled backward, he required several steps to recover his balance (positive pull test). His cognition and memory at this time he felt to be within normal limits. His medication was again increased, but it did little to improve his balance. He found that he was having trouble sleeping because of stiffness of his body at night. On reexamination 2 months later, he was observed to have difficulty looking down and worsening balance on the pull test. A dopamine agonist, pergolide, was added to his regimen, which produced a mild subjective improvement in balance. Despite this treatment, he continued to fall and had a resultant hip fracture in March of 1996.

Clinical Course Back to Top

M. L. was reevaluated 1 month after this injury. By this time, he required assistance in most of his activities of daily living. His bradykinesia and micrographia were more pronounced than in previous visits. He demonstrated apraxia (recognized in an exam in which he had difficulty performing tasks such as brushing his teeth) and persistent dystonic posturing of his right hand with occasional involuntary arm elevation. He required two-person assistance with walking, which was notable because of frequent episodes of freezing of his right foot. Over the succeeding months, his carbidopa/levodopa dose was increased to 2000 mg per day (which is very high) and his pergolide was increased to 1 mg per day (the mean daily dose in PD patients is 3 mg per day). When reexamined in the summer, his vertical eye movements were more clearly abnormal, demonstrating limitations of downward gaze. In addition to the other previously noted cognitive difficulties, he displayed mild trouble in naming objects. When examined on further follow-up in January 1997 (see video 1), all the above findings were present and, according to his wife, his memory continued to worsen and was accompanied by increased confusion. His carbidopa/levodopa, which was felt to be of little benefit and possibly contributing to his confusion, was tapered down to 1000 mg per day. No change was noticeable after this decrease. In April 1997, he was again examined in our office (see video 2). His gaze demonstrated a striking wide-eyed stare, persistent square wave jerks, and an inability to look down. His face made an occasional dystonic grimace. The slowness and posturing of the right arm was more apparent than in previous exams. By August, he was choking on his food and complaining of double vision at night. His exam showed slowness in opening his eyes and increased axial and right-sided rigidity. Trials of various dopamine agonists did not result in any benefit. He complained of spasms and cramping in his right arm, which responded to analgesics and muscle relaxants. His overall decline had a profound effect on his mood and by April of 1998, he expressed a wish to die. His last examination at our center was in November of 1998 (see video 3). He experienced persistent choking, dysphagia, and worsening speech and rigidity. Eating became increasingly difficult, and the family decided, given his profound limitations, not to place a feeding tube. He died in March of 1999 at the age of 75, most likely from aspiration pneumonia due to an inability to protect his airway while eating.

Neuropathology Back to Top

M. L.'s brain was pathologically consistent with a diagnosis of progressive supranuclear palsy (PSP). However, in this section, we will look not at M. L.'s brain but at images from a similar PSP brain that better demonstrates the many hallmarks of the disorder. As was the case for the brain described here, on external examination of a typical PSP brain, one typically observes the following characteristics. Atrophy is usually mild and confined mainly to the frontal lobe. Atrophy of the pons may or may not be detectable. The brunt of the pathological changes involve the diencephalon (which consists predominantly of the thalamus and hypothalamus), brainstem, and cerebellum. When the brain is examined under a light microscope, the changes one observes are neuron loss, gliosis, and the presence of neuropil threads, which are inclusions found in neurons, glial cells, and tufted astrocytes (star-shaped neuroglial cells). These inclusions are heavily stained when subjected to labeling with antibodies to the microtubule-associated protein tau.

Macroscopic Changes Back to Top

Gross examination of the external surface of the fixed brain shows mild widening of the sulci of the frontal lobes, which indicates atrophy. Fig. 1 is remarkable for the severe atrophy and velvety brown discoloration of the internal segment of the globus pallidus. The external segment of the globus pallidus was markedly atrophic and a discolored dirty brown. The dorsal half of both segments of the globus pallidus, which is near the internal capsule (the chief route that connects the cerebral motor cortex with the spinal cord) was more degenerated than the ventral half. The paracapsular outline of the globus pallidus was concave, rather than its usual convex pattern. The neostriatum, which consists of the caudate nucleus and putamen (both components of the basal ganglia), was normal. Likewise normal were the cerebral cortex, white matter, hippocampus, amygdala, claustrum, hypothalamus, and thalamus. However, as is typically the case in PSP, the subthalamic nucleus was severely atrophic and discolored (gray-brown) with a blurred capsule. The ventricular system was slightly widened, reflecting the widespread atrophy in PSP brains.



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Fig. 1. Coronal slice of the fixed right cerebral hemisphere through the amygdala and head of the hippocampus. Both the internal and external segments of the globus pallidus are much smaller than normal and are discolored brown. The mediail outline of the globus pallidus is highly concave instead of convex. The putamen and head of the caudate nucleus are apparently normal, as are the neocortex, amygdala, hippocampus, and white matter.

