DOTTORATO DI RICERCA TOSCANO IN NEUROSCIENZE
CICLO XXXCOORDINATORE Prof. Renato Corradetti
The role of Ocular Movement Analysis in the differential diagnosis of Atypical Parkinsonian Disorders: a study on Multiple System Atrophy, Progressive
Supranuclear Palsy and Corticobasal Degeneration
Settore Scientifico Disciplinare MED/26
Dottorando Tutori
Dott.ssa Rosini Francesca Prof. Federico Antonio
Dott.ssa Rufa Alessandra
Coordinatore
Prof. Corradetti Renato
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Table of contents
1 Introduction ... 4
1.1 Multiple System Atrophy ... 5
1.1.1 Epidemiology and prognosis………5
1.1.2 Causes…..………6
1.1.3 Pathogenesis and neuropathological features……….6
1.1.4 Clinical presentation..………..7 1.1.4.1 Motor symptoms...8 1.1.4.2 Non-motor symptoms...8 1.1.5 Diagnostic criteria….………..9 1.1.6 Diagnostic techniques……….10 1.1.6.1 Autonomic testing………...10 1.1.6.2 Urological evaluation………...10 1.1.6.3 Olfactory function………11
1.1.6.4 Electromiography of the anal sphincter……….11
1.1.6.5 Neuroimaging...11
1.1.7 Differential diagnosis.………..15
1.1.8 Treatment………16
1.2 Progressive Supranuclear Palsy………18
1.2.1 Epidemiology……….18
1.2.2 Neuropathology………18
1.2.3 Pathogenesis……….19
1.2.4 Diagnostic criteria..……….20
1.2.5 Clinical presentation and PSP phenotypes……….20
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1.2.6.1 Neuroimaging...23
1.2.6.2 CSF and blood biomarkers...24
1.2.6.3 Other techniques...24 1.2.7 Treatment...25 1.3 Corticobasal Degeneration………..26 1.3.1 Epidemiology ………...26 1.3.2 Patohogenesis………26 1.3.3 Clinical presentation……….27
1.3.4.Phenotypes and diagnostic criteria………...29
1.3.5 Causes of corticobasal syndrome………..29
1.3.6 Diagnostic techniques ……….29
1.3.6.1 Neuroimaging...29
1.3.6.2 CSF biomarkers...30
1.3.6.3 Genetics...30
1.3.7 Traeatment……….30
2 Role of the study of ocular movements in Atypical Parkinsonisms ... 32
2.1 Saccadic system ... 33
2.2 Saccadic parameters ... 34
2.3 Saccadic paradigms ... 35
2.4 Fixation ... ..37
2.5 Ocular movements in MSA ... 39
2.6 Ocular movements in PSP ... 41
2.7 Ocular movements in CBD/CBS ... 43
3 Our study ... 45
3.1 Aim of the study ... 45
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3.2.1 Participants………...45
3.2.2 Eye movement recording………46
3.2.3 Data analysis……….47
3.2.4 Statistical analysis………..………..49
3.3 Results...50
3.3.1 Clinical findings….………..50
3.3.2 Neuroimaging findings...51
3.3.4 Horizontal visually-guided saccadic parameters...………58
3.3.5 Vertical visually-guided saccadic parameters………62
3.3.6 Saccadic steps analysis………...71
3.3.7 Antisaccadic parameters………76
3.3.8 Fixations………...83
3.4 Discussion...86
3.4.1 Population characteristics...86
3.4.2 Saccadic and antisaccadic parameters...89
3.5 Conclusions...………...95
4 References...96
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1. Introduction
Atypical Parkinsonian Disorders (APD) are a group of neurodegenerative diseases characterized by progressive extrapyramidal symptoms and signs, unresponsive to Levodopa and associated with a wide range of distinctive clinical features. According to the neuropathological substrate, APD may be classified in two broad categories of pathologies related to the accumulation of abnormal aggregates of proteins: the Alpha-synucleinopathies and the Taupathies. More broadly, sinucleinopathies include idiopathic and genetic Parkinson's disease, Lewy body disease and Multiple System Atrophy (MSA), the latter including the two variants MSA-C, predominantly involving the olivopontocerebellar system, and MSA-P, predominantly involving the nigro-striatal system. The Taupathies include Alzheimer's disease (AD), and the spectrum of pathologies including frontotemporal degeneration (FTD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Within these two groups of proteinopathies, MSA-P and Lewy body dementia (among the synucleinopathies), PSP and CBD (among the Tauopathies) are those with prevalent extrapyramidal features. The differential diagnosis between these groups of diseases is often challenging, especially in the early phases, given the numerous clinical overlaps and the absence of definitive biological and neuroradiological markers. For the same reason, their distinction from idiopathic Parkinson’s disease (PD) is arduous1-3.
Eye movement evaluation may contribute to the differential diagnosis of APD, since various types of oculomotor abnormalities have been postulated to be characteristics of each disease4. Nevertheless, the capability in discriminating among APD may be influenced and reduced by several factors, such as atypical presentations or changes due to disease progression. In this regard, we aimed to characterize the oculomotor profile of four group of APD (MSA-C, MSA-P, PSP, CBD), through the analysis of reflexive and voluntary eye movements and steady fixation. Our results reinforce previous findings on different APDs and, furthermore, allow the identification of specific disease profile of each group.
