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Introduction
Corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) were first recognized in the 1960s as distinct clinical and neuropathological entities. Both four-repeat tauopathies, each was initially associated with a distinctive clinical syndrome: CBD with progressive and usually asymmetric dystonia, parkinsonism, and apraxia, and PSP with progressive eye movement disorders and falls. In recent years, increasing attention has been paid to the cognitive and behavioral symptoms associated with both corticobasal syndrome (CBS) and progressive supranuclear palsy syndrome (PSPS). It has also been increasingly recognized that pathological CBD can manifest as three main clinical syndromes, one syndrome reminiscent of classic CBS but with executive function deficits, non-fluent variant primary progressive aphasia (nfvPPA), and behavioral variant frontotemporal dementia (bvFTD). Autopsy studies have revealed that PSP also presents with heterogeneous clinical syndromes, including Parkinson’s disease (PD), CBS, or multiple system atrophy (MSA), though most cases manifest as PSPS.
Here we review the clinical and pathological features of CBD and PSP. We begin by discussing CBD in terms of classic neuropathological findings, epidemiology, and genetics, then discuss the clinical hallmarks of each of the three major clinical presentations of corticobasal degeneration, with particular attention to the behavioral neurology of each. We then consider PSP, again reviewing neuropathology, epidemiological, and genetic characteristics before focusing on the clinical features of PSPS. Clinical case vignettes are used to highlight important features of each major clinical syndrome for both illnesses. Finally, we touch on the use of biomarker studies and neuroimaging for the diagnosis of CBS and PSPS, which will be critical in developing and evaluating future therapeutics.
Corticobasal degeneration
CBD was first described in a 1968 series of three patients with progressive asymmetric movement disorder and swollen, pale neurons with poorly-staining inclusions seen on neuropathology at autopsy [1]. Though these neuropathological features were somewhat similar to those seen in Pick’s disease, their distinctive distribution, as well as the striking motor features seen clinically, convinced Rebeiz and colleagues that they had identified a separate disease entity, which they termed corticodentatonigral degeneration with neuronal achromasia [1]. In the following years, researchers better characterized the clinical features of the disease, focusing on the distinctive movement disorders and apraxia seen in CBS and identifying hallmark features of asymmetric apraxia, parkinsonism, myoclonus, dystonia, focal reflex myoclonus, rigidity, hyper-reflexia, and alien limb [1–3].
As recently as the 1980s, CBD was thought of as primarily a disorder of movement and praxis, though some early work recognized the prominent cognitive symptoms often associated with the illness, leading them to hypothesize that it might be a subtype of Pick’s disease [4]. More recently, clinicians have recognized that the widespread frontal involvement characteristic of the disorder often leads to cognitive symptoms [5, 6], and that these can predate by years the emergence of movement disorders and apraxia [5, 7–10]. That is, a prolonged dysexecutive phase followed by late motor symptoms in no way excludes an underlying pathology of CBD. Further, it has become apparent that the classic executive-motor presentation (often termed corticobasal syndrome [CBS]) is one of three characteristic clinical presentations of CBD, and that patients with nfvPPA and bvFTD can also show underlying CBD at autopsy [5].
Pathology
In 1994, Wakabayashi et al. identified that the neuronal aggregates in CBD consisted of the microtubule-associated protein tau (MAPT) [11], a primarily axonal protein which plays a key role in microtubule structure and stability. Tau is present in six isoforms, which contain either three (“3R tau”) or four (“4R tau”) tubulin-binding repeats. Hyperphosphorylation of tau decreases its affinity for microtubules and promotes its aggregation into multimers [12, 13]. The classification of CBD as a tauopathy placed it into the same family of disorders as PSP and Pick’s disease [14]; like PSP, CBD is a 4R tauopathy, while Pick bodies consist of 3R tau.
