Atypical parkinsonism, parkinsonism-plus syndromes and secondary parkinsonian disorders

Clinical features

Historically, the first case that James Parkinson described in his 1817 “Essay on the Shaking Palsy” had associated autonomic features and might have been the first case of MSA ( ). First coined by Graham and Oppenheimer in 1969 ( ), the term multiple system atrophy (MSA) describes a syndrome characterized clinically by parkinsonism, dysautonomia, and other features previously reported as Shy-Drager syndrome (SDS), striatonigral degeneration, and sporadic olivopontocerebellar atrophy (OPCA) ( ). The term Shy-Drager syndrome is still occasionally used in the literature, particularly by some American clinicians, as a tribute to Dr. Shy, a neurologist from University of Pennsylvania and Columbia University, and Dr. Drager, a urologist at Baylor College of Medicine, who first drew attention to this disorder in 1960 ( ). In their initial report, Shy and Drager described two men who presented with symptoms of orthostatic syncope, impotence, and bladder dysfunction. They later developed parkinsonian features, including gait disturbance, mild tremor, dysarthria, constipation, and bowel and bladder incontinence. The term striatonigral degeneration (SND) was introduced in the 1960s by Adams, Van Bogaert, and Van de Eecken ( ; ). Dejerine and Thomas (1900) introduced the term olivopontocerebellar atrophy to describe a group of heterogeneous disorders characterized clinically by the combination of progressive parkinsonism and cerebellar ataxia and pathologically by neuronal loss in the ventral pons, inferior olives, and cerebellar cortex ( ). OPCA may be inherited, usually in an autosomal dominant pattern, but only the sporadic OPCAs are considered variants of MSA. Although considered a sporadic disease, families with a phenotype suggestive of autosomal recessive MSA have been described (Hara et al., 2007). It is possible, however, that these familial cases represent either some forms, yet to be identified, SCA, or familial OPCA.

A rating scale, the Unified Multiple System Atrophy Rating Scale (UMSARS), that assesses all important symptoms and signs of MSA has been developed and validated against related rating scales, such as the Unified Parkinson’s Disease Rating Scale and the International Cooperative Ataxia Rating Scale ( ). The UMSRAS Motor Examination score, which has been demonstrated to have satisfactory intrarater reliability ( ) seems to be the best outcome measure for future therapeutic trials (May et al., 2007).

The discovery by Papp and colleagues (1989) that the pathologic hallmark shared by all three disorders is the presence of filamentous alpha-synuclein–containing glial cytoplasmic inclusions (GCI) led to the recognition that these disorders are manifestations of the same pathologic process ( ; ). MSA has therefore been redefined as a sporadic, progressive, adult-onset synucleinopathy characterized clinically by autonomic dysfunction (MSA-A), parkinsonism (MSA-P), and cerebellar ataxia (MSA-C) (Gilman et al., 2008). According to the second consensus statement (Gilman et al., 2008), features that would argue against the diagnosis of MSA include age at onset older than 75 years, the presence of typical PD rest tremor, neuropathy, sporadic hallucinations, dementia, white matter lesions in MRI suggestive of multiple sclerosis, and a family history of ataxia or parkinsonism. MSA may be difficult to differentiate from PD associated with autonomic dysfunction ( ). Whereas autonomic symptoms often precede the onset of MSA, this is rarely the case in PD. Furthermore, in contrast to PD, cardiac neuroimaging often shows evidence of sympathetic denervation in PD whereas cardiac sympathetic function remains typically intact in MSA. Besides lack of tremor, the symmetrical onset of SND (MSA-P) is sometimes helpful in differentiating SND from PD. In a study comparing 16 patients with pathologically proven MSA of the SND (MSA-P) variety with PD and PSP, a set of clinical criteria reliably differentiated MSA from PD but not from PSP (Colosimo et al., 1995). In addition to cerebellar and pyramidal signs and early instability with falls, the following features were more typically present in MSA than in PD: autonomic dysfunction (69% versus 5%), absence of rest tremor (87% versus 40%), rapid progression (mean disease duration 7.1 years versus 13.6 years), and poor or unsustained response to levodopa (31% versus 0%). In contrast to other reports, 43.7% of the MSA patients in this series had a symmetrical onset. Although earlier studies and the second consensus statement on MSA (Gilman et al., 2008) considered cognition to be relatively preserved in MSA, there is growing recognition that cognitive disturbances, particularly frontal-executive and visuospatial dysfunction and memory and frank dementia, may be present in patients with MSA ( ). Clinicopathologic studies, however, found no differences in pathologic changes between MSA patients with (n = 9) and without (N = 9) cognitive impairment ( ).

MSA should be considered in the differential diagnosis of adult-onset, sporadic parkinsonism, ataxia, and dysautonomia (Lin et al., 20014; ). The clinical features and natural history of MSA were analyzed in 100 cases with probable MSA, of which 14 were confirmed at autopsy ( ). The population consisted of 67 men and 33 women, with a median age at onset of 53 years (range, 33–76). Autonomic symptoms were present at onset in 41% of the patients, but 97% developed autonomic dysfunction during the course of the disease. Impotence was the most frequent autonomic symptom in men, and urinary incontinence predominated in women. Some evidence of orthostatic hypotension (OH) was present in 68% of patients, but severe OH was noted in 15%. In contrast to PD and other parkinsonian disorders in which the latency to onset of OH is usually several years, patients with MSA usually develop symptomatic OH within the first year after onset of symptoms ( ), and urinary dysfunction may occur even earlier ( , ). In another study of 16 autopsy-proven cases of MSA, Litvan, Goetz, and colleagues (1997) identified early severe autonomic failure, absence of cognitive impairment, early cerebellar symptoms, and early gait problems as the best predictors of the diagnosis of MSA. In a study designed to validate the clinical criteria for MSA, Litvan, Booth, and colleagues (1998) found that the accuracy was best when at least six of the following eight features were present: sporadic adult onset, dysautonomia, parkinsonism, pyramidal signs, cerebellar signs, no levodopa response, no cognitive dysfunction, and no downward gaze palsy. Wenning and colleagues (1997) examined the clinical features of 203 pathologically proven cases of MSA reported in 108 publications. The male-to-female ratio was 1.3:1, dysautonomia was present in 74%, parkinsonism in 87%, cerebellar ataxia in 54%, and pyramidal signs in 49%. MSA-P patients had more rapid deterioration than MSA-C patients. In a study of 49 MSA cases (median age at onset, 56.1 years; 16 women) confirmed by autopsy at Mayo Clinic, symptoms at onset were autonomic in 50%, parkinsonian in 30%, and cerebellar in 20% of cases (Figueroa et al., 2014). The median was 8.6 (6.7–10.2) years; it was shorter in patients with early laboratory evidence of generalized autonomic failure (7.0 versus 9.8 years; P =0.036), and early requirement of bladder catheterization (7.3 versus 13.7 years; P =0.003) compared with those without these clinical features. Another factor that adversely influenced survival was older age at onset, but sex, phenotype, early development of gait instability, aid-requiring ambulation, orthostatic symptoms, neurogenic bladder, or significant anhidrosis did not necessarily indicate shorter survival. In a natural history study, 175 patients with probable MSA-P or MSA-C from 12 U.S. neurology centers specializing in movement or autonomic disorders, evaluated every 6 months for 5 years with the UMSARS, the Composite Autonomic Symptoms Scale (COMPASS), and other instruments, the mean age at study entry was 63.4 years (±8.6), median survival from symptom onset was 9.8 years (95% confidence interval [CI], 8.8–10.7) and median survival from enrolment was 1.8 years (0.9–2.7) ( ). Patients with severe symptomatic autonomic failure at diagnosis progressed more rapidly than those without it, but there was no difference in prognosis between the two types of MSA. In another study from Mayo Clinic, a total of 685 patients were identified; 594 met criteria for probable MSA and 91 for possible MSA (Coon et al., 2015). The study found that the average age at onset was earlier in MSA-C (58.4 years) compared with MSA-P (62.3 years; P < 0.001); median disease duration from symptom onset to death was 7.51 years (95% CI, 7.18–7.78) and time from diagnosis to death was 3.33 years (95% CI, 2.92–3.59). A multivariate model retained the following unfavorable predictors of survival: (1) falls within 3 years of onset (hazard ratio [HR], 2.31; P < 0.0001), (2) bladder symptoms (HR, 1.96; P < 0.0001), (3) urinary catheterization within 3 years of symptom onset (HR, 1.67; P < 0.003), (4) orthostatic intolerance within 1 year of symptom onset (HR, 1.28, P < 0.014), (5) older age of onset (HR, 1.02; P = 0.001); and (6) degree of autonomic failure as measured by a validated composite autonomic severity score (HR, 1.07; P < 0.0023).

Early development of autonomic dysfunction has been found to be an independent predictor of poor prognosis ( ). It should be noted, however, that pure autonomic failure (PAF) might herald the onset not only of MSA but also of PD and DLB ( ; ; ). In PAF, OH and sudomotor dysfunction followed by constipation are the typical initial symptoms, whereas in MSA, the initial presentation usually consists of urinary problems, followed by sudomotor dysfunction or OH, with subsequent progression to respiratory dysfunction ( ; ). A study of 115 patients with MSA showed that autonomic dysfunction, motor impairment, and depression were most closely related to poor outcome in measures of health-related quality of life ( ). Among 437 MSA patients evaluated in 19 centers in 10 European countries, the mean age at onset was 57.8 years and the mean disease duration of symptoms was 5.8 years; 68% were classified as parkinsonian type (MSA-P) and 32% as cerebellar type (MSA-C) ( ). The investigators observed the following symptoms: dysautonomia 99%, erectile dysfunction 84% of males, parkinsonism 87%, symptomatic OH 75%, urinary incontinence 73%, cerebellar ataxia 64%, urinary retention 48%, hyperreflexia 43%, depression 41%, psychosis 6%, and dementia 4.5%. In one series of 29 autopsy-confirmed cases evaluated at the Mayo Clinic, rapid progression, early postural instability, poor levodopa responsiveness, symmetrical involvement, and progressive adrenergic and sudomotor failure, were highly predictive features of MSA ( ) ( Fig. 9.2 ).