 
Transverse sections of the midbrain were remarkable for severe loss of pigment in the pars compacta of the substantia nigra, which contains the brain's main source of dopaminergic neurons. There was also marked atrophy of the superior and inferior colliculi (Fig. 2). As mentioned above, the colliculi are involved in eye movements as well as axial tone, and changes in these areas probably contribute to the characteristic clinical findings of PSP. Furthermore, the red nucleus was markedly smaller than normal, discolored (brown), and exhibited ill-defined borders not seen in normal brains. The decussation (crossing of fibers) of the superior cerebellar peduncle was atrophic and discolored. In contrast to the pallor of the pars compacta of the substantia nigra, the nucleus coeruleus was well pigmented (Fig. 3). In PSP, both the pars reticulata and the compacta of the substantia nigra are involved. Often, however, there is relative preservation of the nucleus coeruleus. In contrast, in PD, the pars compacta of the substantia nigra and the nucleus coeruleus are more or less equally involved. The clinical significance of locus ceruleus involvement may manifest as autonomic instability, which is frequently seen in later stages of PD. The main gross changes noticed in the cerebellum were marked gray discoloration of the hilus and thinning of the gray ribbon of the dentate nucleus, with discoloration of the superior cerebellar peduncle.



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Fig. 2. Transverse slice of the rostral right hemimesencephalon (or midbrain). The pars compacta of the substantia nigra is severely pale in contrast to the relatively preserved nucleus coeruleus (see Fig. 3 and Fig. 7). The contour of the red nucleus is blurred.

 


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Fig. 3. Transverse slice of the rostral right hemimetencephalon (or pons). The nucleus coeruleus is well pigmented as compared to the severely pale pars compacta of the substantia nigra in the midbrain (see Fig. 2).

 

Microscopic Changes Back to Top

Blocks of tissue from representative brain regions were processed for examination by light microscopy. Thin sections were subjected to treatment with antibodies to brain proteins (such as tau and ubiquitin) to assess whether abnormal protein aggregates were present. The neocortex showed normal neuronal density with occasional bizarre argyrophilic neurons especially involving the fifth layer of the frontal lobe, which has diffuse connections throughout the brain and is involved in diverse functions, including aspects of motor and cognitive processing (Fig. 4). The hippocampus and amygdala contained scattered neuronal tangles that consisted of accumulated abnormal tau.



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Fig. 4. Bizarre neuronal tangle with cytoplasmic, agryophilic, filamentous inclusion involving the fifth cortical layer of the precuneus. In PSP, bizaare neocortical neuronal tangles are scant and are more readily found in the frontal lobe than in other lobes. Neuronal tangles are often found in the hippocampus, amygdala, and entorhinal cortex. Bielchowsky staining was used. Original magnification, 400x.

 
Most of the pathological changes observed in this brain involved, in decreasing order of severity, the internal and external segment of the globus pallidus (Fig. 1), the subthalamic nucleus, the substantia nigra (both pars compacta, and reticulata), the red nucleus (Fig. 2), the substantia innominata, the dentate nucleus of the cerebellum, the pontine nuclei, the inferior olivary nucleus, the neostriatum, and the nucleus of the oculomotor nerve. The pathological changes in this brain consisted of neuronal loss, the presence of argyrophilic neurons of globosum (spherical) type (Fig. 5), and more neuropil threads and reactive gliosis than normal. In addition to these changes, the dentate nucleus of the cerebellum (which is normally involved with postural stability) showed eosinophilic granular structures or grumose (thick and lumpy) degeneration around the dentate neurons, reflecting the cerebellar dysfunction seen in PSP. The neuronal density of both the pars compacta and reticulata of the substantia nigra (Fig. 6) was severely decreased in contrast to the moderate involvement of the nucleus coeruleus (Fig. 7), which was in accordance with the findings made on gross examination (Fig. 2 and Fig. 3).



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Fig. 5. Globose, agyrophilic, neuronal tangles involving the oculomotor nucleus (III). In PSP, the neuronal tangles are globose in the striatum, substantia innominata, brainstem, and dentate nucleus of the cerebellum. Bielchowsky staining was used. Original magnification, 400x.

 


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Fig. 6. The pars compacta of the substantia nigra shows severe neuronal loss, fibrillary reactive gliosis, and dark pigmented debris. In PSP, both the pars compacta and pars reticulata are involved. In contrast, the brunt of the changes in IPD are confined to the pars compacta. Luxol fast blue counterstained with hematoxylin and eosin (LHE) staining was used. Original magnification, 250x.

 


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Fig. 7. The nucleus coeruleus is much less involved than the pars compacta of the substantia nigra (see Fig. 6). In PSP, the nucleus coeruleus is usually relatively preserved as compared to the degeneration of the pars compacta. However, in IPD, the severity of the degeneration of the pars compacta parallels that of the nucleus coeruleus. LHE stain was used. Original magnification, 250x.

 
Mainly two types of neurons populate the neostriatum: medium-sized neurons and large cholinergic neurons. Many large cholinergic neurons of the neostriatum consisted of argyrophilic globose neurofibrillary tangles. However, the medium-sized neurons of the neostriatum were apparently normal. The white matter of the cerebral cortex and cerebellum was remarkable for the presence of scattered argyrophilic glial-cell tangles (oligodendrocytes and astrocytes). Severe myelin loss with scant macrophages (indicative of an inflammatory reaction) involved the hilus of the dentate nucleus (Fig. 8) and superior cerebellar peduncle. Sections subjected to antibodies (AT8) to hyperphosphorylated tau protein demonstrated wide tau presence in neurons, neuropil threads, and glial cells (Fig. 9). Their presence, distribution, and density were also revealed on silver-stained sections (Bielschowsky staining). However, sections subjected to tau antibodies revealed, in addition, the presence of tufted astrocytes (Fig. 10), which were not detected in the silver-stained sections. Tufted astrocytes contain tau-positive material localized primarily to the cell body and proximal processes. Tufted astrocytes were readily found in the neostriatum and to a much lesser extent in the neocortex.