On gross evaluation, CBD is associated with cortical atrophy particularly affecting the parasagittal, perirolandic, and inferior frontal and temporal cortices, which may be asymmetric [15], and pallor of the substantia nigra. Current micropathological criteria developed by a working group of the Office of Rare Diseases of the National Institutes of Health (ORD NIH) include the presence of tau-immunoreactive lesions in neurons, glia, and cell processes, particularly astrocytic plaques and thread-like lesions in both gray and white matter and involving both cortex and striatum, as well as neuronal loss in cortex and substantia nigra [2, 16]. Astrocytic inclusions are more common than the tau-positive oligodendroglial inclusions known as coiled bodies, but both are seen in CBD [15]; oligodendroglial inclusions are considered a supportive but not required feature for diagnosis. Although ballooned, pale neurons are often present in CBD (and were one of the original neuropathological features described in the first description of CBD by Rebeiz and colleagues in 1968), these are also considered a supportive but not required feature of illness as they are not present in all cases [16–18].
Epidemiology and genetics
CBD is a relatively rare neurodegenerative disorder, with age-adjusted prevalence of approximately five per 100,000 individuals in American and British studies [19, 20] and 1.7 per 100,000 in a Japanese study [21].
Although symptom onset as early as 45 years of age has been reported, most patients with pathologically proven CBD have their first symptoms in the sixth to eighth decades of life [22]. One large series of 267 individuals showed a mean age of onset of 64 years, with a mean disease duration of 6.6 years. Both men and women are affected, with some studies suggesting higher disease incidence in women [23].
Although most cases of CBD are sporadic, some patients with MAPT mutations can present with CBS and with CBD-like features on neuropathology [24–26]; patients with familial progranulin mutations can also present with CBS [27–29]. In terms of common genetic mutations, the H1 haplotype of the MAPT gene, seen in nearly 100% of Japanese and over 70% of Caucasian individuals [30, 31], is over-represented in patients with CBD (as well as other tauopathies including PSP, FTD, and PPA) [32–36].
Clinical syndromes: executive-motor (corticobasal syndrome)
The case below illustrates a patient with CBS in whom dysexecutive features predated movement disorder by approximately 5 years. Her motor features include classic findings of CBS, with progressive loss of function, parkinsonism, alien limb phenomena, dystonia, and rigidity, which can be asymmetric, in her case first affecting the left upper extremity. Although neuropsychological profiles in CBS are fairly non-specific, many patients show deficits in attention and executive function out of proportion to memory deficits (as in this case) as well as visuospatial deficits, and some additionally show significant language impairments [5, 7, 8, 37–40]. As in her case, predominantly frontal cortical atrophy is typical; patients often show focal atrophy in perirolandic and supplementary cortex, as well as striatum and insula [5].
Vignette 1
A 63-year-old woman began having difficulty with multitasking and managing her work as a accountant about 6 years prior to presentation. Around the same time, her personality changed, describing herself as “more assertive.” Several years later, she began having language difficulties, with effortful, aprosodic speech and yes/no confusion. Family members noticed that she was progressively more reliant on them to plan activities, but felt that her memory and navigation skills were unaffected. They also noticed changes in her eye movements. In the year prior to presentation, motor deficits became more prominent: she had a progressive loss of function in her left upper extremity, followed half a year later by her right upper extremity and left lower extremity. She began to have frequent falls and also began to report that her left upper extremity would occasionally grab at her right upper extremity without her intent. She also endorsed depressed mood, as well as episodes of inappropriate laughter and crying.
On neurological exam, her speech was effortful, somewhat nasal, aprosodic, and apraxic. She had prominent apraxia in the left more than right and upper more than lower extremities, and mirrored left-sided movements with the right hand. She had square-wave jerks with attempted gaze fixation and difficulty initiating saccades in the vertical plane, with increased latency on horizontal movements. There was flattening of the left nasolabial fold. The left upper extremity was dystonic, with increased tone and cogwheeling and slowed, dysrhythmic taps and alternating movements; a left-sided grasp reflex and astereognosis were also present. The right upper extremity showed milder increased tone and dysrhythmia. She was unable to arise from a seated posture without use of her arms; gait was unsteady with propulsion, a short stride length, and dystonic posturing of both arms.