Movement disorders other than parkinsonism that are seen in patients with MSA include dystonia, myoclonus, hemiballism, and chorea, unrelated to dopaminergic therapy ( ; ; ). Dystonia is relatively rare in MSA patients ( ; ), but in one study, 46% of patients with MSA were found to have dystonia, particularly if anterocollis is considered a form of cervical dystonia ( ). Some investigators, however, think that the neck flexion, often associated with anterior sagittal shift, is due to disproportionally increased tone in the anterior neck muscles leading to secondary fibrotic and myopathic changes (van de Warrenburg et al., 2008). Although dystonia is frequently considered to be a cause of the MSA-associated anterocollis, the mechanism of progressive neck flexion, so characteristic of MSA, particularly MSA-P, may be multifactorial. In some cases, the neck flexion has been attributed to neck extensor weakness as part of “dropped head” syndrome associated with axial myopathy ( ; ; Askmark et al., 2001), motor neuron disease (Gourie-Devi et al., 2003; Gilbert et al., 2010), or other causes. Neck flexion, however, is not unique to MSA and can be also seen in patients with otherwise typical PD (Djaldetti et al., 1999). In some cases of PD, more frequently than in MSA, the axial postural abnormality may lead to severe flexion of the trunk, the so-called bent spine syndrome, or camptocormia ( ; ; ). Another abnormal posture frequently encountered in MSA is the “Pisa syndrome” manifested by leaning of the body to one side reminiscent of leaning tower of Pisa ( ) ( Video 9.1 ). Besides anterocollis, another form of dystonia that is relatively frequently encountered in patients with MSA is facial and oromandibular dystonia associated with levodopa therapy, a typical form of levodopa-induced dyskinesia in patients with MSA.

Video 9.1 Multiple system atrophy (MSA).

In addition to action and stimulus-sensitive cortical myoclonus ( Video 9.1 ), focal reflex myoclonus, induced by pinprick, may be seen in MSA patients ( ; ). This form of myoclonus has a longer latency than that seen in patients with CBD (see later). In 9 of 11 patients with MSA and myoclonic tremulous movements, jerk-locked averaging technique showed premyoclonic potential, suggesting that the jerklike movements represent a form of cortical myoclonus ( ). Besides the classic motor signs, MSA is associated with a variety of oculomotor abnormalities, including sustained gaze evoked nystagmus, square wave jerks, slow and hypometric saccades, diminished vestibular-ocular reflex suppression, internuclear ophthalmoparesis, and reduced vertical gaze (Fabbrini et al., 2011; ).

Although dysautonomia is a cardinal feature of MSA, this neurodegenerative disorder should be differentiated from PAF, which has no central component ( ). Autonomic dysfunction is essential for the diagnosis of MSA, and in many cases of MSA, autonomic failure, particularly impotence, precedes other neurologic symptoms or signs by several years. In contrast to PD associated with dysautonomia, in which there is predominantly peripheral (ganglionic and postganglionic) involvement, including myocardial and sympathetic denervation, the peripheral autonomic system appears to be spared in MSA and the primary lesion is preganglionic ( ). In fact, some persistence of central autonomic tone might be responsible for the frequently observed supine hypertension in MSA ( ). MSA patients also have more autonomic symptoms at baseline and more progression to global anhidrosis, as demonstrated by the thermoregulatory sweat test, than patients with PD ( ; ; ). The “cold hands” sign, manifested by cold, dusky, violaceous appearance of the hands, is another characteristic feature of MSA ( ). Some patients have the “cold feet” sign ( Video 9.2 ). Liquid meal, consisting chiefly of glucose and milk, markedly reduces blood pressure in patients with MSA but not in those with PD ( ) ( Video 9.2 ).

Video 9.2 Multiple system atrophy (MSA).

Respiratory disturbance, including severe obstructive sleep apnea, and vocal cord paralysis with stridor may be found in more advanced stages of the disease ( ), but respiratory insufficiency may be the presenting symptom of MSA (Glass et al., 2006). Inspiratory stridor as a result of the paradoxical movement of the vocal cords (also known as Gerhardt syndrome) has been described in MSA (Eissler et al., 2001). The observation that inspiratory stridor improves with botulinum toxin injections into the adductor laryngeal muscles suggests that this symptom of MSA could be due to focal laryngeal dystonia ( ). The occurrence of nocturnal or daytime stridor carries a poor prognosis, particularly when it is associated with central hypoventilation ( ). Occasionally, however, vocal cord abductor paralysis can be seen even in the initial stages of the disease, and it has been associated with nocturnal sudden death ( ). In a study of 136 patients with MSA, stridor was diagnosed in 42 patients and 22 presented early stridor onset (Giannini et al., 2016). Patients with early stridor onset had a worse prognosis than those developing this symptom later and early stridor onset was an independent predictor for shorter survival; tracheostomy could control stridor, influencing disease duration.

Early diagnosis can be made by laryngoscopy during sleep. Hypoxemia with increased alveolar-arterial oxygen gradient, associated with laryngopharyngeal movements, however, has been demonstrated in MSA patients even during wakefulness ( ). The presence of impaired hypoxic ventilatory response has helped differentiate MSA-C from idiopathic late-onset cerebellar ataxia ( ).

Natural history

The natural history of MSA has been the subject of several studies. In contrast to the approximately 1.5% annual decline in Unified Parkinson’s Disease Rating Scale (UPDRS) III noted in patients with PD ( ), the average annual decline in MSA-P is 28.3% ( ). Most of the studies were based on pathologically proven cases; therefore, the prognosis in these series has been worse than otherwise predicted. On the basis of a meta-analysis of 433 reported cases of MSA, Ben-Shlomo and colleagues (1997) found survival to range from 0.5 to 24 years (mean: 6.2 years), and cerebellar features were associated with marginally better survival. In one study of 100 patients clinically diagnosed with probable MSA (14 of whom were pathologically confirmed), nearly half of all the patients were markedly disabled or wheelchair bound within 5 years after onset, and the median survival was 9.5 years ( ). This is similar to the findings from a prospective study of 141 patients with moderately severe MSA (mean age at symptom onset 56.2 ± 8.4 years) who had a median survival of 9.8 years (95% CI, 8.1–11.4) ( ). Shorter survival was suggested by the parkinsonian variant of MSA and incomplete bladder emptying, and shorter symptom duration at baseline and absent levodopa response predicted rapid progression. In one retrospective study of 100 patients with MSA the mean survival was 8 years; disease onset before 55 years predicted longer survival in, but there was no difference in survival between, MSA-P or MSA-C, although the frequency of abnormal magnetic resonance imaging (MRI) findings was higher in the MSA-C group ( ). In another study involving 22 patients followed prospectively with pathologically proven MSA, the median survival was 8.6 years for men and 7.3 years for women ( ). This is a rapidly progressive neurodegenerative disorder with death occurring usually within 7 to 8 years after the initial symptoms ( ; ).

MSA patients usually die of aspiration, sleep apnea, or cardiac arrhythmia. Survival data and clinically relevant milestones, that is, frequent falling, cognitive disability, unintelligible speech, severe dysphagia, dependence on wheelchair for mobility, the use of urinary catheters, and placement in residential care, were determined based on a retrospective chart review of pathologically confirmed cases of PSP (N = 110) and MSA (N = 42) ( ). Patients with PSP had an older age of onset ( P < 0.001) and reached their first clinical milestone earlier than patients with MSA ( P < 0.001). Patients with PSP generally had a less favorable prognosis than those with MSA. Although some authors have suggested that the earlier and the more severe the involvement of the autonomic nervous system, the poorer the prognosis ( ), this has not been confirmed by other studies ( ).

Differential diagnosis

When patients present with parkinsonism alone, without other evidence of MSA, their MSA might be difficult to differentiate from PD during the first 6 years ( ). In one study, the following features were found to be the best predictors of MSA: dysautonomia, poor response to levodopa, speech or bulbar dysfunction, falls, and absence of dementia and levodopa-induced confusion ( ). As in PD, PSP, and other subcortical neurodegenerative disorders, the cognitive deficit in MSA consists chiefly of mild impairment of memory and executive functions, with prefrontal dysfunction more severe in patients with MSA-P than those with MSA-C ( ). Although pseudobulbar affect associated with emotional incontinence, also referred to as emotional expression disorder, is typically seen in patients with PSP, pathologic laughter and crying has been described in autopsy-proven cases of MSA, particularly the MSA-C type ( ) and other neurodegenerative disorders, particularly amyotrophic lateral sclerosis. In one study, episodes of pseudobulbar crying or laughing were often induced by contextually appropriate emotional stimuli as a result of loss of inhibition in frontal neural systems that normally regulate emotion (Olney et al., 2011).

