7: Corticobasal degeneration and progressive supranuclear palsy

CHAPTER 7
Corticobasal degeneration and progressive supranuclear palsy

Suzee E. Lee and Bruce L. Miller

University of California, San Francisco, San Francisco, CA, USA

History and nomenclature

Corticobasal degeneration

In 1968, Rebeiz and colleagues first described three patients with a progressive movement disorder and swollen neurons with poorly staining inclusions found at autopsy, a condition they named “corticodentatonigral degeneration with neuronal achromasia” [1]. Although the authors noted neuropathological overlap with Pick’s disease, they believed that the clinical features of these patients were inconsistent with Pick’s. Subsequent groups emphasized motor features of the disease, including focal reflex myoclonus, alien limb phenomena, apraxia, rigidity and akinesia, postural–action tremor, limb dystonia, hyperreflexia, and postural instability [2, 3]. Other researchers classified these patients as a subtype of Pick’s disease, emphasizing behavioral and cognitive symptoms in addition to extrapyramidal features of the condition [4]. Over time, this disorder came to be known as corticobasal degeneration. Neuronal aggregates in CBD were shown to consist of the microtubule-associated protein tau (MAPT) [5], drawing links to other tau-associated disorders, including PSP, progressive aphasia [6], and Pick’s disease [7].

Progressive supranuclear palsy

In 1964, Richardson, Olszewski, and Steele observed a syndrome of postural instability, supranuclear gaze palsy with prominent downgaze difficulty, spastic facies, axial rigidity, and dementia with personality changes [9]. Neuropathological studies revealed “cell loss, gliosis, neurofibrillary tangles, granulovacuolar degeneration and demyelination in various regions of the basal ganglia, brainstem and cerebellum”; these pathological changes bore a striking resemblance to postencephalitic parkinsonism and the parkinsonism–dementia complex of Guam [9]. Subsequent studies confirmed the consistency of clinical findings [10, 11], and clinical consensus criteria for PSP were established in 1996 (Table 7.1) [12]. Neuronal aggregates found in PSP consist of tau protein [13], linking PSP to other tau disorders.

Table 7.1 NINDS–SPSP clinical criteria for PSP (1996).

I. Mandatory inclusion criteria

A. PSP possible

Gradually progressive disorder
Onset at age 40 or later
Either vertical (upward or downward gaze) supranuclear palsy or both slowing of vertical saccades and prominent postural instability with falls in the first year of disease onset
No evidence of other diseases that could explain the foregoing features, as indicated by mandatory exclusion criteria

B. PSP probable

Gradually progressive disorder
Onset at age 40 or later
Vertical (upward or downward gaze) supranuclear palsy and prominent postural instability with falls in the first year of disease onset
No evidence of other diseases that could explain the foregoing features, as indicated by mandatory exclusion criteria

C. Definite

Clinically probable or possible PSP and histopathologic evidence of typical PSP

II. Mandatory exclusion criteria

Recent history of encephalitis
Alien limb syndrome, cortical sensory deficits, focal frontal, or temporoparietal atrophy
Hallucinations or delusions unrelated to dopaminergic therapy
Cortical dementia of Alzheimer’s type (severe amnesia and aphasia or agnosia, according to NINCDS-ADRA criteria)
Prominent, early cerebellar symptoms or prominent, early unexplained dysautonomia (marked hypotension and urinary disturbances)
Severe, asymmetric parkinsonian signs (i.e., bradykinesia)
Neuroradiologic evidence of relevant structural abnormality (i.e., basal ganglia or brainstem infarcts, lobar atrophy)
Whipple’s disease, confirmed by polymerase chain reaction, if indicated

III. Supportive criteria

Symmetric akinesia or rigidity, proximal more than distal
Abnormal neck posture, especially retrocollis
Poor or absent response of parkinsonism to levodopa therapy
Early dysphagia and dysarthria
Early onset of cognitive impairment including at least two of the following: apathy, impairment in abstract thought, decreased verbal fluency, utilization or imitation behavior, or frontal release signs

Autopsy series highlight the clinical heterogeneity of CBD and PSP. Thus, the terms corticobasal syndrome [14] and progressive supranuclear palsy syndrome distinguish the clinically defined syndrome from the pathological entities, CBD and PSP. For the remainder of this chapter, we will use the terms CBD and PSP to refer to pathologically defined diseases and CBS and PSP syndrome to refer to the clinically defined syndromes.