Neuropsychological testing showed profound difficulties on an array of measures of attention, executive function, and visuospatial tasks, as well as acalculia. There were more moderate deficits in visual more than verbal memory testing. Linguistic function was relatively spared.
Neuroimaging showed profound right-sided cortical atrophy, which was most pronounced in the frontal lobe and especially in perirolandic regions and striatum, and more moderate left-sided frontal atrophy. She was given a clinical diagnosis of corticobasal syndrome (executive-motor) and passed away 8 years after symptom onset. Autopsy confirmed CBD.
Non-fluent variant primary progressive aphasia (nfvPPA)
Below we describe a patient who presented with progressive speech impairment characteristic of nfvPPA. Patients with this form of aphasia classically have effortful, aprosodic speech characterized by sound distortions, substitutions, and agrammatism (dropping function words, making errors of number) with relative sparing of single-word comprehension, though comprehension of more syntactically complex sentences is often impaired [41]. Deficits are thought to localize to the posterior left inferior frontal gyrus, commonly accompanied by atrophy of the basal ganglia, anterior insula, and supplementary motor area, and patients often have corresponding atrophy in these regions on MRI or hypometabolism in these regions on PET. CBD is one of many underlying pathologies seen in cases of nfvPPA, which is seen in a range of tauopathies as well as FTLD-TDP pathologies [5, 42–45].
Vignette 2
An 80-year-old woman presented for evaluation 2 years after developing word-finding difficulties and episodes of anger which were characterized by speech arrest, stamping feet, and pounding fists. Later that year, she met with a financial advisor and had difficulty communicating her concerns. Over time, her speech became increasingly halting and effortful; she generated increasingly little spontaneous speech and would often respond to questions with words opposite to her intended meaning. She became increasingly dysarthric and complained that others around her were “talking too fast,” as she could not understand them. Her daughter noticed during visits that she often watched television with the sound off. She became increasingly irritable, tearful, and socially withdrawn over time, though her ability to manage her finances, make purchases at local shops, and manage her own medications remained intact.
Her neurological evaluation was notable for halting speech with frequent phonemic and semantic paraphrasias, lower motor neuron dysarthria, and hypophonia. She had a left-sided hemifacial spasm during the exam with possible flattening of the right nasolabial fold; cranial nerve, motor, and sensory exam was otherwise unremarkable. She had a smooth, narrow-based casual gait and was able to heel, toe, and tandem walk without difficulty, but consistently veered to the left when walking.
Neuropsychological evaluation showed profound deficits on language testing, as well as executive dysfunction; visuospatial and memory domains were relatively spared.
Neuroimaging showed left more than right ventral frontotemporal atrophy and more symmetric bilateral parietal atrophy.
She was given a clinical diagnosis of non-fluent variant primary progressive aphasia. She passed away 6 years after symptom onset. Neuropathological evaluation on autopsy showed CBD.
Behavioral variant frontotemporal dementia (bvFTD)
As illustrated in the case below, bvFTD often presents with striking alterations in personality and behavior. Clinical criteria include early behavioral disinhibition (including socially inappropriate behavior, impulsivity, and carelessness), early apathy or inertia, early loss of sympathy or empathy, perseverative, stereotyped, or ritualistic behaviors (including both simple repetitive movements and more complex behaviors and stereotypies), hyperorality, and dietary changes (often with “food fads” and an increased preference for sweet foods, as well as oral exploration of non-edible objects), and a neuropsychological profile of executive dysfunction out of proportion to deficits in episodic memory and visuospatial skills [46]. Neuroimaging typically shows atrophy in frontotemporal cortex by MRI, with hypometabolism in these regions on PET scans.