Several clinical studies have addressed the differentiation between MSA-P and other parkinsonian or ataxic disorders. A collection of “red flags” has been generated and validated as having high diagnostic specificity ( ; ; ; Fanciulli and Wenning, 2015; ; Fanciulli et al., 2019) ( Table 9.4 ). The red flags were grouped into the following six categories: (1) early instability, (2) rapid progression, (3) abnormal postures (includes Pisa syndrome, disproportionate anterocollis, and/or contractures of hand or feet), (4) bulbar dysfunction (includes severe dysphonia with “squeaky” voice, dysarthria, and/or dysphagia), (5) respiratory dysfunction includes diurnal or nocturnal inspiratory stridor and/or inspiratory sighs, and (6) emotional incontinence (includes inappropriate crying and/or laughing). A combination of two of these six red flag categories were used as additional criteria for the diagnosis of probable MSA-P. In one study the clinical records of 203 patients with a clinical diagnosis of MSA were reviewed and the following red flags were considered in support of the diagnosis of MSA: orofacial dystonia, disproportionate antecollis, camptocormia and/or Pisa syndrome, contractures of hands or feet, inspiratory sighs, severe dysphonia, severe dysarthria, snoring, cold hands and feet, pathologic laughter and crying, jerky myoclonic postural/action tremor and polyminimyoclonus, and seven disability milestones ( ). Of the 203 cases, 160 (78.8%) were correctly diagnosed in life and had pathologically confirmed MSA; the remaining 21.2% (43/203) had alternative pathologic diagnoses, including DLB (12.8%; n = 26), PSP (6.4%; n = 13), cerebrovascular diseases (CVD) (1%; n = 2), amyotrophic lateral sclerosis (ALS) (0.5%; n = 1), and cerebellar degeneration (0.5%; n = 1). More patients with MSA developed ataxia, stridor, dysphagia, and falls than patients with DLB; resting tremor, pill-rolling tremor, and hallucinations were more frequent in DLB. Autonomic dysfunction within the first 3 years from onset can differentiate MSA from PSP; patients with MSA had shorter latency to reach use of urinary catheter and longer latency to residential care than PSP patients.

Some features of MSA-C overlap with SCAs, particularly SCAs 2, 3, 7, 8, and 17 (Doherty et al., 2014; ). Also the fragile X–associated tremor/ataxia syndrome caused by permutations of the fragile X intellectual disability 1 gene (FMR1), and fragile X–associated tremor/ataxia syndrome may be a rare cause of MSA phenotype ( ). Pathologically, there might be some similarities between the central disorders, including the presence of GCI in rare cases of SCA, but the spinal cord is usually more atrophied in SCA than in MSA. There are many other disorders that clinically resemble MSA, and careful diagnostic approach is required before the diagnosis is secure ( ) ( Fig. 9.3 ).

Epidemiology

The average annual incidence for MSA has been estimated to be three new cases per 100,000 person-years ( ), but other have estimated an incidence of 0.7 per 100,000 person-years ( ). The age-adjusted prevalence has been reported to vary between 3.4:100,000 ( ) and 4.4 per 100,000 ( ). MSA appears to be more common in men than in women, with symptoms first beginning in the sixth decade, although rare cases of MSA with onset before age 40 have been reported ( ). Some studies have shown that, similar to PD, smoking is significantly less frequent in patients with MSA, and farming is an independent risk factor for MSA ( ).

Neurodiagnostic studies

In addition to tests of autonomic function, patterns of plasma levels of catecholamines and their metabolites may be helpful in differentiating the various forms of autonomic failures. These studies are designed primarily to localize the site of autonomic impairment and include investigation of neurogenic bladder, sphincter electromyography (EMG), and other investigations designed to test the integrity of the autonomic nervous system. External anal sphincter EMG denervation was once thought to be a sensitive measure of anorectal dysfunction in MSA, but it does not differentiate MSA from PD or from many other neurodegenerative disorders ( ). Although the peripheral sympathetic neurons are spared in MSA, there is some evidence that they lack the normal preganglionic activation ( ). Furthermore, the relatively well preserved sympathetic tone is probably responsible for the supine hypertension seen in many patients with MSA. In neurogenic OH, the rise in norepinephrine (NE) levels is minimal or absent despite a marked drop in blood pressure after either head-up tilt or an upright position. Clonidine has been found to increase growth hormone (GH) in normal controls, patients with PAF, and patients with PD but not patients with MSA ( ). In a study of 69 MSA patients, 35 PD patients, and 90 healthy controls, the GH response to arginine was found to be significantly lower in MSA patients compared with PD or healthy controls, a finding with over 90% sensitivity and specificity ( ). Whereas somatosensory, visual, and auditory evoked responses are often abnormal, motor evoked potentials are usually normal ( ).

Sleep abnormalities have been documented in patients with MSA even before the onset of motor symptoms ( ). A strong relationship between some form of RBD and subsequent MSA has been demonstrated by a number of other studies. Using video-polysomnography, RBD was observed in 43 of 49 (88%) patients with MSA, and in 81% bed partners reported some improvement in parkinsonian features during RBD episodes (Cochen et al., 2011). Obstructive sleep apnea in MSA is related to a thalamic cholinergic deficit, possibly owing to decreased pontine cholinergic projections.

Pharmacologically, MSA and PAF may be distinguished by supine and standing plasma NE levels. In PAF, both standing and supine NE levels are low, whereas in MSA, only the standing value is diminished. This is consistent with the notion that postganglionic sympathetic neurons are intact in MSA but their function is markedly impaired in PAF.

Neuroimaging techniques, including MRI, transcranial sonography, functional imaging (positron emission tomography [PET] and single-photon positron emission tomography [SPECT]), and imaging cardiac sympathetic innervation, can be very helpful in differentiating MSA from other parkinsonian disorders, and neuroimaging criteria have been proposed (Brooks et al., 2009). MRI in patients with MSA sometimes reveals areas of decreased signal bilaterally in the posterolateral putamen on T2-weighted images. Although increased levels of iron may contribute to this hypointensity, reactive microgliosis and astrogliosis may also play an important role. In addition to striatal (putaminal) hypointensity on T2-weighted MRI scans, a characteristic finding in patients with MSA, particularly MSA-P, is the slit-hyperintensity in the lateral margin of the putamen ( ). The combination of increased signal on T2 or fluid-attenuated inversion recovery (FLAIR) imaging in the lateral putamen (indicating iron deposition) and the slit hyperintensity at the posterolateral border of the putamen on T2-weighted images provides a sensitivity for MSA of 97% ( ) ( Fig. 9.4A ). Using diffusion-weighted imaging (DWI)-MRI, Schocke and colleagues (2002) found that regional apparent diffusion coefficients values are increased in the putamen of patients with MSA, and this evidence of striatal degeneration apparently reliably differentiates MSA from PD. DWI imaging showing abnormal signal in the middle cerebellar peduncle is apparently relatively specific for MSA-C and is not seen in PSP or PD ( ; ). Several studies have highlighted the “hot cross bun” sign in the pons as a characteristic feature of MSA ( ) (see Fig. 9.4B ). This sign is best visualized by proton density–weighted imaging (PDWI) ( ). Degenerated pontocerebellar tracts on diffusion tensor imaging (DTI) seems to correspond to the transverse portion of the hot cross bun sign (Fujimori et al., 2011). Another MRI sign that helps differentiate MSA from other parkinsonian disorders is the “zebra sign,” which may reflect the degeneration of the upper motor neurons within the motor cortex because it is also observed in patients with ALS ( ). A diagnostic algorithm based on brain MRI has been proposed ( ).

PET scanning has revealed decreased striatal and frontal lobe metabolism and a reduction in D2 receptor density in the striatum. In a study of 167 patients [ ¹⁸ F]fluorodeoxyglucose (FDG) PET was found to have high specificity and sensitivity in distinguishing among parkinsonian disorders ( ).

Besides neuroimaging, transcranial ultrasonography has been reported to provide high diagnostic yield in differentiating PD from atypical parkinsonian disorders. Brain parenchyma sonography was used in one study to differentiate PD from atypical parkinsonism, mostly MSA ( ). The investigators found that 24 of 25 (96%) patients with PD exhibited hyperechogenicity, whereas only 2 of 23 (9%) patients with atypical parkinsonism showed a similar pattern. They concluded that brain parenchyma sonography might be highly specific in differentiating between PD and atypical parkinsonism. Sonographic studies in 102 patients with PD, 34 with MSA, and 21 with PSP found marked unilateral or bilateral hyperechogenicity in 89% of 88 patients with PD, 25% of 32 patients with MSA-P, and 39% of 18 patients with PSP ( ).

Neuropathology, neurochemistry, and pathogenesis

The spectrum of pathologic changes in MSA includes cell loss, gliosis, and demyelination in the striatum (caudate and putamen), substantia nigra (SN), locus coeruleus (LC), inferior olives, pontine nuclei, dorsal vagal nuclei, Purkinje cells of the cerebellum, intermediolateral cell columns, and Onuf nucleus of the caudal spinal cord. Involvement of at least three of these areas, including the putamen and SN, is required for the pathologic diagnosis of MSA ( ; ).