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Fig. 8. Severe loss of myelinated fibers involves the dentate nucleus, evidenced by the pale myelin stain of the hilus, in contrast to the purple-stained album. The pallor of the hilus of the dentate nucleus reflects the loss of neurons involving the dentate nucleus, the ribbon of which is thinner than normal. Thus, the cerebellar output via the superior cerebellar peduncle is impaired. The cerebellar cortex is unremarkable except for scant segmental swelling of axons (torpedoes) of Purkinje cells that is probably secondary to the degeneration of the hilus. LHE stain was used. Original magnification, 1x.

 


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Fig. 9. Glial cytoplasmic inclusion (GCI) involving the subcortical white matter of the superior parietal lobule. The GCIs are labeled with antibodies (AT8) directed against the hyperphosphorylated microtubule-associated protein tau. These inclusions are agryophilic. Mainly oligodendrocytes of gray and white matter are involved. They are more prominent in the areas that are prone to degenerate in PSP than in the relatively preserved areas. GCIs may involve the intracerebral fibers of the ocular cranial nerves, including the oculomotor nerve. In addition to the GCI, the picture shows tau-labeled neuropil threads. Their density more or less parallels the severity of the degeneration. Original magnification, 640x.

 


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Fig. 10. Tufted astrocyte involving the prefrontal cortex (Brodmann area 9). Tufted astrocytes are the hallmark of PSP and are found mainly in the striatum, thalamus, subthalamic nucleus, and neocortex (especially the motor cortex). The tau-labeled aggregates are present primarily within the cell body and proximal processes. AT8 labeling was used. Original magnification, 640x.

 
In summary, the brunt of the degenerative changes fell on the globus pallidus, substantia nigra, and subthalamic nucleus and on connections to and from the cerebellum. There was a diffuse presence of tau aggregates and neurofibrillary tangles as well as other inclusions thoughout the brain, affecting the cortex, white matter, brainstem, and cranial nerves. The presence of neurofibrillary tangles and neuropil threads, particularly when located in the pallidum, subthalamic nucleus, and pons, is considered a necessary inclusion criterion for the neuropathological diagnosis of PSP.

Discussion Back to Top

M. L.'s first symptom was a unilateral resting tremor that responded to carbidopa/levodopa. The asymmetric tremor and robust response to dopaminergic medications are generally considered a hallmark of idiopathic PD (IPD). There was thus little to suggest an alternate diagnosis when M. L. was first examined in 1989. The generalized slowness and slightly slurred hypophonic speech that followed were, likewise, common features of IPD and not likely to raise any red flags heralding a possible atypical parkinsonian variant. By 1995, however, M. L. was beginning to suffer frequent falls and a rapid deterioration in his balance and gait that were less responsive to increases in his carbidopa/levodopa. This was a sign that M. L.'s course was beginning to diverge from that typical of IPD and fit into the more nebulous category of atypical parkinsonism or Parkinson's Plus disorder. This category of disorders includes PSP, cortical basal ganglionic degeneration (CBGD), and multisystems atrophy (MSA), which have many overlapping features. CBGD is particularly hard to distinguish from PSP (see Scarmeas Case Study). By this time, M. L. had been seen in our Movement Disorders clinic where, because of the above clinical factors, a possible diagnosis of PSP was already being considered. Features on his exam that suggested an alternate diagnosis to IPD were the presence of square wave jerks, a feature occasionally found in IPD but more consistent with MSA and PSP, and early postural instability. His subsequent course was marked by a steady decline that was only marginally slowed by adjustments in his medications. His gait, falls, and balance continued to be a major source of disability, culminating in a fractured hip. When reexamined in 1996, two significant findings that had developed were apraxia of the right upper extremity and abnormal limitation of vertical eye movements. Both strongly suggest a diagnosis other than PD, although the former is more frequently associated with CBGD, whereas the latter is more specific to PSP. The precise diagnosis thus remained elusive at this time. The patient's gaze problems then became more prominent, with the eventual loss of downward gaze; because disorders of eye movement are the most specific clinical signs associated with PSP, this diagnosis became more likely. He concomitantly began to have difficulties with his memory followed by a precipitous decline in his ability to care for himself. M. L. died 10 years after his initial symptoms manifested, unable to feed himself and wishing to die because of his greatly disabled state. An autopsy confirmed the diagnosis of PSP.

Great strides have been made in understanding many underlying aspects of PSP, but its cause remains unknown. It is classified as a tauopathy, underscoring the critical role of the protein tau in affected neurons. Tau is a phosphoprotein that is a part of a heterogeneous family of microtubule-associated proteins. It is normally involved in the assembly and stabilization of tubulin, a protein important in maintaining cell infrastructure. In tauopathies, tau becomes hyperphosphorylated and, as a result, builds up in various regions of the brain, forming neurofibrillary tangles. In the case of PSP, many areas of the brain are affected and, as will be outlined below, the particular locations of the abnormal tau are directly related to the specific findings observed clinically in PSP.