Vignette 3
A 68-year-old man presented for evaluation of 3 to 4 years of personality changes and cognitive deficits. Initially, his wife noticed that he was having difficulty recognizing famous faces in movies. At the same time, he became more argumentative and critical, began driving aggressively, and was once run off the road by a car for tailgating. He lost interest in attending his grandchildren’s school events and was not interested in moving to his new home. His difficulty recognizing names and faces progressed to the point that he had trouble identifying his siblings and grandchildren. He became more disinhibited, approaching strangers to tell them jokes, and he stopped showering unless requested to do so. He began to follow a rigid daily schedule and became compulsive about relocating household items to their correct spots. He began craving sweet foods, leading to a 75-pound weight gain, and also insisted on eating a particular cereal multiple times a day. He began kicking the family cat for no clear reason. He became unable to pay his bills or use the telephone; he stopped being able to assist with more complex household tasks. He became forgetful, both for day-to-day activities and for autobiographical information; his wife noticed subtle word-finding difficulties and phonemic paraphasias. He had some episodes of inappropriate crying and occasionally choked on his food.
Neurological exam was notable for socially inappropriate and at times sexually suggestive behaviors, as well as frequent allusions to excrement. He was restless during the evaluation and repeatedly ran his hands through his hair. A snout reflex was present. No cranial nerve abnormalities were noted; a mild intention tremor was seen on motor exam, but he had a normal, narrow-based casual gait and could tandem walk easily. His neuropsychological evaluation was remarkable for perseveration on multiple tasks and particularly poor performance on tests of executive function, with difficulties on a naming task but good performance on other language tasks, as well as relative sparing of visuospatial functioning. Neuroimaging showed severe right temporal atrophy with particularly dramatic volume loss in the right insula and amygdala; prominent right- more than left-sided orbitofrontal atrophy was also present. Although no fasciculations or other signs concerning for motor neuron disease were noted on neurological exam, EMG showed long-duration motor units in the tongue and left tibialis anterior.
He was given a clinical diagnosis of behavioral variant frontotemporaldementia and passed away 7 years after symptom onset; autopsy confirmed a diagnosis of CBD.
CBS, CBD, and the problem of clinical–pathological correlation
As discussed above, not all patients found to have CBD on pathology present with CBS clinically. The three main clinical syndromes associated with CBD, as above, are an executive-motor syndrome (similar to earlier descriptions of CBS), nfvPPA, and bvFTD; more rarely, other clinical syndromes including PSPS, PD, AD, and even posterior cortical atrophy (PCA) prove to have underlying CBD on autopsy [37, 42, 47–49]. New clinical criteria for CBD (Armstrong, 2013) have incorporated this clinical heterogeneity and describe the presence of CBS, nfvPPA, frontal behavioral–spatial syndrome, or PSPS as clinical phenotypes associated with CBD; non-CBS presentations must have one of the six cardinal features of CBS (limb rigidity or akinesia, limb dystonia, limb myoclonus, orobuccal or limb apraxia, cortical sensory deficit, or alien limb phenomena). Symptoms must have been present for 1 year at minimum, arise insidiously, and progress gradually to meet criteria for possible CBD [50].
Conversely, not all patients with clinical CBS are found to have CBD on autopsy. Senstivities, in fact, are quite poor, ranging from 31–56% [5, 7, 8, 51]. Alternate underlying pathologies include other tauopathies (ranging from PSP to Pick’s disease to frontotemporal dementia and parkinsonism linked to tau mutations on chromosome 17 [FTDP-17]), frontotemporal lobar degeneration with TAR DNA binding protein-43 (TDP-43), immunoreactive inclusions (FTLD-TDP), Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), and even Creutzfeldt–Jakob disease [42–44, 47, 51–53]. Of non-CBD pathologies, PSP is perhaps the most common, with one study showing nearly 50% PSP pathology in a series of 21 patients [44].