Because the discovery by Papp and Lantos ( ) of the characteristic histologic marker, the GCIs, there has been substantial improvement and clarification of MSA as a specific clinicopathologic entity ( ). These inclusions, which represent the pathologic hallmark of MSA, are particularly concentrated in the oligodendrogliocytes and have been found in all autopsied brains of patients previously classified as SDS, SND, and sporadic OPCA. This shared pathologic feature strongly argues in support of the notion that these three disorders should be regarded as variants of the same disease entity, namely, MSA. GCI, argyrophilic, perinuclear inclusions, with a diameter varying from 4 to 20 μm, are found particularly in the oligodendrogliocytes in the supplementary motor cortex, anterior central gyrus, putamen, pallidum, basal pons, and medullary reticular formation. They are composed of 20- to 30-nm straight tubules and contain ubiquitin, tau protein, alpha- and beta-tubulin, MAP-5, αB-crystallin, and alpha-synuclein. Several studies have documented the presence of alpha-synuclein in the GCI ( ; ; ). Although very characteristic of MSA, GCIs have been rarely found in other disorders, such as CBD, PSP, and autosomal dominant SCA. Alpha-synuclein is selectively and extensively phosphorylated at serine 129, especially by casein kinase 1 and 2, in various synucleinopathies, including MSA (Fujiwara et al., 2002). Because of increasing evidence of dysregulation of myelin basic protein and p25α, also called tubulin polymerization promoting protein, in MSA, there is an emerging notion that MSA represents an oligodendrogliopathy ( ). A significant correlation has been found between the frequency of GCIs, severity of neuronal cell loss, and disease duration ( ). Whereas in PD and DLB, alpha-synuclein forms neuronal inclusions called Lewy bodies, in MSA alpha-synuclein aggregates in glia and Lewy bodies are found in 10% of MSA cases ( ). Several studies found biochemical, conformational, and other differences between alpha-synuclein strains in PD versus MSA ( ; ). One pathologic study of 100 MSA cases (46 men and 54 women) showed that GCIs might be contributing to neuronal damage in the MSA-C type more than the MSA-P type, suggesting the possibility of different mechanisms of cell death in the subtypes of MSA ( ). In addition to GCI, it is increasingly recognized that widespread neuronal inclusions are also important pathologic findings in brains of patients with MSA (Cykowski et al., 2015).

The fundamental pathologic changes in MSA-C, whether familial or sporadic, are a loss of Purkinje cells in the cerebellar cortex, particularly in the vermis, and degeneration of the olivopontine nuclei. In addition to cerebellar atrophy, SN degeneration and depigmentation, neuronal loss in other brainstem nuclei, and demyelination of corticospinal tracts and posterior columns are seen. The medial spiny neurons that give rise to both the direct pathway from the striatum to the globus pallidus internus (GPi) and the indirect pathway from the striatum to the globus pallidus externus (GPe) are affected. Gliosis, however, seems to be much more prevalent in the GPe than in the GPi. Upregulation of dopamine 1 (D1) receptors, determined by dopamine-stimulated adenylyl cyclase, has been demonstrated in brains of patients with PD compared with PSP and MSA ( n = 10 each); it is actually reduced in MSA ( ). In another study, the investigators analyzed 35 pathologically confirmed cases of MSA and confirmed a direct correlation between severity of disease and nigrostriatal cell loss ( ). Although marked degeneration in the olivopontocerebellar system, particularly the cerebellar vermis, was noted in 88% of the brains, the cerebellar pathologic findings did not correlate with the presence of cerebellar signs.

Cholinergic neurons in the pedunculopontine nucleus (PPN) and laterodorsal tegmentum and noradrenergic neurons in the LC were found to be markedly depleted in the brains of patients with MSA, whereas the serotonergic rostral raphe neurons are well preserved (Benarroch et al., 2013). Degeneration of the catecholaminergic neurons in the intermediate reticular formation of the rostral ventrolateral medulla seems to correlate well with autonomic failure in patients with MSA. Lewy bodies or neurofibrillary tangles (NFTs) are not common. Loss of arginine-vasopressin synthesizing neurons in the hypothalamic suprachiasmatic nucleus has been demonstrated in the brains of patients with MSA. Calbindin-D28k immunoreactivity in the striatal projection system is markedly decreased in the Purkinje cells of the cerebellum in patients with MSA ( ). In the early stages of MSA-P, the medium spiny neurons staining for calbindin (localized to the matrix), but not those staining for calcineurin (localized striasomes), appear to be depleted first ( ). Reduced calcium-binding capacity in these neurons might affect the bcl-2 family of proteins and lead to apoptosis of selected neuronal regions not only in PD but also in other neurodegenerative diseases, such as MSA. The small, myelinated fibers innervating the vocal cord are lost in nearly all patients with MSA, but when the large, myelinated fibers of the recurrent laryngeal nerve become affected, as is seen in some patients with MSA, vocal cord paralysis becomes evident and may be life-threatening (Hayashi et al., 1997).

The autonomic failure in MSA has been largely attributed to the depletion of sympathetic preganglionic neurons in the spinal intermediolateral cell column and its afferent medullary catecholaminergic and serotonergic neurons. In 12 MSA patients who had died within 3.5 years after disease onset, 4 died suddenly and 8 died as a result of established causes ( ). The investigators found that the spinal intermediolateral and medullary catecholaminergic and serotonergic systems were involved even in the early stages of MSA, and their degeneration may be responsible for sudden death in patients with MSA.

Diffuse degeneration of the white matter, particularly involving the central tegmental tract associated with vacuolation, has been an increasingly recognized pathologic feature of MSA ( ). Other studies found evidence of apoptosis in the glia, but not neurons, of MSA brains ( ). Furthermore, microglial activation involving translocation of nuclear factor (NF)-kappB/Rel A to the nucleus was found to be particularly prominent in affected brain regions ( ).

In addition to the typical findings in the brain, there is a marked loss of neurons in the lateral horns of the spinal cord, but these pathologic changes correlate poorly with dysautonomia. Substance P–like immunoreactivity was markedly decreased in laminae I + II of the fourth thoracic and third lumbar spinal cord segments in 10 of 11 SDS patients, and all had a decrease in small and large myelinated fibers in the fourth thoracic ventral roots. In addition to the central nervous system, alpha-synuclein pathologic findings can be demonstrated in other organs, including the enteric system. For example, alpha-synuclein findings were seen in a colonic biopsy sample of the enteric nervous system in 1 of 6 MSA patients and in 5 of 9 PD patients (Pouclet 2012). Thus, although synuclein pathologic findings are less common in MSA than in PD, they may involve the entire enteric nervous system.

The cause of MSA is unknown, and genetic factors probably do not play an important role. Because MSA is classified as alpha-synucleinopathies, variations in the gene coding for alpha-synuclein (SNCA) were examined in a genome-wide association study (GWAS) of PD in 413 MSA cases and 3974 control subjects and the 10 most significant single nucleotide polymorphisms (SNPs) were then replicated in an additional 108 MSA cases and 537 controls ( ). The study found that SNPs at SNCA were associated with increased risk for the development of MSA at an odds ratio (OR) of 6.2 ( P = 5.5 × 10–12). Although no gene mutations have been identified in several families with MSA phenotype, homozygous mutation and compound heterozygous mutations in the COQ2 gene was found in two multiplex families (The ). In addition, a common variant (V343A) and other variants in COQ2 were found to be associated with sporadic MSA. The COQ2 gene encodes an enzyme that is essential for the biosynthesis of coenzyme Q10 and the authors suggested that “oral supplementation with coenzyme Q10 may be helpful in treating MSA, particularly for patients with susceptibility-conferring COQ2 variants.” A GWAS performed on 918 patients with MSA of European ancestry and 3864 controls found no significant loci, although potentially interesting regions were identified, including SNPs in the genes FBXO47, ELOVL7, EDN1, and MAP (Sailor et al., 2016).

Although many studies have investigated the putative role of environmental toxins in the pathogenesis of idiopathic PD, the possible role of such toxins in MSA has received little attention. We reported on 10 patients whose clinical features were consistent with those of MSA and in whom toxins were suspected to play an etiologic role (Hanna et al., 1999). One patient with pathologically confirmed MSA was exposed to high concentrations of various toxins, including formaldehyde, malathion, and diazinon. The other MSA patients had a history of heavy exposure to various agents, such as n-hexane, benzene, methyl-isobutyl-ketone, and pesticides. The pathologic case revealed extensive advanced glial changes, including GCIs, which were seen particularly in the deep cerebellar white matter, brainstem, cortex (superior frontal, insula, and hippocampus), and putamen. Additionally, there was notable neuronal cell loss with depigmentation of the SN and LC. Although a cause-and-effect relationship cannot be proven, these cases suggest that environmental toxins could play a role in the pathogenesis of some cases of MSA. The inverse relationship between PD and smoking also has been found with MSA but not with PSP ( ).

Although there is no experimental model of MSA, intraperitoneal injection of 3-acetylpyridine in rats produces neurochemical and histologic changes that are consistent with MSA-C (Deutch et al., 1989). In addition to causing degeneration of the nigrostriatal dopaminergic pathway, this neurotoxin causes degeneration of the climbing fibers, which normally originate in the inferior olive and terminate in the cerebellum. Another possible animal model of MSA is the “double lesion” rat model in which an initial 6-hydroxydopamine (6-OHDA) SN lesion is followed by a quinolinic acid–induced lesion in the striatum ( ). Transgenic mice overexpressing human wild-type alpha-synuclein in oligodendrocytes exhibit many of the features of MSA ( ). The selective neuronal loss in a transgenic MSA mouse model has been attributed to deficiency of oligodendroglial glial–derived neurotrophic factor (GDNF) release ( ). Another important finding is that tubulin polymerization promoting protein, also known as p25alpha, was shown to specifically accelerate oligodendroglial alpha-synuclein oligomer formation and to promote alpha-synuclein–positive GCI-like inclusions. Interestingly, cerebrospinal fluid (CSF) from patients with MSA seems capable of promoting in vitro alpha-synuclein fibril formation (Hirohata et al., 2011). Finally, there is growing evidence that MSA is caused by a human prion, different from the scrapie isoform of the prion protein (PrP ^Sc ), that causes CJD ( ; ).