What predisposes affected individuals, such as M. L., to accumulate abnormal tau? The definitive answer remains inconclusive, but progress has been made in unraveling some of the suspected factors. As far as we now know, PSP is by and large a sporadic disorder, although a small number of families have more than one affected member. Rarer still are a select few with an autosomal dominant form of the disease. Epidemiological and environmental links have included rural living, a low level of education, and specific environmental toxins, such as the benzyltetrahydroisoquinolines (found in, among other things, certain tropical fruits). Genetic predisposition is an area of ever-increasing study where PSP is concerned. Much focus has been concentrated on the tau gene, which is located on chromosome 17 and can generate six different isoforms of the protein depending on how the RNA is spliced. Certain isoforms appear to be more prevalent in the PSP population than in normal people. The diagnostic ramifications of specific variants, however, remain problematic. For example, HapA, a specific haplotype that has been identified in 98% of PSP cases, is also found in over 30% of normal people. This specific finding can thus, at present, be regarded only as a possible risk factor for developing PSP.

One of the great challenges in understanding PSP is the frequent difficulty in identifying actual cases in living patients. M. L. provides a good example of the diagnostic conundrum that these patients often pose. For years, he was identified as having IPD, a diagnosis that was later revised in light of subsequent findings. The frequent mislabeling of these patients complicates issues such as prevalence, incidence, and course of and response to treatment. Results of various studies, for example, have yielded prevalences from 1.4 to 6.4 per 100,000. The incidence is about 1 to 2%, as common as that of IPD. Early identification of these patients is important if one is to target clinical trials to this particular population. One of the main clinical efforts in the past decade has thus been to establish more reliable diagnostic criteria. Toward this end, several criteria have been proposed since the first descriptions of the disorder appeared in 1963 (named, at that time, after its first describers: Steele, Richardson, and Olszewski). The most common criteria currently in use are those proposed jointly by the National Institute of Neurological Disorders and Stroke (NINDS) and the Society for PSP (SPSP) and one proposed by Tolosa et al. These are particularly helpful for research purposes but will be used here to point out the typical features of M. L.'s case as well as those features that are somewhat less characteristic.

As a 63-year-old male, M. L. fits the PSP profile in terms of his age of onset. PSP is about two times more common in men than in women and has a mean age of onset of 60 to 63 years old. It is not a disorder of the young, and had M. L. been less than 40 at the time of onset, the diagnosis of PSP would have been highly unlikely. His first symptom, however, was a resting tremor, which is not very common in PSP. Tremor does occur in as many as 30% of PSP cases, but it is seldom the initial clinical finding. When it does occur, it tends to affect both sides of the body, thus differentiating it from IPD, which is characterized by a unilateral tremor. Also atypical is M. L.'s robust response to levodopa. An initial modest improvement with treatment is not uncommon in PSP, but several years of sustained response are generally considered inconsistent with the diagnosis. The usual lack of response is at least partly a result of the widespread loss of postsynaptic dopaminergic receptors. In one study of PSP patients, 38% reported some improvement when taking levodopa, only modestly more than the 30% of patients in the placebo group who reported benefit. The tremor and its improvement with treatment were thus thought to be more compatible with IPD. This initial misdiagnosis is not at all uncommon for PSP patients. In one study, out of 187 patients ultimately diagnosed with PSP, 43 were initially given no diagnosis and 42 were classified as having either IPD or parkinsonism. Tremor was observed in 21% of the 187 cases, but it was not the classic "pill-rolling" tremor that is observed in IPD (see video 4).

The increased amount of time required for M. L. to perform his activities of daily living is a trait common to PSP and IPD. It is the result of a combination of factors that include, most prominently, bradykinesia and rigidity. Motor function is slowed in both diseases as a direct result of degeneration of the basal ganglia, which are central in the control of planned movements. Its component parts, the substantia nigra, striatum, pallidum, and subthalamic nucleus, are all affected, either directly or indirectly, both in IPD and PSP.

Six years into the disease, M. L. began to experience frequent falls. Falls are common in IPD but are usually a late feature of the disease. In PSP, falls occur early, often within the first year, and are so prominent a feature that they constitute a defining aspect of the disease. In both IPD and PSP, falls reflect a loss of postural reflexes that normally help maintain one's center of gravity. The cause of the underlying postural loss is, however, not identical in the two disorders. This can be observed clinically and through the use of ancillary tests such as computerized posturography. In PSP, there is specific degeneration within the cerebellum that is not found in IPD. This accounts, in part, for the more frequent falls observed in PSP. It also accounts for the characteristic wide-based gait of patients with PSP, which is an attempt to compensate for the inherent imbalance. This contrasts with the generally narrow-based gait seen in IPD patients. In PSP, visual impairment and prominent axial rigidity are also among the factors that precipitate falls. Unlike in IPD patients, those with PSP tend to make quick pivot turns that can throw off their already tenuous balance. It has also been observed that many PSP patients have a reckless tendency and continue to attempt to walk unassisted in spite of their disability, further increasing their fall risk. Because the etiology of falls in PSP is multifactorial (beyond, for example, an isolated dopamine deficiency), this symptom is challenging to treat and is thus a significant cause of morbidity in PSP patients. M. L.'s broken hip is an all-too-common result of this disability. The positive pull test (see a normal pull test in video 5), as observed in M. L., is a useful office test for assessing a patient's fall risk.