Given the clinical heterogeneity of patients with underlying CBD, and the pathological heterogeneity of patients with clinical CBS, researchers have understandably searched for clinical features that can help predict underlying pathology with more accuracy. However, to this point, there is no specific symptom or sign in a CBS patient that can accurately predict the presence of underlying CBD. Motor symptoms classically associated with CBS such as dystonia and asymmetric parkinsonism are not specific for CBD and can be seen at similar rates in a variety of other pathologies, including AD, PSP, FTLD-TDP or mixed pathologies [5]. Further, these symptoms may not emerge until late in the disease course, as in our CBS case above. Cortical signs classically seen in CBS such as apraxia and cortical sensory loss are not highly specific for CBD pathology and are in fact frequently seen in AD [5]. Specific eye movement abnormalities may be characteristic of CBS, with quantitative studies showing increased latency and preserved velocity in CBD, though one study showed no difference in latency or velocity from control subjects and instead showed impairments in patients with underlying CBD on an anti-saccade task [54–59]. The early presence of memory and visuospatial deficits may suggest underlying AD [5], though the utility of these features on the individual level is not clear. Similarly, neuropsychological testing that shows poorer performance on tests of visual and verbal memory may be somewhat predictive of underlying AD, rather than CBD pathology in CBS [5, 53], though there is not yet evidence that these features are predictive on an individual level. The classic teaching that CBD is associated with asymmetric motor features and apraxia has been questioned by several studies showing CBD in patients with symmetric motor findings and symmetric atrophy on imaging [5, 60–62].
Progressive supranuclear palsy (PSP)
The clinical and pathological features of PSP were first described by Steele, Richardson, and Olszewski in 1964, who presented nine cases of “a progressive brain disease featured by supranuclear ophthalmolplegia affecting chiefly vertical gaze, pseudobulbar palsy, dysarthria, dystonic rigidity of the neck and upper trunk, and other less constant cerebellar symptoms,” as well as a “usually… mild” dementia [63]. They noted common pathological features including neurofibrillary tangles in specific regions within the basal ganglia, brainstem, and cerebellum and suspected an underlying degenerative or infectious process based on the pathological similarities to post-encephalitic parkinsonism and the parkinsonism–dementia complex of Guam [63]. The neurofibrillary tangles were later found to consist of tau protein [64], confirming PSP as a four-repeat tauopathy in the same family as CBD.
The clinical features of PSP (recently often termed PSP syndrome [PSPS] to distinguish it from the pathological entity) were further described in the late 1960s and 1970s [65, 66]; current diagnostic criteria include the core features noted by Richardson and colleagues and also include early cognitive features such as apathy, impairment in abstract thought, decreased verbal fluency, utilization or imitative behvaiors, or frontal release signs, as well as executive dysfunction on neuropsychological testing, as supportive diagnostic features [67]. Core diagnostic features consist of progressive impairment beginning after 40 years of age; supranuclear vertical gaze palsy; and postural instability with falls in the first year of disease onset [67].
As with CBD, not all patients found to have PSP at autopsy are diagnosed with PSPS on presentation. A majority (roughly half to two-thirds) are diagnosed with PSPS at symptom onset [47, 68–73], and roughly 80% of individuals diagnosed with PSPS do in fact have PSP at autopsy [68, 70]. Alternate clinical diagnoses with autopsy findings consistent with PSP include CBS, PD, and MSA [51, 73], with CBS being a particularly common clinical syndrome: in some series, fully half of patients with CBS have underlying PSP pathology [44, 74], illustrating the substantive clinical overlap between these two disorders. Of patients with PSPS who do not have PSP on autopsy, underlying pathological processes include DLB, AD, MSA, Picks’ disease, and FTDP-17 [71].
Pathology
Gross pathology reveals clear thalamic, dorsal midbrain, and dentate nuclear atrophy, with the globus pallidus, subthalamic nucleus, and superior cerebellar peduncle being the most affected [75]. Mild frontal cortical atrophy may also be appreciated.