Treatment

Despite marked involvement of the striatum, about two-thirds of patients with MSA do improve with levodopa, at least initially. In contrast to patients with PD, MSA patients often experience dyskinesias without concomitant improvement in motor functioning ( ). The levodopa-induced dyskinesias that are seen in MSA patients seem to be more dystonic, often involving the face, rather than the choreic or stereotypic movements that are characteristically seen in patients with PD. Furthermore, MSA patients do not seem to notice a recurrence of parkinsonian symptoms until several days after levodopa withdrawal. Ataxia, present in patients with MSA-C, does not respond to pharmacologic therapy, and most patients with this type of MSA increasingly rely on a cane, walker, or wheelchair. The autonomic symptoms associated with MSA are treated similarly to dysautonomia associated with PAF or other disorders with prominent autonomic dysfunction ( ) ( Table 9.5 ).

Levodopa not only can cause dyskinesia without motor improvement but frequently also exacerbates the already prominent symptoms of OH. The addition of liberal salt, fludrocortisone, and elastic stockings can improve standing blood pressures. However, parkinsonian patients have difficulty putting on elastic stockings, such as the Jobst stockings. In addition, physical maneuvers such as leg-crossing and squatting can alleviate orthostatic lightheadedness. In a double-blind, placebo-controlled study of 97 patients with various causes of autonomic failure, including 18 patients with MSA and 22 patients with PD, midodrine, a peripheral alpha-adrenergic agonist, was found to be effective in the treatment of OH ( ). The safety and efficacy of midodrine were later confirmed by a larger controlled study involving a total of 171 patients with OH ( ). Wright and colleagues (1998) showed dose-dependent increases in standing systolic blood pressure with midodrine in patients with MSA. The most frequent side effects associated with the drug included piloerection, scalp pruritus, urinary retention, and supine hypertension. The effects of subcutaneous injections of octreotide, a somatostatin analog, were tested in a group of nine patients with MSA ( ). The drug improved OH and allowed patients to maintain an upright posture for a longer time compared with placebo. Because fludrocortisone and midodrine, particularly when combined with liberal salt intake, increase the risk for supine hypertension, patients should be instructed to place their beds in the reverse Trendelenburg position. The use of nighttime nitroglyceride or clonidine patches has been suggested for the treatment of supine hypertension, but these measures are not always successful. Although this modest improvement was attributed to a release of NE by octreotide during maintenance of erect posture, no increase in plasma NE levels could be demonstrated.

Other agents that are used to increase standing blood pressure include indomethacin, ibuprofen, pseudoephedrine and other sympathomimetics, caffeine and dihydroergotamine, yohimbine, and NE precursors, such as 3,4-dihydroxy phenylserine, also known as L-threo DOPS or droxidopa. Droxidopa appears to increase NE in the brains of normal and NE-depleted animals, suggesting that it acts as an NE precursor. The drug may also act in the peripheral nervous system, as evidenced by increased heart rate and elevated blood pressure. In 32 patients (26 MSA, 6 PAF) with symptomatic OH, droxidopa (up to 300 mg twice daily) reduced the fall in systolic blood pressure during orthostatic challenge (by a mean of 22 ± 28 mm Hg) and 78% of the patients were considered clinically improved. There were no reports of supine hypertension ( ). Carbidopa may partially blunt the effects of droxidopa, but this does not appear to be clinically meaningful in patients with PD or MSA who also take carbidopa/levodopa ( ). In a large class I pivotal trial, patients with symptomatic OH because of PD, MSA, PAF, or nondiabetic autonomic neuropathy, there was a significant improvement (0.90 units, P = 0.003) with droxidopa in the Orthostatic Hypotension Questionnaire (OHQ) composite score compared with placebo ( ). Furthermore, the mean standing systolic blood pressure increased by 11.2 versus 3.9 mm Hg ( P < 0.001) and mean supine systolic blood pressure by 7.6 versus 0.8 mm Hg ( P < 0.001). Supine systolic hypertension (blood pressure greater than 180 mm Hg) was observed in 4.9% of droxidopa and 2.5% of placebo subjects.

Bladder problems, particularly urinary retention and incontinence, are relatively common and often troublesome manifestations of MSA ( ). Increased urinary frequency because of overactive bladder is less common and often improves with 5 mg of antimuscarinic oxybutynin three to four times per day and 2 mg of tolterodine three times per day. The latter drug may be better tolerated because it has eight times less affinity for the salivary gland, thus having much lower frequency of dry mouth. Use of 0.4 mg of the alpha-blocker tamsulosin twice daily may be effective if the urinary frequency is associated with benign prostatic hypertrophy; this condition must be excluded before the use of antimuscarinic agents. Prazosin and moxisylate are specific antagonists of bladder alpha-adrenergic receptors. In a controlled study in 49 patients, there was improvement in symptoms in 47.6% in the prazosin group and 53.6% in the moxisylate group. Orthostatic hypotension was seen in about 23% in the prazosin group and 11% in moxisylate group. More than 35% of patients had reduction in residual volume, and there was improvement in urinary urgency, frequency, and incontinence. The dosage used was 1 mg of prazosin and 10 mg of moxisylate three times daily in an oral form ( , ). The combination of intravesical prostaglandin E2 and oral bethanechol chloride has been found to be of limited usefulness in treating urinary retention (Hindley et al., 2004). Sildenafil citrate has been found to be safe and effective in the treatment of erectile dysfunction associated with PD, but it may unmask OH in patients with MSA (Hussain et al., 2001; Farooq et al., 2008).

Constipation represents the most frequent gastrointestinal manifestations of MSA. Psyllium was found to increase stool frequency and weight but did not alter colonic transit or anorectal function. Other effective treatments for constipation include polyethylene glycol, bisacodyl, magnesium sulfate, and macrogol. Mosapride citrate, a novel 5HT ₄ agonist and partial 5HT ₃ antagonist, has been found to ameliorate constipation in parkinsonian patients ( ). Other drugs for constipation include lubiprostone, which locally activates intestinal ClC-2 chloride channels and increases intestinal fluid secretion without altering serum electrolyte levels, and tegaserod maleate, a novel selective serotonin receptor type-4 (5HT ₄ ) partial agonist that stimulates upper gastrointestinal tract motility ( ). Linaclotide may be another medication useful in the treatment of constipation associated with MSA ( ).

MSA is often associated with a variety of respiratory problems, shortness of breath, aspiration pneumonia, stridor, and sleep apnea ( ). In a study of 20 patients with MSA, Iranzo and colleagues (2000) found vocal cord abduction dysfunction in 14 (70%); and in 3 of 3 patients, continuous positive airway pressure (CPAP) completely eliminated laryngeal stridor, obstructive apnea, and hemoglobin desaturation. In another study, CPAP effectively ameliorated nocturnal stridor in 13 patients with MSA ( ). Tracheostomy or other airway restoration techniques sometimes must be performed in patients who have vocal cord abductor paralysis ( ). Stridor has been reported to improve with botulinum toxin injections into the adductor laryngeal muscles ( ).

The following trials of drugs studied as potential disease-modifying agents were negative: riluzole, minocycline, rifampin ( ), and rasagiline ( ). In the latter study, 174 patients with clinically diagnosed MSA were randomized to rasagiline (n = 84) or placebo (n = 90) treatment. At week 48, patients in the rasagiline group had progressed by an adjusted mean of 7.2 (standard error [SE], 1.2) total UMSARS units versus 8 (1.1) units in those in the placebo group (not significant [NS]). The most common adverse events in the rasagiline group were dizziness (12%), peripheral edema (11%), urinary tract infections (11%), and OH (10%). Intravenous immunoglobulin has not been found to be effective in patients with MSA ( ). In one study, 33 patients with probable MSA-C were evaluated in a randomized clinical trial of mesenchymal stem cells administered via intra-arterial and intravenous routes ( ). The study showed a modest but significant reduction in UMSARS II scores compared with the placebo. There were no serious adverse effects except for small ischemic lesions on MRI related to intra-arterial infusion. In another study involving 24 patients with MSA who received between 10 and 200 million adipose-derived autologous MSCs intrathecally the rate of progression (UMSARS total) was markedly lower compared with a matched historical control group (0.40 ± 0.59 versus 1.44 ± 1.42 points/month, P = 0.004) with an apparent dose-dependent effect ( ).

Patients with MSA are not candidates for deep brain stimulation except when the goal is to relieve severe camptocormia or Pisa sign, but even in these situations, the surgical intervention is usually not completely beneficial ( ).

Clinical features and natural history

First described by Steele, Richardson, and Olszewski ( ; ) in 1964, PSP has become a well-recognized, clinicopathologic entity that may overlap in some clinical and pathologic features with other tauopathies such as CBD and AD ( ; ; ; ; Houghton and Litvan, 2007; ; ; Ling et al., 2018; ). Although the motor subscale of the UPDRS has been found to reliably assess most aspects of PSP (Cubo et al., 2000), the PSP Rating Scale (PSPRS) has been found to be sensitive to disease progression, increasing at a mean rate of about 1 point per month ( ). PSPRS, along with the Quality of Life Scale ( ), should be used in future clinical trials investigating novel therapeutic interventions.