Epidemiology

Typically, symptoms in pathologically proven CBD emerge between the sixth and eighth decades of life [15]. To our knowledge, the youngest patient with pathologically confirmed CBD had symptom onset at age 45 [15]. Both women and men are affected with some studies citing higher rates in women [16]. To date, there have been no population-based studies of CBD, and CBD is regarded as a rare neurodegenerative disorder, although studies have estimated of 4.9 cases per 100 000 people in the United States [17] and 1.7 per 100 000 in Japan [18a]. Mean age at onset in a series of 267 patients with CBD was 64 years with a disease duration of 6.6 years [18b].

A study from the United Kingdom found that an age-adjusted prevalence of PSP is approximately 5 per 100 000 [19, 20]. Men appear to have a slightly higher incidence of PSP. A study in the United States showed an average annual incidence rate of 5.3 per 100 000 person-years, and incidence was higher in men than women [21]. Most patients with PSP are affected in the sixth decade of life, with ages of presentation ranging from the 50s to the 60s [22, 23].

Studies of the MAPT gene (MAPT) reveal overrepresentation of the H1 MAPT haplotype in both CBD and PSP [24, 25]. Association between the H1/H1 genotypes also occurs with FTD [26, 27] and primary progressive aphasia [28]. H1/H1 is the common genotype found with near 100% prevalence in Japanese and approximately 70% in Caucasians [29, 30]. In one cohort of 64 Caucasian patients with PSP, the prevalence of the H1 haplotype was greater than 90%, with 87.5% H1/H1 and 12.5% H1/H2 [24].

Clinical features of corticobasal syndrome

In the 1980s, clinicians in the movement disorder community suggested that CBD was a progressive neurodegenerative condition characterized by asymmetric parkinsonism, apraxia, myoclonus, dystonia, and alien limb syndrome [1–3]. Clinicopathological studies eventually demonstrated that the CBS clinical syndrome poorly predicts CBD pathology [14]. Despite CBD’s initial characterization as a movement disorder, CBD also manifests frontal lobe degeneration presenting with cognitive and behavioral symptoms [8, 31], with motor symptoms sometimes emerging only during advanced disease stages [8, 32–35]. Thus, the absence of early motor findings does not exclude CBD from the picture. Moreover, features of bvFTD, nfvPPA, and CBS may overlap or evolve within individual patients throughout the disease course [33, 36]. The three main clinical presentations of CBD include a motor syndrome with prominent, early executive dysfunction, nfvPPA, and bvFTD [8]. Case studies are presented below as examples.

Case 1 Executive–motor syndrome

A 68-year-old right-handed woman started having difficulty with balance 4 years prior to presentation. Initially, she tripped on uneven ground, usually with her right foot, although her leg was not weak. Three years before presentation, she noted trouble with organizing and multitasking; memory seemed intact. She noted progressive difficulty controlling her right leg. Once, she tried to step over her grandchild’s toy on the ground, but her right leg remained in the air, and she could not put it down. When seated, she noticed difficulty crossing her right leg over her left. She gradually lost dexterity of her right hand, and her handwriting deteriorated. About 1 year ago, her right forearm moved suddenly and uncontrollably, knocking over a vase of flowers. Her gait slowed. Six months before presentation, she developed increasing apathy and social withdrawal, slowing losing interest in her grandchildren and ending most of her social relationships.