Falls may be the most common symptom of PSP, but abnormal eye findings are the most common sign (a symptom is something a patient reports, as opposed to a sign, which is an objective finding seen on examination). The manifestations are manifold and include blurring, diplopia, limitation of gaze, loss or abnormal persistence of fixation, and a host of other eye aberrations). M. L. eventually presented with a constellation of abnormal eye movements that proved key to his diagnosis. The first significant finding was square wave jerks of the eyes. The cause and localization of these abnormal saccadic movements, which interfere with ocular fixation, are not known. They can be found in a diverse array of neurological disorders but are most common in PSP and cerebellar dysfunction (see video 6). One year later, M. L. was noted to have abnormal vertical eye movements when tested with an optokinetic nystagmus (OKN) tape (see a normal OKN test in video 7). Limitation of vertical gaze, particularly downward gaze, is the hallmark of PSP and is generally used to differentiate it from other parkinsonian diseases. It is generally the earliest eye finding in patients and is attributed to dysfunction of affected neurons in the midbrain that control vertical saccades. Degeneration of neurons leading from the substantia nigra and pars reticulata to the superior colliculi, as seen in pathological studies of brains from PSP patients, may also play a role in the limitation of gaze. The limitation of gaze tends to progress as it did with M. L. who, by the next year, was unable to look down. In extreme cases, eye movements are absent in all directions. Early in the disease, the limitation can often be overcome by eliciting the oculocephalic reflex, but this, too, can be lost as the disease progresses.

An interesting feature of M. L.'s case was the development of an apraxic and alien right upper extremity. His inability to perform learned motor tasks despite essentially normal motor function typifies the apraxia, whereas the uncontrolled elevation of the arm is more compatible with the alien phenomenon. These, together, are uncommon occurrences in PSP and raised the possibility of an alternate diagnosis of CBGD, in which these findings are common. The abnormal posturing, or dystonia, of the limb that preceded the alien movements, however, is somewhat more common in PSP, although it is still found in less than 15% of cases.

Dystonia is not limited to the limb in PSP. Blepharospasm, an involuntary forced closure of the eyes, is perhaps the most common focal dystonia in this disease. Prominent truncal stiffness with markedly increased tone in the neck is seen in most PSP patients and is thought to result, at least in part, from axial dystonia. Pathological changes found in the superior colliculi and interstitial nuclei of Cajal are posited as contributing to the development of axial dystonia. In addition, an astonished or quizzical look is often observed in PSP patients as a result of dystonic furrowing of the brow and facial muscles, the latter also leading to a characteristic deepening of facial folds.

Six years after he experienced his first symptoms, M. L. began complaining of memory problems. Over the years that followed, his memory worsened and he became increasingly confused. Although part of this change can be attributed to the side effects of medications, some may have been the result of his neurodegenerative disorder. The cognitive component of PSP can be quite varied, ranging from normal to demented. Many studies have reported deficits in memory retrieval, sequencing tasks, and concentration. Apathy, anxiety, irritability, and emotional incontinence with rapid fluctuations of emotional expression are also quite common. In the extreme, a schizophrenia-like psychosis can develop. Many of these cognitive impairments are thought to result from dysfunction of neuronal circuits involving the frontal lobes of the brain; PSP brains frequently display mild atrophy of the frontal lobes. Diffuse neuronal loss and neuropil threads scattered throughout the subcortical gray matter have also been associated with dementia.

M. L. died a decade after his first reported symptoms. The average life expectancy from time of diagnosis ranges from 5.6 to 8.6 years, with the most common cause of death being aspiration. Placement of a percutaneous endoscopic gastrotomy tube for feeding assistance is often necessary to decrease this risk, but many patients, like M. L., choose not to pursue this option. Patients that display falls, bulbar signs (such as dysarthria and dysphagia), and diplopia early in their disease tend to have a more rapid course, as do individuals with a later age of onset.

M. L. demonstrated many common features of PSP as well as some less usual manifestations. The list of alternative findings has been touched on in this case study, but is itself quite extensive. In the end, given the presence of features that overlapped with those of CBGD, his diagnosis was not wholly clear until the autopsy results were reviewed. Could anything have been done in retrospect to help establish a more concrete premortem diagnosis? There is no gold standard for making the diagnosis of PSP. At best, one can bolster the clinical impression with diagnostic imaging. Magnetic resonance imaging (MRI) may reveal thinning of the quadrigeminal plate and atrophy of the midbrain. It has been noted that a differential diagnosis can sometimes be made between MSA and PSP by comparing the diameter of the midbrain and pons, with the latter being normal in PSP and reduced in MSA (and vice versa as regards the midbrain). Positron emission tomography (PET) scanning can provide further clues by demonstrating low blood flow in all areas of the cerebrum, but most notably in the frontal lobes. This finding, however, is not specific for PSP and can be seen in other neurodegenerative mimics. Other imaging modalities, such as MR spectroscopy and single-photon emission computed tomography (SPECT) can also be employed in the pursuit of early diagnosis. In addition to uncovering supportive findings, these tests can help identify other diseases that can masquerade as PSP. MSA is one example, but others include Alzheimer's disease, multi-infarct dementia, IPD, Huntington's disease variants, and a several more diseases that have their own radiographic signatures.