Several diagnostic criteria for PSP have been proposed ( ; ).The application of National Institute of Neurological Disorders and Stroke (NINDS)-SPSP diagnostic criteria ( ) and other criteria improved the accuracy of initial clinical diagnosis only marginally. On the basis of an analysis of 103 pathologically confirmed consecutive cases of PSP, Williams and colleagues (2005) divided PSP into two categories: Richardson syndrome, characterized by the typical features described in the original report, and PSP-P, in which the clinical features overlap with PD and the course is more benign. The latter group, representing about a quarter of all patients with PSP ( ), has fewer tau pathologic findings than the classic Richardson’s syndrome (PSP–Richardson syndrome) ; ; ). The mean 4R-tau/3R-tau ratio of the isoform composition of insoluble tangle-tau isolated from the pons was significantly higher in Richardson’s syndrome (2.84) than in PSP-P syndrome (1.63). The PSP-P phenotype has better survival with longer disease duration and slower rate of disease progression than the classic PSP-RS phenotype.

Another subgroup of PSP that has been identified is the so called “frontal” PSP, representing about 20% of all PSP patients ( ). These patients initially present with behavioral and cognitive symptoms, with or without ophthalmoparesis, that then evolve into typical PSP. In a retrospective chart review of 100 patients with autopsy-confirmed PSP there was marked phenotypic heterogeneity with 24% presenting as the classic PSP-RS ( ). Besides PSP–Richardson syndrome, other subtypes of PSP included PSP with parkinsonism (PSP-P), PSP with pure akinesia with gait freezing (PSP-PAGF), PSP with CBS (PSP-CBS), PSP with predominant speech and progressive nonfluent aphasia (PSP-PNFA), PSP with predominant frontotemporal dysfunction (PSP-FTD), PSP with cerebellar ataxia (PSP-C), and PSP with primary lateral sclerosis (PSP-PLS) ( ).

The MDS criteria identified four functional domains (ocular motor dysfunction, postural instability, akinesia, and cognitive dysfunction) as clinical predictors of PSP ( ). Within each of these domains, there are three clinical features that contribute different levels of diagnostic certainty. Specific combinations of these features define the diagnostic criteria, stratified by 3degrees of diagnostic certainty (probable PSP, possible PSP, and suggestive of PSP); clinical clues and imaging findings represent supportive features. The overall sensitivity of the MDS-PSP criteria was 87.9% and specificity 85.7% ( ), compared with 45.5% and 90.5%, respectively, for the NIH-PSP criteria (Litvan et al., 1996a,b). Another set of diagnostic criteria, that largely overlap with the MDS criteria have been proposed using data from a sample of 274 clinically diagnosed PSP patients participating in the Environmental Genetic PSP (ENGENE-PSP) case control study ( ).

Diagnosis of PSP should be considered in any patient with progressive parkinsonism, postural instability, and disturbance of ocular motility. The earliest and most disabling symptom of PSP usually relates to gait and balance impairment, as a result of which patients frequently fall and sustain injuries. The following factors significantly increase the risk for falls in patients with PSP: abnormal saccades, eyelid dysfunction, modified turning, bradykinesia, axial rigidity, neck dystonia, and postural stability, symptom duration, and overall disease severity (Bluett et al., 2016).

Video 9.3 Progressive supranuclear palsy (PSP).

The average period from onset of symptoms to the first fall in PSP is 16.8 months, compared with 108 months in PD, 42 months in MSA, 54 months in DLB, and 40.8 months in VP ( ). The marked instability is presumably a result of visual-vestibular impairment, axial rigidity, and bradykinesia. Using computerized posturography, certain measures of balance impairment can reliably differentiate between PSP and PD even in early stages of the disease ( ). In contrast to the short and shuffling steps, stooped posture, narrow base, and flexed knees that are typically seen in PD, PSP patients have a stiff and broad-based gait, with a tendency to have their knees (and trunk) extended and arms slightly abducted. Instead of turning en bloc, they tend to pivot, which further compromises their balance ( Video 9.3 ). Some PSP patients may present with the syndrome of “pure freezing,” also referred to by some as motor blocks, gait ignition failure, and primary progressive freezing of gait. This gait disorder is manifested chiefly by akinesia of gait associated with start-hesitation, freezing of gait, festination, and disequilibrium with frequent falling and in some cases this gait disorder may be not only the presenting symptoms feature but the only motor feature (Compta et al., 2007; ; Facheris et al., 2008; ). Patients with pure freezing may evolve into or eventually have neuropathologic evidence of PD, CBD, pallidonigroluysian degeneration ( ; ), and diffuse Lewy body disease (Factor et al., 2006; ). In addition to PSP, frontal gait disorder may be the initial manifestation of AD and CBD ( ). Although the PSP may be associated with ataxia and the gait may appear ataxic, the patients usually do not exhibit prominent cerebellar findings. The uncompensated loss of postural reflexes and motor blocks (freezing) especially on turning, coupled with a peculiar lack of insight into the difficulties with equilibrium (possibly secondary to frontal lobe dysfunction), leads to frequent falling and slumping into the chair on an attempt to sit down. There is, however, emerging evidence for cerebellar abnormalities, both clinically and pathologically, in PSP ( ). Abnormal otolith-mediated reflexes may also contribute to the falls of PSP ( ). Based on physiologic and functional imaging studies, there is growing support for the notion that vestibular thalamus is involved in postural instability associated with PSP ( ), similar to thalamic astasia ( ). Another feature of PSP is symmetrical or asymmetrical arm levitation ( ) which may be exaggerated arm abduction, the so-called gunslinger’s walk, typical of PSP gait.

Gait and postural abnormalities are often later accompanied by impairment of speech (stuttering, stammering, and monotonous hypophonia without normal modulation), handwriting difficulty (micrographia), and eyelid motor disturbance (blepharospasm, apraxia of eyelid opening or closure, also referred to as eyelid freezing) ( ) and other neuro-ophthalomogical signs ( ). Although hand tremor, typically seen in PD, is usually not a feature of PSP, one pathologically proven case of PSP manifested with jaw tremor has been reported ( ). In contrast to PD, PSP patients have small finger separation without progressive decrement on repetitive finger tapping, and have more severe micrographia ( ). Although cognitive and psychiatric symptoms are well recognized in PSP, overall functional disability is more related to motor impairment (Duff et al., 2013). Loss of insight, particularly inability to accurately predict performance on future tasks (anticipatory awareness), is a common feature not only in PSP but also in patients with FTD and CBD ( ). This is often present even in the early stages of the disease and helps differentiate PSP from PD ( ).

Along with postural instability, supranuclear ophthalmoparesis typically manifests by paralysis of downgaze, the most important distinguishing sign of PSP ( ; ) ( Video 9.4 ). The predictability of these two features with regard to the final pathologic diagnosis was confirmed by a clinicopathologic study of 24 autopsy-proven cases of PSP ( ). About one-third of PSP patients complain of blurred vision, diplopia, and eye discomfort, but most eventually lose their ability to read or maintain eye contact. Involuntary persistence of ocular fixation is a typical, though rarely mentioned, feature of PSP. In addition to transient persistence of gaze on oculomotor testing, PSP patients often lag with their head turning behind turning of their body (presumably because they continue to fixate their gaze in primary position even though their body is making the turn). Other oculomotor abnormalities that are seen in patients with PSP include impairment of saccades, optokinetic nystagmus (OKN), and the presence of square wave jerks. In early stages of PSP, patients might have only mild limitation of voluntary downgaze and inability to converge, but slowing of horizontal and vertical saccades appears to be the earliest oculomotor sign of PSP ( Video 9.5 ). Marked slowing of vertical compared with horizontal OKN, best noted when the OKN tape moves in an upward direction, demonstrates impairment of down-saccades. Indeed, slowing of vertical saccades, even in the presence of normal vertical saccade amplitude, was found to be one of the earliest signs of an autopsy-proven PSP (Hardwick et al., 2009). One study compared saccades, OKN, and other ophthalmologic signs in six patients with PSP compared with PD and normal control (Garbutt et al., 2004). All PSP patients showed (1) slowing of vertical saccade and quick phase of nystagmus; (2) square wave jerks, which were more frequent and larger during fixation; and (3) impaired vertical OKN. Deficient generation of the motor command by midbrain burst neurons has been suggested as the primary mechanism for the slow vertical saccades ( ). Slowing of vertical saccades might help differentiate PSP from other parkinsonian disorders, including PD, MSA, and CBD, although some slowing of vertical saccades also can be seen occasionally in these parkinsonian disorders ( ; ; ), including PD ( ). In addition to slow vertical saccades, bilateral impairment of the antisaccade task (the patient is instructed to look in the direction opposite to the visual stimulus) correlates well with frontal lobe dysfunction in PSP ( ) and other neurodegenerative and frontal lobe disorders (Condy et al., 2004; ; ). Abnormalities in antisaccades, which imply a dysfunction of the dorsolateral prefrontal cortex and the superior colliculus, often precede impairments in vertical and eye movements. The ophthalmoparesis can be overcome by the oculocephalic (doll eyes) maneuver (Videos 9.3, 9.4, 9.6), but with disease progression and brainstem involvement, vestibulo-ocular reflexes can be lost, suggesting additional nuclear involvement ( ). Another characteristic feature of PSP is the “round the houses” sign (Quinn et al., 1996).

Supranuclear ophthalmoparesis may occur in DLB (Daniel et al., 1995; ; ), CBD, postencephalitic parkinsonism and encephalitis lethargica (Vilensky et al., 2010a,b), prion disease, Wernicke encephalopathy, dorsal midbrain syndrome, paraneoplastic syndrome, progressive subcortical gliosis, Whipple disease ( ; ; ), Niemann–Pick and Gaucher diseases ( ; ), Kufor–Rakeb syndrome (PARK9; secondary to mutation in ATP13A2 gene on chromosome 1p36) (Hampshire et al., 2001), stiff-person syndrome, primary pallidal degeneration, and other disorders ( ).