On exam, affect was sad and facies were masked. On primary gaze, there were no square wave jerks. Saccadic eye movement testing showed increased latency to initiating saccadic eye movements in all directions, with normal velocity and full excursion of extraocular movements. There was moderate cogwheel rigidity in the upper extremities, more prominent on the right, and hypertonia in the right lower extremity. Mild axial rigidity was present. Strength was full. A mild, high-frequency bilateral postural hand tremor was present, more prominent on the right. There was no rest tremor. Deep tendon reflexes were symmetric and 2+; plantar response was flexor bilaterally. Sensory exam was intact. Gait revealed diminished arm swing, worse on the right, with mild shuffling and difficulty with turns. She intermittently held her right arm in a flexed posture.

Neuropsychological testing revealed significant deficits in executive function, particularly with verbal fluencies and set-shifting. Mild deficits in naming and episodic memory were noted. Visuospatial skills were intact. A brain MRI revealed focal atrophy in dorsomedial frontal cortex and insula and bilateral primary motor cortices (see Figure 7.1).

Figure 7.1 Brain MRI in executive–motor CBD. T1-weighted brain MRI of a 68-year-old right-handed woman with pathological-proven CBD with an executive–motor syndrome. Sagittal MRI (left) shows dorsolateral frontal atrophy, and axial MRI (right) shows bilateral parietal atrophy, particularly in the primary motor cortex. Orientation is radiological (left is right).

In subsequent evaluations, her gait grew progressively worse, and her memory deteriorated. She developed retrocollis, and severe appendicular rigidity ensued. She had trouble with swallowing and began to choke, particularly when drinking liquids. She grew nonverbal but remained cooperative on examination. She died 5 years after symptom onset. Autopsy showed CBD.

As described in the case above, the executive–motor syndrome presents with extrapyramidal syndromes including axial or appendicular rigidity, dystonia, and progressive loss of limb function, findings classically associated with CBS. Poor performance on executive function measures occurs early during the disease course. Perirolandic, supplementary motor area, striatal and insular atrophy are associated with the executive–motor syndrome [8].

Case 2 Nonfluent variant primary progressive aphasia

A 54-year-old right-handed woman first noted difficulty with speaking 3 years prior to evaluation. Initially, she had trouble finding words in conversation, and pauses in her speech evolved into stuttering. Even though she knew what she wanted to say, her speech grew slow and effortful. Her speech was slurred; she made frequent phonemic paraphasic errors, and she occasionally stressed the wrong syllable in pronouncing words. Her speech grew agrammatical and she tended to omit articles and conjunctions. She had no difficulty with comprehension, reading, or spelling. About 1 year prior to evaluation, behavioral symptoms emerged. She compulsively arranged the books on her coffee table with the edges aligned. She also took food from her family members’ plates without permission. Six months prior, she developed difficulty using her right hand and began to use her left hand to pick up objects. Her right arm appeared stiff, and she frequently held it fixed at her side.

On exam, she was cooperative. Speech was effortful, dysarthric, and agrammatical. Apraxia of speech and orobuccal apraxia were noted, but limb apraxia was absent. There were no square wave jerks and saccadic eye movements were normal. There was mild cogwheel rigidity in the right upper extremity, but no axial rigidity. Strength was full. A mild, high-frequency postural right-hand tremor was present. Deep tendon reflexes were symmetric and 2+; plantar response was flexor bilaterally. Sensory exam was normal. Gait revealed diminished arm swing on the right with normal stride and turns.

Neuropsychological testing revealed significant deficits in language testing, including naming and repetition. Verbal memory and executive function were impaired, but the prominence of her language impairments rendered the interpretation of other cognitive testing less clear. Visuospatial skills were intact. A brain MRI revealed severe focal left insular and left inferior frontal gyrus atrophy with mild atrophy in bilateral orbitofrontal cortex and medial frontal regions (see Figure 7.2).

Figure 7.2 Brain MRI in nonfluent variant primary progressive aphasia secondary to CBD. Coronal T1-weighted brain MRI of a 54-year-old right-handed woman showing severe focal left insular and left inferior frontal gyrus atrophy with mild atrophy in bilateral orbitofrontal cortex and medial frontal regions. Orientation is radiological.