For those who do not respond to dopaminergic medications, there are unfortunately very few consistently effective treatments currently available. The disheartening lack of new treatments is modestly buffered by promising new insights into the potential causes of the disease. It is our hope that these clues will pave the way for the discovery of new medications aimed at both the symptoms of and the process underlying PSP. Several current research approaches might yield a description of the pathogenesis of this disorder. Genetic discoveries have been briefly noted above. The role of tangles that contain phosphorylated tau is central to the understanding of PSP pathology, but the presence of these tangles in other conditions, such as FTDP-17 and CBGD, indicates that they are not specific to PSP, thus complicating research. So similar are many of the features of these neurodegenerative disorders that a controversy exists as to whether they are distinct entities or different manifestations of a similar disease process. Whatever predisposes individuals to accumulate abnormal tau would appear to predispose them to these disorders. It has been postulated that damage caused by reactive oxygen species (ROS) results in the creation of a version of tau that is resistant to dephosphorylation and thus accumulates abnormally.

Various metal ions, including iron, copper, and zinc, have been proposed as free radical sources for this oxidative stress. Intracellular calcium levels rise in circumstances of oxidative stress, which leads to the up-regulation of calcium-dependent enzymes. One of these, transglutaminase, has been reported to stabilize aberrantly hyperphosphorylated tau. Mitochondrial dysfunction is another alluring suspect in the ROS model, although the trigger for the observed abnormalities remains elusive. M. L.'s case highlights the widespread disability that can result from PSP and the many regions of the brain that are affected, but it does provide insights into the causes of these changes in the brain. In the end, it seems that we are still very much at the beginning of our understanding of PSP.