On microscopic analysis, rounded “globose” neurofibrillary tangles are found in affected nuclei on microscopic evaluation; both glial and neuronal tau inclusions are seen on tau immunohistochemistry staining. The highest burden of tauopathy is seen in the subthalamic nucleus, substantia nigra, and globus pallidus [76–78]. Neuronal loss and gliosis are seen particularly in the dentate nucleus and superior cerebellar peduncle as well as within the thalamus, striatum, and nucleus basalis of Meynert, and there is clear loss of dopaminergic neurons in the subthalamic nucleus and substantia nigra [79, 80].
Glial cells, termed “tufted astrocytes” based on the appearance of their tau-positive, argyrophilic inclusions, are seen in both PSP and CBD but are more common in PSP [17]; these are seen most commonly in striatum and motor cortex [81, 82]. “Coiled bodies,” also characteristic of PSP, are tau-positive, argyrophilic perinuclear fibers seen in oligodendrocytes [83].
Epidemiology and genetics
Like CBD, PSP is a relatively rare neurodegenerative disorder, with an age-adjusted prevalence of approximately 5 to 6 per 100,000 individuals in two community-based British studies [84, 85], and an American study showing an approximate incidence of 5.3 per 100,000 [86].
Most patients are diagnosed within their sixth to eighth decades of life, with average symptom onset in the sixth decade [87, 88]. Some studies show a higher incidence in men [85, 86], although both men and women are affected.
As with CBD, most cases are sporadic; however, as many as one-third of PSP patients have a first-degree relative with dementia or parkinsonism [89], implying that genetic factors influence the development of disease at least in a subset of patients. As in CBD, the H1/H1 haplotype of the MAPT gene is over-represented in patients with PSP [32–36]. One recent cohort study showed a greater than 90% prevalence of the H1 haplotype in a group of 64 Caucasian PSP patients (87.5% H1/H1 and 12.5% H1/H2) [32]. Variations in chromosome 1q31 have also been associated with PSP risk [90]. Recent genome-wide association studies have identified new candidate susceptibility genes for PSP, but their significance largely remains to be explored [91].
Clinical features
As above, Richardson and colleagues initially defined the core clinical features of PSPS as consisting of a supranuclear ophthalmoplegia, particularly of vertical gaze, dysarthria with dystonic rigidity of the axial musculature, and pseudobulbar palsy, with a usually mild dementia [63]. As a result of rigidity and ophthalmoplegia, often with a contribution of poor postural reflexes and impulsivity, patients develop progressive difficulties with balance and gait and suffer frequent and often dramatic falls. These often occur initially on uneven surfaces, but as the disease progresses may occur without any clear provoking factors. In addition to axial and proximal rigidity and akinesia, patients often develop retrocollis; dysarthria is often accompanied by progressive dysphagia; and many patients also suffer from urinary incontinence.
PSPS is also associated with a number of eye movement abnormalities in addition to the classic finding of vertical gaze palsy, which itself is a strong predictor of PSP on autopsy [69]. Square-wave jerks, followed by slowing of vertical saccade velocity, may precede the development of florid supranuclear gaze palsy. Abnormalities in vertical (more than horizontal) saccade velocity and excursion are particularly characteristic of PSP when compared to other neurodegenerative disorders (such as CBS, AD, and frontotemporal dementias) [59]. PSP patients also show the most prominent deficits in saccade gain (adjusting saccadic amplitudes relative to a target to maintain accuracy) when compared to patients with CBS and AD [54–57]. Reduced blink rate, blepharospasm, and eyelid-opening apraxia are also characteristic oculomotor changes [92], and the procerus sign, a chronic furrowed appearance of the brow related to contraction of the corrugator and orbicularis oculi muscles, is a characteristic physical finding. Although the gaze palsy of PSPS is initially supranuclear, late in the course of illness the oculocephalic reflex may disappear.
More recently, cognitive symptoms of PSPS have received greater attention. Interestingly, behavioral changes and dysexecutive features overlap substantially with a subset of key criteria for bvFTD, with symptoms like apathy and disinhibition being the most common and hyperorality and repetitive behaviors less so [93–95]. Such behavioral symptoms may be the earliest symptoms in some patients, preceding falls and motor symptoms [68, 94, 96] and leading to diagnostic ambiguity in the earlier stages of illness. In contrast to dysexecutive features, memory symptoms in PSPS are usually mild and often consist of retrieval deficits [97].