Over the next few years, she developed severe right-sided rigidity and grew mute. She had involuntary movements in her right hand and foot, which also intermittently assumed dystonic postures, and eventually had trouble using utensils in her left hand. On exam, her eye movements were extremely limited, and she had right-sided visual neglect. She died 7 years after symptom onset; at autopsy, she was diagnosed with CBD.

Features of nfvPPA include agrammatism with effortful, halting speech and impaired comprehension of syntactically complicated sentences, with spared single-word comprehension and object knowledge [37]. Left frontoinsular atrophy on MRI or hypometabolism on PET might be observed. Some studies suggest that nfvPPA correlates most strongly with FTLD-tau within the FTLD spectrum [8, 38–40] although FTLD-TDP pathology [8, 41] has also been found underlying nfvPPA.

Case 3 Behavioral variant frontotemporal dementia

A 64-year-old gentleman began to develop personality changes 7 years prior to evaluation. He developed a newfound interest in painting, and began to wear bizarre, brightly colored outfits. Over the next several years, his obsession with painting burgeoned, and he created hundreds of pieces of art. He also became less risk-averse. Previously conservative with money, he developed an interest in gambling, both winning and losing large amounts of money in casinos. He became a “born-again” Christian 5 years prior to evaluation and began praying several times a day. He was evaluated by a psychiatrist who diagnosed him with depression and started an SSRI, which did not significantly alleviate his symptoms.

Four years after his personality changes began, he developed short-term memory difficulty. Word-finding difficulties emerged and he spoke less. He grew emotionally blunted and withdrawn. In the few months prior to evaluation, his family noted that his gait grew slower and that he had a hand tremor.

On exam, he remained quiet and had a flat affect. Speech was clear and grammatical, but he spoke only in short phrases. Cranial nerve, motor, reflex, and sensory examination appeared normal. Gait exam revealed diminished right arm swing with normal stride and turns.

Neuropsychological testing revealed significant deficits in memory, language, and executive function. Visuospatial skills were intact. A brain MRI revealed bilateral frontoinsular and dorsomedial frontal and dorsolateral prefrontal atrophy, more prominent on the right (see Figure 7.3).

Figure 7.3 Brain MRI in behavioral variant frontotemporal dementia secondary to CBD. Coronal T1-weighted brain MRI in a 64-year-old gentleman showing bilateral frontoinsular, dorsomedial frontal, and dorsolateral prefrontal atrophy. Orientation is radiological.

In follow-up evaluations, his postural hand tremor worsened. When walking, he developed dystonic posturing of his right arm. He stopped initiating conversations and needed to be monitored and encouraged to perform basic activities of daily living, such as toileting and grooming. His speech grew sparser and he answered questions with single words. He died 12 years after his initial symptoms of personality changes. Autopsy revealed CBD.

The earliest and more salient features of behavioral variant frontotemporal dementia (bvFTD) include changes in behavior and personality [42]. bvFTD clinical criteria include early behavioral disinhibition, apathy or inertia, and loss of sympathy or empathy, compulsive behaviors ranging from simple repetitive movements to complex, ritualistic behaviors, and hyperorality or dietary changes, such as altered food preferences, binge eating or drinking alcohol, and placing inedible objects in the mouth. Often, behavioral changes are misdiagnosed as psychiatric disease early in the disease course. Typically, visuospatial skills and memory are spared early in bvFTD. Frontal and temporal brain atrophy on MRI brain or hypometabolism on PET scans emerges.