July 28, 2004

Abbreviations: Activities of daily living. A general term for activities felt to be reflective of basic elements of independent function. Taken collectively, they provide a sense of the degree of an individual's level of autonomy or level of dependence on caregivers. • Alzheimer's disease. Progressive mental deterioration correlated pathologically with brain atrophy and the presence of amyloid plaques and neurofibrillary tangles concentrated in the frontal and temporal regions of the brain. It is the most common form of age-related dementia, accounting for an estimated 60 to 70% of cases. • Amygdala. Almond-shaped mass of subcortical gray matter within the tip of the temporal lobe, with olfactory, limbic, thalamic, and hypothalamic connections. The amygdala receives highly preprocessed sensory impressions, is responsible for initiation and integration of somatic and autonomic responses, and is associated with affective behavior. The amygdala is also referred to as the amygdaloid body. • Apraxia. A disorder of voluntary movement, such as impairment in the performance of skilled or purposeful movements, despite the preservation of normal comprehension, muscular power, and coordination. • Argyrophilic. Any substance, such as connective tissue fibers, that contains proteins that react with silver salts and appear black microscopically. • Autosomal dominant. Autosomal inheritance is the transmission, from parent to offspring, of a gene that is located on any chromosome other than the X or Y chromosome. Dominant inheritance indicates that only one abnormal gene in a pair of genes is necessary to produce the condition. • Basal ganglia. A neuroanatomical grouping of neurons located within the cerebral hemispheres and upper brainstem, composed of the putamen, caudate nucleus, and globus pallidus. The cells of this region are involved in the initiation and coordination of movement. • Bradykinesia. A slowness of voluntary motor activity and a reduction of autonomic movement. It is generally indicative of a disorder of the basal ganglia. • Brainstem. The portion of the brain immediately superior to the spinal cord, consisting of the pons, medulla, and midbrain. Collected here are neuronal circuits that control respiration, cardiovascular function, eye movement, equilibrium, and many stereotyped movements of the body. Many of the cranial nerves arise in the brainstem, and all of the nerve fibers running between the spinal cord and higher brain centers pass through this region. • Carbidopa/levodopa. A combination medication used for the treatment of Parkinson's disease. Levodopa is converted to dopamine, thus replacing depleted stores in affected individuals. It is administered with carbidopa, which prevents its breakdown outside the brain, so as to maximize the amount of effective drug within the brain. • Cerebellar peduncle. One of three stalklike projections that connect the cerebellum with the brainstem. The superior, middle, and inferior peduncles are the major conduits relaying information to and from various regions of the cerebellum. • Cerebellum. Portion of the brain that lies just below the posterior part of the cerebrum and behind the brainstem. Integrating information from the cerebrum and peripheral parts of the body, the cerebellum plays an essential role in coordinating voluntary movement, controlling muscle tone, and maintaining balance. Symptoms of cerebellar lesions include motor incoordination, tremors, disturbances of gait and balance, slurred speech, and nystagmus. • Claustrum. A thin strip of gray matter abutting the putamen that is associated with sensory associations. • Cerebral cortex. Thin mantle of gray matter that covers the cerebral hemispheres, folded into ridges and furrows (gyri and sulci). The cortex is involved in cognition, memory, consciousness, behavioral reactions, and speech. Deficits associated with lesions of the cerebral cortex depend on the specific area affected. • Colliculi. The inferior and superior colliculi together make up the colliculi. The inferior colliculus is involved with reflexive responses to auditory stimuli. The superior colliculus is involved with reflexive responses to visual stimuli. • Computerized posturography. Also called computerized dynamic posturography (CDP), computerized posturography is a research study used to isolate the functional contributions of vestibular inputs, visual inputs, somatosensory inputs, central integrating mechanisms, and neuromuscular system outputs for postural and balance control. During CDP testing, the patient stands on a movable, dual forceplate support surface within a moveable surround (enclosure). Under control of a computer, the force platform can either move in a horizontal plane (translate) or rotate out of the horizontal plane. • Cortical basal ganglionic degeneration. A degenerative neurological disorder most commonly characterized by an asymmetric akinetic-rigid syndrome with associated involuntary movements and cortical dysfunction. It is believed to result from abnormalities in processing of the protein tau within the central nervous system. • Dentate nucleus. The largest of the cerebellar nuclei and the major source of output fibers forming the superior cerebellar peduncle. • Diencephalon. The part of the brain that lies anterior to the midbrain and is composed of the thalamus and hypothalamus. • Diplopia. Double vision generally caused by misalignment of perceived images on the fovea, which can result from abnormalities within the eye(s) or muscles that control their movements. • Dopamine. 3,4 dihydroxyphenylethylamine; a central nervous system neurotransmitter localized most prominently in the substantia nigra, which is located in the midbrain. Dopamine is critical to the normal function of movement and balance, and its selective loss is the hallmark of Parkinson's disease. • Dysphagia. Disturbance of the mechanical process of swallowing. • Dystonia. Alteration in muscle tone causing sustained abnormal postures and disruption of voluntary movement, existing as a separate disease entity or as one of a complex of symptoms in a broader condition (for example, Parkinson's disease). Changes in activity in several brain areas--the basal ganglia, thalamus, and cerebral cortex--appear to be present in dystonia. • Freezing. A situation common to parkinsonian disorders, in which the feet get stuck to the ground when the individual attempts to walk. It tends to occur when dopaminergic concentrations are low but does not consistently respond to an increase in dopaminergic medications. • Frontotemporal dementia. A tauopathy characterized by dementia, disinhibition, and parkinsonism linked to chromosome 17 (FTDP-17). • Haplotype. Aspects of a phenotype determined by a set of closely linked genes inherited from one parent. • Glial cells. The nonneuronal cells of the nervous system. • Gliosis. A proliferation of glial cells in response to injury or disease in the central nervous system, which leaves a glial scar composed primarily of astrocytes. Gliosis coupled with neuronal loss in certain brain regions is associated with various neuronal injuries. • Globus pallidus. One of the basal ganglia, with connections to the striatum, thalamus, and mesencephalon. The globus pallidus acts as an antagonist of the striatum and facilitates motor information. Dysfunction in this area results in hypokinesia and poor timing of movements. • Gray matter. The portion of the brain and spinal cord that appears gray in unstained specimens. It is composed of nerve cell bodies, dendrites, unmyelinated portions of axons, and glial cells, and it forms the cortex of the cerebrum and the cerebellum. • Hilus. The folded cell layer in the cerebellum that consists of numerous relay tracts critical to the integration of cerebellar information with itself and other regions of the nervous system. • Hippocampus. Part of the limbic system located in the medial temporal lobe and important in memory formation. Hippocampal lesions lead to an inability to transfer contents of short-term memory. • Huntington's disease. A neurodegenerative disorder characterized by uncontrollable abnormal movements (particularly hyperkinetic movements such as ballism and chorea), as well as cognitive, psychiatric, and personality changes. It is inherited in an autosomal-dominant manner and is caused by an abnormal triple-repeat genetic sequence. It is a progressive and ultimately fatal disease. • Hypophonia. An abnormally weak voice resulting from