Rigidity, bradykinesia, and hypertonicity of the facial muscles produce deep facial folds and a typical worried or astonished facial expression ( Fig. 9.5 ). The worried appearance is partly due to contraction of the procerus (and possibly corrugator) muscle, the so-called procerus signs ( ) (Videos 9.3, 9.4). Blepharospasm, the most common form of dystonia in PSP, is encountered in nearly a third of all patients with PSP; other frequently encountered eyelid abnormalities include “apraxia” of eyelid opening, eyelid closure, or both. Although some ( ) have hypothesized that these lid abnormalities are due to involuntary supranuclear inhibition of levator palpebrae, others have drawn attention to the similarity of this disorder of eyelid motor control and the parkinsonian phenomenon of sudden transient freezing, hence suggesting the term lid freezing ( ). Other terms that are used to describe this condition include pretarsal blepharospasm (Elston, 1992) and focal eyelid dystonia ( ).

Video 9.4 Progressive supranuclear palsy (PSP).

Video 9.5 Progressive supranuclear palsy (PSP).

Video 9.6 Progressive supranuclear palsy (PSP).

Video 9.7 Progressive supranuclear palsy (PSP).

Pseudobulbar symptoms in PSP patients are characterized chiefly by dysarthria, dysphagia, and pseudobulbar affect, also referred to as “emotional incontinence” or “emotional expression disorder” ( Video 9.7 ). Speech in PSP is characterized by a spastic, hypernasal, hypokinetic, ataxic, monotonous, low-pitched dysarthria (Video 9.3, 9.6, 9.7). The speech rate may be slow or fast, and some patients have severe palilalia and stuttering. An “apraxia of phonation” has been reported in one patient who was aphonic except during periods of excitement or during sleep. In contrast, some patients have almost continuous involuntary vocalizations, including loud groaning, moaning, humming, and grunting sounds. Progressive dysphagia causes most patients to modify their diet, and some eventually need a feeding gastrostomy to maintain adequate nutrition. As a result of chewing difficulties, inability to look down, and poor hand coordination, PSP patients are often described as “sloppy eaters.”

Dystonia may be a feature in all forms of atypical parkinsonism ( ). In a review of dystonia in pathologically proven cases of PD, MSA, and PSP, Rivest and colleagues (1990) found dystonia to be an uncommon feature, noted in 15 of 118 (13%) cases. They regarded the frequently reported neck extension as a form of axial rigidity rather than dystonia. In another study, the increased neck muscle tone was thought to have features of both dystonia (tonic shortening reaction) and rigidity (antagonist muscle contraction indicative of increased tonic stretch reflex) ( ). Neck extension, although often noted in published reports, is actually an uncommon sign in PSP. Indeed, neck flexion, usually associated with MSA, can occasionally be seen in PSP (Daniel et al., 1995). In contrast to the typical presence of neck rigidity, truncal muscle tone is only slightly increased, and distal limbs may actually seem hypotonic ( ). In some patients, however, distal dystonia can be seen ( ). Although PSP is usually a symmetrical disorder, dystonia represents an occasional exception in that unilateral dystonia may be present, particularly in the more advanced stages of the disease. In one study of 83 patients with PSP, 38 (46%) had some form of dystonia, 22 (24%) had blepharospasm, 22 (27%) had limb dystonia, and 14 (17%) had axial dystonia ( ). Sometimes, spontaneous arm levitation, a well-recognized sign in CBD, is also seen in patients with PSP and may be wrongly attributed to dystonia ( ).

In their original monograph, indicated that mild dementia was present during early stages of the disease. Although some investigators have reported severe cognitive impairment in this population, others have attributed these deficits, at least in part, to poor visual processing (Daniel et al., 1995). In a Neuroprotection and Natural History in Parkinson Plus Syndromes (NNIPPS) study, a randomized, multicenter, double blind, placebo-controlled trial of riluzole that included 372 MSA and 311 PSP patients (with 94% diagnostic accuracy based on postmortem examination, cognitive impairment on the Dementia Rating Scale (DRS) was observed in 57% of the PSP group and 20% of the MSA group. On the Frontal Assessment Battery (FAB), impairment was observed in 62% of patients with PSP and 32% of those with MSA. Cognitive slowing, impairment of executive (goal-directed) functions, and subcortical dementia with deficits in tasks requiring sequential movements, conceptual shifts, and rapid retrieval of verbal knowledge are typically present in patients with PSP ( ). The apathy, with or without depression, and other hypoactive behaviors that are typically seen in PSP have been attributed to a dysfunction in the frontal cortex and associated circuitry ( ). This is in contrast to HD, in which behaviors such as agitation, anxiety, and irritability have been related to hyperactivity of the medial and orbitofrontal cortical circuitry. Sparing of olfactory function in PSP, in contrast to that in PD, is another clinical difference between the two neurodegenerative disorders (Doty et al., 1993). Litvan, Mega, and colleagues (1996) studied the neuropsychiatric aspects of PSP in 22 patients and found that apathy occurred in 91%, disinhibition in 36%, dysphoria in 18%, anxiety in 18%, and irritability in fewer than 9%. Another sign of frontal lobe dysfunction in PSP is the “applause sign” (signe de l’applaudissement), which probably represents a perseveration of automatic behavior (Dubois et al., 2005) ( Video 9.8 ). This sign, characteristically present in patients with PSP (but also present in some patients with FTD with parkinsonism and CBD), is manifested by persistence (perseveration) of clapping after the patient is instructed to clap consecutively three times as quickly as possible. In a study of patients with various neurologic disorders evaluated at Baylor College of Medicine, the applause sign was present in 77.8% of 9 patients with CBD, 53.9% of 13 patients with MSA, 52.6% of 19 patients with PSP, 20% of 10 patients with HD, and 12.5% of 24 patients with PD ( ). Although the test differentiated patients with CBD from those with PD ( P < 0.005) and HD ( P < 0.005), it failed to discriminate patients with PSP from other parkinsonian groups, but had a 100% specificity in distinguishing parkinsonian patients from normal subjects. Another study also showed no difference in applause sign when comparing PSP with FTD and FTD with AD ( ).

Video 9.8 Progressive supranuclear palsy (PSP).

After idiopathic PSP, the most common cause of PSP is a multi-infarct state. Multi-infarct or vascular PSP can be difficult to differentiate clinically from the more common idiopathic variety ( ; ). In addition to a much higher frequency of stroke risk factors and abnormal imaging studies, the vascular PSP patients are more likely to have asymmetrical and predominantly lower body involvement, cortical and pseudobulbar signs, dementia, and bowel and bladder incontinence ( ). The concept of vascular PSP is supported by the observation that up to 81.0% of patients with clinically diagnosed PSP have hypertension (Ghika and Bogousslavsky,1997; ). A clinicopathologic study of four patients who were clinically diagnosed with PSP but found to have vascular PSP at autopsy showed that vascular PSP is characterized by asymmetrical signs, falls within 1 year of onset, and vascular lesions on MRI ( ). One cause of vascular PSP is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) as a result of mutations in NOTCH3 gene (Erro et al., 2013). Other reported causes of secondary PSP include exposure to organic solvents ( ), paraneoplastic syndrome ( ), mesencephalic tumor ( ), autoimmune disease (e.g., anti-IgLON5) (Gaig et al., 2017), surgery on the aorta ( ; Nandipatti et al., 2013), and other rare and often unsubstantiated causes.

The natural history of PSP has been addressed in several studies. In one longitudinal study involving 43 patients, 60.5% died after a median survival of 7.1 years (2.2–18) ( ). Early dysphagia and early cognitive impairment are predictors of poor prognosis ( ). Richardson syndrome (compared with PSP–Parkinsonism phenotype), older age at onset (older than 63 years), early dysphagia, and early cognitive deficits were predictors of shorter survival ( ). The relentlessly progressive course leads to death, usually from aspiration, within 10 years of onset in the majority of cases. In one clinicopathologic study of 24 patients with PSP, the median survival from onset was 5.6 years, and this was shorter in men and in patients who experienced falls during the first year of symptoms and with early dysphagia or supranuclear palsy ( ; ). In another clinicopathologic study involving 16 cases of PSP, Birdi and colleagues (2002) found the mean survival to be 8.6 years (range, 3–24), and the mean age at death was 72.3 years (range, 60–89). In a review of 187 cases, those with early bulbar features had around 5 years less life expectancy than did those who had no or late bulbar features ( ). Similar to other series, the median survival in this study was 5.7 years. Because this figure is based on deceased cases, it might be too pessimistic because slowly progressive cases are still being followed. In another study of 50 PSP patients, Goetz and colleagues (2003) found the median survival from the onset of first symptom to be 7.9 years (6.5 years in the 21 patients who were followed to death). In addition to the short survival, PSP is associated with many symptoms that have a serious impact on the quality of life ( ). Overall, the median latency from onset to chairbound state is 5 years and to death is 7 years ( ). In a report of 37 studies presenting findings on 6193 patients (1911 PSP), early dysphagia and early cognitive symptoms were identified as unfavorable predictors of survival (Glassmacher et al., 2017).