Correlation between CBS and CBD

Clinicopathological correlation studies attest to the significant challenges of diagnosing CBD. Autopsy studies demonstrate that the sensitivities of CBS for CBD are poor ranging from 31 to 56% [8, 32, 34, 43]. The pathologies underlying CBS are protean and include CBD, tauopathies other than CBD (including PSP, Pick’s disease, 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 Creutzfeldt–Jakob disease [38–40, 43–46]. Recent autopsy series have shown that underlying CBD pathology is found in only 35–55% of all patients who present with CBS during life [8, 38, 40, 44, 47, 48]. PSP pathology commonly manifests as CBS with one study citing nearly 50% of 21 CBS patients with PSP at autopsy [40].

Conversely, many patients with autopsy-confirmed CBD are not suspected of having the disease during life [38, 44, 47, 49, 50]. As described previously, the clinical presentations of CBD are heterogeneous and include bvFTD, nfvPPA, PSP syndrome, Parkinson’s disease (PD), AD, and occasionally posterior cortical atrophy (PCA) [8, 40, 49, 51, 52], rendering diagnosis challenging. Based on 267 pathologically confirmed CBD cases, new criteria for possible and probable CBD have been established [18b]. These 2013 criteria for possible CBD include insidious onset and gradual progression, with symptoms lasting at least 1 year, with one of four clinical syndromes (possible corticobasal syndrome, frontal behavioral–spatial syndrome or nonfluent/agrammatic primary progressive aphasia, PSP syndrome) with an additional feature of CBS. The more stringent criteria for probable CBD include those for possible but also require age at onset to be greater than 50 years and no family history of similar conditions or known tau mutations [18b]. Future studies are necessary to determine the sensitivity and specificity of the new CBD criteria.

Despite attempts to characterize symptoms and signs predictive of CBD pathology, the overlap of these symptoms and signs with other neurodegenerative diseases makes pathological prediction at the bedside extremely challenging. Although cortical symptoms and signs for CBD have historically included visuospatial deficits, limb apraxia, and cortical sensory loss, these parietal lobe-associated features are not specific for CBD pathology and are common in AD [8]. Although memory and visuospatial deficits in CBS may suggest underlying AD in group studies, it remains unclear how such deficits improve diagnosis at individual patient level [8]. Motor symptoms in CBD may be absent up to 8 years after symptom onset, and motor symptoms classically associated with CBS are not exclusive to CBD pathology, presenting in similar rates in patients with CBS with underlying AD, PSP, FTLD-TDP, or mixed pathologies [8]. Quantitative eye movement studies of CBS suggested that saccadic eye movement latency is increased with relatively preserved velocity in CBD [53–57, 57a], although an eye movement study of autopsy-proven CBD suggests similar saccadic latency and velocity compared with controls, but impairments on an antisaccade task [57b]. This contrasts with the saccadic eye movement changes in PSP, in which the velocity of movements are slowed with relatively preserved latency [53, 54, 57b].

Neuropsychological testing in patients with CBS shows impairments in attention, executive function, and/or language impairments, with memory relatively less affected [8, 32, 34, 50, 58–60]. Although some studies have demonstrated that poorer performance on visual and verbal memory measures suggests underlying AD pathology in CBS [8, 46], the utility of neuropsychological testing in predicting CBD pathology remains unproven for individual patients.

Although the symptoms, signs, and neuropsychological profile described previously have been associated with CBD, they are variably present in individual patients. In patients with CBS, the presence or absence of any specific clinical sign or symptom does not reliably predict CBD pathology [8]. Furthermore, although asymmetry has been stressed as a core feature of CBD, several studies have revealed that CBD can emerge with symmetric parkinsonism and with symmetric brain degeneration [8, 61–63].

Clinical features of progressive supranuclear palsy syndrome

Progressive supranuclear palsy was first defined as a neurodegenerative syndrome consisting of supranuclear vertical gaze palsy, axial dystonia with a hypererect posture, bradykinesia, rigidity, and early falls [9]. In 1996, clinical consensus criteria for PSP syndrome defined core features as a progressive course of impairment beginning after the age of 40, with supranuclear gaze palsy, slowing of vertical saccadic eye movements, and postural instability with falls in the first year of onset (Table 7.1) [12].

Case study

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