incoordination of the muscles involved in speech. • Hypothalamus. A part of the limbic system, this structure is involved in homeostatic control of the body (for example, body temperature, blood flow, and food and water intake). Through the secretion of hormones, it affects the function of the pituitary gland and the autonomic nervous system. • Incidence. The number of new events. For example, persons falling ill with a specified disease during a specified period in a specific population. • Interstitial nuclei of Cajal. A group of widely spaced medium-sized neurons in the dorsomedial region of the upper midbrain believed to be involved in the integration of head and eye movements. • Magnetic resonance imaging (MRI). MRI is a diagnostic technique based on the physical principle of nuclear magnetic resonance. The body to be imaged is inserted into a magnetic field, causing the magnetic spin of the hydrogen nuclei to align with the magnet. Radio signals are used to transiently perturb this alignment. As the nuclei snap back to alignment, weak electromagnetic signals are produced. The use of additional spatial magnetic field gradients, and the integration of multiple signals, allow computerized reconstruction of an image of the tissue. MRI provides excellent sensitivity and resolution for detecting and localizing brain pathologies. • Micrographia. Writing with minute letters, often seen in parkinsonian disorders, in which the script becomes progressively smaller as the individual continues to write. • Midbrain. Also known as the mesencephalon, it is the most rostral portion of the brainstem and is, among its varied functions, the source of some of the nuclei that control eye movements. • MR spectroscopy. An imaging method of detecting and measuring physiologic activity at the cellular level. It provides chemical information and is used in conjunction with MRI, which gives spatial (three-dimensional) information. • Multi-infarct dementia. A diffuse cognitive decline caused by multiple cerebrovascular infarcts (strokes), generally differentiated from other dementias by a stepwise decline and evidence of numerous strokes on imaging. • Multisystems atrophy (MSA). A classification of neurodegenerative syndromes characterized by parkinsonism (rigidity, bradykinesia, and postural imbalance) combined with other features, including autonomic dysfunction and ataxia. Underlying pathology can be found in the basal ganglia, cerebellum, peripheral sympathetic ganglia, and spinal cord. Striatonigral degenereation, olivopontocerebellar atophy, and Shy-Drager syndrome together make up the MSA group. • Neocortex. Six-layered portion of the cerebral cortex that formed most recently during evolution and consists of the cortex excluding the olfactory, hippocampal, and piriform regions. The wrinkled surface of the neocortex has distinct territories concerned with sensory, motor, and association functions. • Neostriatum. The later-developed part of the corpus striatum that includes the caudate nucleus and the putamen. • Neurofibrillary tangles. Abnormal structures located in various parts of the brain and composed of dense arrays of paired helical filaments. These filaments likely incorporate intermediate filaments, the microtubule-associated proteins tau and MAP-2, actin, and ubiquitin. • Neuropil. A dense area in the gray matter of the central nervous system made up of interwoven dendrites and axons (the cytoplasmic processes of nerve cells) and neuroglial cells. • Nucleus coeruleus. The small collection of pigmented cells within the brain that provides the main source of the neurotransmitter norepinephrine. • Oculocephalic reflex. A reflex in which rotation of the head leads to a compensatory counter-rotation of both eyes, thus allowing the eyes to maintain fixation on a target despite head movement. • Optokinetic nystagmus. Rhythmic oscillation of the eyeballs induced by looking at moving visual stimuli. • Pons. Brainstem region lying superior to the medulla. The pons serves as a relay station between the cerebral hemispheres and the cerebellum and is involved in regulating blood pressure, respiration, facial sensation and movements, and aspects of eye movement. Alterations in eye movement are symptomatic of lesions in this region. • Positron emission tomography (PET). Also called a PET scan, this diagnostic technique uses positron-emitting radioactive tracers injected into the body. When a positron combines with an electron, two high-energy photons are emitted in opposite directions. When two photons are detected on opposite sides of the body simultaneously, this information is combined with other such events to create a three-dimensional image that depicts blood flow patterns, metabolic activity, neuroreceptor density, and other functional aspects of tissues and organs. • Prevalence. The number of cases of a disease existing in a given population at a particular moment in time. • Pull test. A clinical test in which a patient is pulled from behind and instructed to maintain their balance. If a patient is unable to catch him/herself with a corrective step, the pull test is abnormal and is considered positive. • Quadrigeminal plate. The thin roof-like lamina, or uppermost layer, of the midbrain. • Putamen. One of the basal ganglia, with an inhibitory role in motor movement programs and diverse connections with the globus pallidus, substantia nigra, and motor cortex. It is histologically similar to the caudate and, taken together, composes the striatum. • Red nucleus. A large cell mass in the midbrain composed largely of fibers from the cerebellum and thus related to fine control of movement. • Rigidity. Stiffness or inflexibility due to an increase in muscle tone at rest and characterized by increased resistance to passive movement of a limb. • Single-photon emission computed tomography. SPECT is an imaging modality that measures regional cerebral blood flow. 123I-beta-CIT is a tropane analog used as a tracer to measure dopamine transporter binding on nigrostriatal terminals. SPECT is thus useful in assessing the integrity of presynaptic dopaminergic systems. • Square wave jerks. Abnormal eye movements most commonly seen with cerebellar dysfunction. • Substantia innominata. A region in the forebrain containing cells that produce and distribute acetylcholine to various regions throughout the brain. Depletion of cholinergic cells in this region is associated with Alzheimer's disease. • Substantia nigra. A large cell mass composed of a dorsal stratum of tightly packed dopamine-containing cells (the zona compacta) and a larger, ventral region of more scattered nonpigmented cells (the zona reticulata). The former provides a major input to the basal ganglia, whereas the latter is involved with the output of signals from the basal ganglia. • Subthalamic nucleus. A key component of the basal ganglia that integrates pallidal inputs and transmits excitatory output control of movement commands to the thalamus and, ultimately, to the motor cortex. • Superior colliculi. A paired eminence located at the roof of the midbrain that participates in eye movements and the general integration of the visual pathway. • Thalamus. Ovoid mass of gray matter that forms part of the lateral wall of the third ventricle. It is the principle relay site for sensory signals traveling to the cerebral cortex and is involved in emotional associations of sensations and in arousal and alerting mechanisms. Thalamic lesions can cause decreased or increased sensitivity to sensory stimuli. • Tau. A microtubule-associated protein that can form neurofibrillary tangles. The tangles arise from the aggregation of tau into twisted threads inside neural cells. Such masses of tau-containing filaments are a feature of Alzheimer's disease, corticobasal ganglionic degeneration, and some other neurodegenerative diseases referred to as tauopathies. • Ventricular system. The cavities within the brain that contain and circulate the cerebrospinal fluid. • White matter. The portion of the brain and spinal cord that appears white in unstained specimens and occurs in the more central (nonsurface) regions of the central nervous system. It is composed of myelinated nerve fibers and myelin-producing oligodendrocytes.

Suggested ReadingBack to Top

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Citation: M. Pourfar, J.-P. Vonsattel, Progressive Supranuclear Palsy. Sci. Aging Knowl. Environ. 2004 (30), dn1 (2004).








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