Epidemiology

About 6% of all parkinsonian patients who are evaluated in a specialized clinic fulfill the clinical criteria for PSP. On the basis of a medical record review of the Rochester Epidemiology Project, the average annual incidence rate has been estimated to be 1.1 to 5.3 new cases per 100,000 person-years ( ; ). The prevalence, after age adjustment to the U.S. population, has been estimated to be 1.39 per 100,000 ( ). In a review of computerized records of 15 general practices in and around London, Schrag and colleagues (1999) found an age-adjusted prevalence for PSP of 6.4 per 100,000. In other studies carried out in the United Kingdom, the prevalence of PSP ranged from 1 to 6.5 per 100,000 ( ). Similar to the European studies, a prevalence of 5.82 per 100,000 has been reported in Yonago, Japan ( ).

Like PD, PSP occurs more often in men, but its onset at a mean age of 63 years, is about 10 years later than the typical onset of PD. Although no well-designed epidemiologic studies have been performed in PSP, one case-control study found that PSP patients were more likely to live in areas of relatively sparse population (Davis et al., 1988). Another study by the same investigators failed to identify any risk factors, except for low likelihood of completing at least 12 years of education that would differentiate patients with PSP from a matched control population ( ).

Neurodiagnostic studies

There is no blood or CSF test that can diagnose PSP but CSF neurofilament light (NfL) protein is elevated in PSP and other atypical parkinsonian disorders compared with PD and healthy controls ( ; ). Blood levels of NfL correlate with CSF levels and they are more elevated in atypical parkinsonism than in controls and patients with PD (Hansson et al., 2017; ).

Electrophysiologic studies have been helpful in documenting other abnormalities, such as sleep difficulties and seizures. One study showed marked reduction in percentage of REM sleep in patients with PSP ( ). The same study also showed frontal electroencephalogram (EEG) slowing in patients with PSP. In a review of 62 patients seen over a 9-year period, Nygaard and colleagues (1989) noted seizures in 7 patients and suggested a higher than expected frequency of seizures in this population. Although not reported by others, the relatively high frequency of seizures reported by Nygaard and colleagues (1989) might have been secondary to cortical infarcts. Abnormalities in motor and frontal sensory evoked potentials have been found in 8 of 13 patients with the clinical diagnosis of PSP ( ).

The typical findings on computed tomography (CT) or MRI scans of patients with PSP include generalized and brainstem, particularly midbrain, atrophy ( ). Measuring the anteroposterior diameter of the suprapontine midbrain, Warmuth-Metz and colleagues (2001) found that in contrast to PD patients (mean 18.5 mm), PSP patients had a significantly lower diameter (13.4 mm) on axial T2-weighted MRI, and as a result the authors concluded that this finding reliably differentiates between PD and PSP and recommended that this evaluation “should be incorporated into the diagnostic criteria for PSP.” In another study, using midsagittal MRI, the average midbrain area of patients with PSP was 56 mm ² , which was significantly smaller than that of patients with PD (103 mm ² ) or MSA-P (97.2 mm ² ), and this parameter, particularly the ratio of the area of the midbrain to the area of the pons, was found to reliably differentiate among the three disorders ( ). Other studies have established the utility of using the ratio of pons to midbrain diameter to differentiate between various PSP disorders and other parkinsonian syndromes ( ; ). On the midsagittal view of the MRI, as a result of atrophy of the rostral midbrain tegmentum, the most rostral midbrain, the midbrain tegmentum, the pontine base, and the cerebellum appear to correspond to the bill, head, body, and wing, respectively, of a hummingbird ( ) or penguin ( ; ) ( Fig. 9.6 ). The “hummingbird sign” was demonstrated in all 8 MRI scans of PSP patients but not in any of the 12 scans of PD patients or 10 scans of normal controls ( ). The “morning glory sign,” a peculiar MRI finding of midbrain atrophy with concavity of the lateral margin of the midbrain tegmentum, resembling the lateral margin of the morning glory flower, is observed in patients with PSP ( ). MRIs in patients with PSP, MSA, and other parkinsonian syndromes have been associated with putaminal hypointensity on T2-weighted MRI, but this finding is less consistently noted in PSP than in the other parkinsonism-plus syndromes. In one study, PSP could be differentiated from MSA by the presence of marked atrophy and hyperintensity of the midbrain and atrophy of the frontal and temporal lobes. The “eye of the tiger” sign on brain MRI, typically associated with neurodegeneration with brain iron accumulation type 1 (NBIA1), also has been reported in PSP. PSP is associated with dorsal midbrain atrophy and as a result of degeneration of superior colliculi, the floor of the third ventricle is flattened on sagittal MRI images.

With DTI and voxel-based morphometry in PSP, provided evidence of both gray and white matter degeneration even in early stages of PSP. Voxel-based morphometry in 15 patients with clinically proven PSP and 14 with CBD showed distinct patterns of atrophy that differentiated between the two disorders with 93% accuracy ( ). Whereas CBD patients had a marked asymmetrical (L > R) pattern of atrophy involving premotor cortex, superior parietal lobules, and striatum, PSP was characterized by atrophy of the midbrain, pons, thalamus, and striatum. Indeed a systematic review and meta-analysis of studies that evaluated DTI in various parkinsonian disorders identified different patterns of distribution that allowed the abnormal neuroimages to be categorized as PD, PSP, or MSA (Cochrane and Ebmeier, 2013). Using diffusion-weighted MRI (DWI-MRI), Seppi and colleagues (2003) were able to differentiate between PSP and PD with 90% sensitivity and 100% specificity, but this technique could not differentiate between PSP and MSA. Degeneration predominantly affecting brainstem, association, and commissural fibers was demonstrated in a study of 20 patients with probable PSP and 20 age- and sex-matched healthy controls ( ). Compared with controls, PSP patients showed abnormal diffusivity predominantly in the superior cerebellar peduncles, body of the corpus callosum, inferior longitudinal fasciculus, and superior longitudinal fasciculus in patients with PSP. Furthermore, fractional anisotropy values in the superior cerebellar peduncles correlated with disease severity, inferior longitudinal fasciculus correlated with motor function, and superior longitudinal fasciculus correlated with severity of saccadic impairments. A magnetic resonance parkinsonism index (MRPI) greater than 13.55 is more predictive of evolving clinically unclassifiable parkinsonism into PSP than clinical features ( ). The MRPI is calculated by multiplying the pons area–midbrain area ratio (P/M) by middle cerebellar peduncle (MCP) width–superior cerebellar peduncle (SCP) width ratio (MCP/SCP) ([P/M] × [MCP/SCP]). Although MRPI has adequate utility in supporting the diagnosis of PSP–Richardson syndrome and differentiating it from both PD and healthy controls, it has low sensitivity and specificity profile in differentiating PSP-P from PD ( ).

Stroke risk factors and a multi-infarct state on CT or MRI have been noted in patients with PSP with a higher frequency than in those with PD ( ). One cause for a subgroup of PSP might be small vessel disease producing subcortical ischemia with reduction of regional cerebral blood flow, cerebral hypometabolism, and a multi-infarct state.

PET scans have revealed decreased metabolic activity in the caudate, putamen, and prefrontal cortex, but the earliest sign of PSP appears to be decreased glucose metabolism in the midbrain ( ). In one study, ¹⁸ FDOPA uptake was markedly reduced in the caudate and the anterior and posterior putamen of PSP patients ( ). In contrast, the uptake was reduced only in the posterior putamen in PD patients. Similarly, dopamine transporter (DAT), imaged by [ ¹¹ C]-WIN PET, showed a relatively uniform reduction involving the entire striatum, whereas patients with PD had involvement chiefly of the posterior putamen ( ). F-dopa and F-deoxyglucose PET were abnormal in 5 (33%) individuals among 15 subjects at risk for familial PSP even though they did not (yet) exhibit any symptoms ( ). Using ¹¹ C-raclopride as a D2 ligand, Brooks and colleagues (1992) showed a 24% reduction in D2 density in the caudate and a 9% reduction in the putamen of patients with PSP. The marked reduction in postsynaptic D2 receptor density probably explains the poor response of PSP to levodopa. Using [ ¹²³ I]β-CIT SPECT, Pirker and colleagues (2000) showed marked reduction of striatal binding in PD, PSP, MSA, and CBD, but the pattern of abnormality (reduction in overall binding and asymmetry) did not allow a differentiation between the various disorders. Using the receptor ligand [ ¹⁸ F]altanserin, PET scans in 8 patients with PSP showed upregulation of 5-HT _2A receptors in the SN and to a lesser degree in the striatum, compared with 13 controls, and these changes significantly correlated with the UPDRS III and PSP-Rating Scale ( ).

In addition to measuring metabolism, neurotransmitters, and receptors, PET technology has advanced to the point of measuring depositions of tau protein. [ ¹⁸ F]FDDNP is a ligand that can be used to image by PET hyperphosphorylated tau fibrillar aggregates ( ). In 15 patients in whom this PET scan was used, [ ¹⁸ F]FDDNP binding was demonstrated in subcortical areas (e.g., striatum, thalamus, subthalamic region, midbrain, and cerebellar white matter) with progressive involvement as disease severity increased. These findings provide evidence that PET [ ¹⁸ F]FDDNP imaging is a sensitive tool to detect tau fibrillar aggregates in PSP and may serve as a biomarker for disease progression.

In addition to imaging studies, analysis of the CSF may also be helpful in evaluation of patients with PSP. One study, for example, found a low ratio of light (33 kDa) to heavy (55 kDa) tau protein in the CSF of patients with PSP, which differentiated (without any overlap) this group from other tauopathies such as AD, CBD, and FTD and from synucleinopathies such as PD and DLB ( ; Ling et al., 2018). This finding had an 87% sensitivity and 86% specificity and was validated against MRI voxel-based morphometry of brainstem gray matter.