The case below illustrates a fairly classic presentation of PSPS, incorporating many of the core diagnostic criteria defined by Litvan in 1996 including progressive impairment with early falls. The impulsive, often dramatic nature of this patient’s falls is highly characteristic of patients with this syndrome. Notably, this patient does not yet show the classic vertical supranuclear gaze palsy but instead has subtler findings of square wave jerks and slowed saccade velocity.
Vignette 4
A 77-year-old woman had noticed progressive imbalance over the past 5 years, with increasingly frequent and dramatic falls, particularly on uneven surfaces. By the time she presented to our center, she had begun using a cane for balance and using her husband’s arm to help guide her down their front steps. Most falls occurred when she would impulsively decide to complete a task – such as picking up her grandchildren’s toys – that involved bending over; she would fall while straightening back up. In recent months, she had begun to notice other physical changes, including difficulty swallowing dry or chewy foods and difficulty with fine motor tasks such as placing earrings and using a knife skillfully at dinner.
More recently, she had begun noticing cognitive changes as well, predominantly in her memory. She felt she would easily forget plans she and her husband had made for the day; she typically would not know the date or day of the week. Her husband was most concerned about changes in her personality. Previously a social and artistic woman, she had become apathetic and socially disengaged. On one occasion, a friend came to visit her at home and she barely turned from the television to acknowledge her. She became less excited about outings and would complain of fatigue after a single activity and ask to return home. She began smoking in her bedroom, leaving burn holes in her clothing, on furniture, and on the rug. Her husband began to notice that when they read books together in the evening she seemed to be opening to a random page and then reading from there, without seeming to care where she was in her book.
Her neurological exam was particularly notable for postural and gait instability, with parkinsonian features. Although she had no limitation in vertical or horizontal gaze, her eye movements were abnormal for horizontal square-wave jerks on primary gaze and decreased saccade velocity. A snout reflex was present. On cognitive testing, she had marked deficits in memory and executive functioning, with particularly notable deficits in recall and verbal fluency (both phonemic and semantic) when compared to prior exams, as well as more moderate difficulties with visuospatial tasks. Her language function was relatively spared. Her imaging showed prominent midbrain atrophy as well as diffuse atrophy throughout the cortex and mesial temporal structures, which was felt to be non-focal. She was given a clinical diagnosis of PSP.
Diagnostic studies in CBD and PSP
Labs and biomarker studies
Although there are currently no clinical laboratory tests to screen for CBD or PSP, as with any patient with cognitive impairment, patients with suspected CBD or PSP should have routine laboratory testing for vitamin B12 deficiency and thyroid dysfunction (as well as HIV and syphilis in selected populations) to evaluate for reversible contributors to cognitive decline.
Research studies have evaluated whether CBS or PSPS, given that they are both tauopathies, might be associated with abnormal levels of total and phosphorylated tau in cerebrospinal fluid (CSF). While some studies show no differences between individuals with these syndromes and controls [98, 99], two studies showed higher levels of CSF total tau in CBS patients compared to those with PSPS and controls [100, 101]. It is worth emphasizing that most studies were limited by being performed in patients with clinical diagnoses without autopsy confirmation, limiting their power and generalizability.
Other CSF studies in CBS and PSPS evaluated for differences in CSF A-beta42 levels between these patient populations and controls; while two groups found no differences [102, 103], one study found decreased levels in both patient populations compared to controls [99]. A study evaluating for CSF neurofilament heavy chain (a measure of axonal injury) showed higher levels in PSPS patients when compared to PD patients and controls [104].
Imaging
In general, quantitative brain imaging studies show distinct patterns of atrophy in CBD and PSP, which correspond to the most affected regions on autopsy. Patients with underlying CBD, no matter their clinical syndrome, tend to show atrophy in bilateral dorsomedial prefrontal cortex, supplementary motor and perirolandic cortex, and striatum, as well as certain brainstem regions [5], corresponding to the regions which show the greatest degree of pathology on autopsy (frontal lobes, basal ganglia, and brainstem) [5, 105]. As described above, neuroimaging often also reveals atrophy specific to patients’ clinical syndromes. For example, patients with CBS show dorsomedial frontal, perirolandic, and dorsal insular atrophy no matter their underlying pathology [5, 105], though those with underlying FTLD pathology show more extensive frontal and brainstem atrophy while those with underlying AD pathology show more atrophy in parietal regions including precuneus and temporoparietal cortex [5].
In PSP, although classic imaging features include third ventricle dilatation and dorsal midbrain atrophy (the so-called “humming bird sign”), studies attempting to differentiate PSP from other neurodegenerative disorders based on midbrain anteroposterior diameter have had mixed results [106, 107]. VBM analysis of imaging features of patients with PSPS shows significant atrophy of frontal cortex, pons, thalamus, and striatum [108, 109]; the degree of midbrain and cerebral peduncle atrophy is significantly greater in PSPS than PD [110]. One study of patients with autopsy-proven PSP (n = 13) showed atrophy in premotor and supplementary motor cortex in addition to subcortical and brainstem structures [62].
In terms of other imaging modalities, amyloid PET imaging may be useful for confirming clinical suspicion of underlying AD pathology in patients with CBS and has been approved by the FDA for clinical use. Studies of novel tau PET ligands are currently ongoing on a research basis and may be helpful to evaluate for tauopathy in CBS and PSPS patients in the future [111].
Therapy
There are currently no disease-modifying therapies or FDA-approved therapies available for CBD or PSP. Clinical trials are currently evaluating the efficacy of anti-tau therapies, in hopes of addressing the underlying cause of these illnesses. In terms of symptomatic relief, a small subset of patients with CBD or PSP report transient symptomatic benefit from low doses of carbidopa–levodopa [112]; for this reason, although most patients will not respond, a trial of carbidopa–levadopa is indicated. Because of the high incidence of comorbid depression, many patients will benefit from the use of antidepressant medications [113]. Serotonin reuptake inhibitors seem to be particularly beneficial in our clinical experience, potentially because of underlying serotonergic dysfunction in these disorders. Botulinum toxin injections can be helpful for patients struggling with dystonia or blepharospasm [112]. Finally, as with other patients with AD, CBS patients with suspected underlying AD pathology may benefit from the use of an acetylcholinesterase inhibitor.
Many patients will benefit from physical and occupational therapy to maximize balance and gait and maintain flexibility and range of motion; home safety evaluations in collaboration with occupational therapy can help minimize the risk of falls. Serial dysphagia evaluations and collaboration with speech therapy can help assess and address aspiration risk and maximize speech and language function in the setting of dysarthria.
Summary and future directions
CBD and PSP are closely related neurodegenerative diseases, each associated with a four-repeat tauopathy, which are associated with significant clinical heterogeneity and overlap. Initially associated with a clinical syndrome of progressive and usually asymmetric motor findings, CBD is now known to be associated with several potential clinical presentations, including the classic corticobasal syndrome (CBS) but also nfvPPA and bvFTD. PSP, too, initially associated with progressive ophthalmoplegia and falls, can manifest clinically as several distinct syndromes, though a clinical presentation of PSPS strongly predicts underlying PSP. The prevalence and importance of early cognitive and behavioral symptoms in both CBD and PSP have been increasingly recognized, and such symptoms may precede the onset of clear motor and eye movement findings. Current investigations into tau-PET and other imaging modalities, as well as CSF biomarker analyses, hold great potential for future diagnostic precision and monitoring of therapeutic outcomes; clinical trials of anti-tau therapies may directly combat the build-up of toxic tau protein aggregates.
References
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