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1.1 Multiple System Atrophy
MSA is clinically characterized by a variable combination of autonomic dysfunctions, parkinsonism, cerebellar ataxia and pyramidal symptoms and, on the basis of anatomopathological findings, is classified as a synucleinopathy analogously to Parkinson's disease and Lewy body dementia. The term multiple system atrophy was firstly used in 1969 by Graham and Oppenheimer to pool three previously described neurologic entities: nigro-striatal degeneration, olivopontocerebrellar ataxia and Shy-Drager disease5. These entities correspond to multiple-system atrophy with predominantly cerebellar, autonomic, or parkinsonian features, respectively6. The diagnosis is defined on the basis of criteria established by a consensus in 1998, subsequently revised in 2008 with the introduction of neuroradiological patterns7-8.
1.1.1 Epidemiology and prognosis
The annual incidence of MSA is estimated at about 0.6 to 0.7 cases per 100,000 person-year, reaching 3 cases per 100,000 person-year in the population over 50 years. The prevalence varies from 1.9 to 4.9 per 100000 inhabitants9. The average age of onset is around 60 years, with no gender difference. The prognosis is generally worse than Parkinson's disease, with an average survival rate of about 7-9 years. In the European
population (study carried out by study group MSA, EMSA-SG)10, MSA-P variant with
extrapyramidal symptoms is found to have a higher prevalence than MSA-C (58% vs 42% cerebellar prevalence). The same distribution is observed in the American population (NAMSA-SG), where the prevalence of extrapyramidal form is 60% vs 13%. In contrast, in the Japanese population, the cerebellar variant is present in 83% of cases. The prognosis quod vitam, usually 6 to 10 years11, is negatively influenced by the early onset of dysautonomia, as well as by the female sex, age of advanced onset and rapid progression of disease12.
1.1.2 Causes
MSA is mostly considered a sporadic disease. In few European and Japanese pedigrees MSA has been transmitted in an autosomal dominant or recessive inheritance pattern.
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These families often have atypical clinical features, and the genetic analysis led to the discovery of mutations in the COQ2 gene, which plays a role in synthesising the mitochondrial electron transporter and antioxidant coenzyme Q1013. A genomic screening in MSA identified some polymorphisms (rs11931074, rs3857059, rs3822086) of the SNCA locus that would be associated with an increased risk of developing the disease14.
To date, no environmental factors have been associated with MSA; similarly to Parkinson’s disease, nicotine and alcohol use are less frequent among MSA patients.
1.1.3 Pathogenesis and neuropahological features
The distinctive neuropathological characteristic of MSA is represented by the widespread presence of proteinaceous oligodendroglial cytoplasmic inclusions (GCIs), which are mandatory to hystopathological diagnosis. The density of GCIs containing alpha-synuclein significantly correlates with neuronal degeneration and disease duration15. The main constituent of glial cytoplasmic inclusions is misfolded α-synuclein, a protein normally located in neuronal axons and synapses. Hence, multiple-system atrophy is classified as an oligodendroglial α-synucleinopathy, whereas Parkinson’s disease, dementia with Lewy bodies, and pure autonomic failure are characterized by neuronal α-synuclein aggregates (Lewy bodies)11.
Alpha-synuclein aggregation is probably preceded by relocalization of p25α protein (tubulin polymerisation-promoting protein), an important stabilizer of myelin integrity, into the oligodendroglial soma, followed by oligodendrocytes swelling. The interaction between p25α and α-synuclein promotes phosphorylation and aggregation of synuclein into insoluble oligomers first and GCIs later on16. The formation of GCIs, in turn, interferes with neuronal support and activates quiescent microglial cells. Progressively dysfunctional oligodendrocytes release misfolded α-synuclein into the extracellular space; this misfolded α-synuclein may be taken up by neighboring neurons to form neuronal cytoplasmic inclusions. At this point, neuroinflammation, loss of oligodendroglial neurotrophic support, and neuronal dysfunction due to α-synuclein inclusions may synergistically promote neuronal death and subsequent reactive
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astrogliosis. Toxic α-synuclein species may then spread in a prion-like fashion to other functionally connected brain areas leading to the multisystem neuronal involvement that is typical of multiple-system atrophy11,17.
Moreover, an abnormal accumulation of fibrillary alpha-synuclein has been found in the cytoplasm and nucleus of neurons and in neurites of brains affected by MSA; these inclusions, even if they are not part of the pathological criteria of diagnosis of MSA, still have an important role for the pathological process. Indeed, recent data show how these inclusions develop early in the Pontine neurons and in the lower olives of MSA patients. These findings would also indicate a neuronal dysfunction in the alpha-synucleinopathies involving an alteration of the cytoskeleton with protein aggregation. For this reason, two parallel degenerative processes have been proposed for the MSA: the GCIs oligodendrogliopatia associated with secondary neuronal degeneration, and a neuronal alpha-synucleinopathy with formation of aggregates18.
In transgenic mice, provoked phosphorylation of alpha-synuclein induced neuronal loss with patterns similar to those found in humans: alpha-synuclein aggregation and axonal degeneration; miochondrial dysfunction; oxidative stress19,20.
Macroscopically, variable degrees of olivopontocerebellar atrophy and striatonigral degeneration are typically found at postmortem examination of patients with multiple-system atrophy. Central autonomic nervous multiple-system, including the hypothalamus, noradrenergic and serotoninergic brain-stem nuclei, dorsal nucleus of the vagus nerve, nucleus ambiguus, intermediolateral columns of the spinal cord, and Onuf nucleus may also present with changes. Frontal-lobe atrophy may be observed after a long disease duration11.
1.1.4 Clinical presentation
The main clinical features of the disease include autonomic dysfunction, parkinsonism, cerebellar ataxia and pyramidal signs. Approximately 30% of patients with adult-onset cerebellar symptoms (ILOCA) and 8% of those with parkinsonism are estimated to develop MSA. Like Parkinson’s disease, MSA might have a prodromal phase with sexual dysfunction, urinary incontinence or retention, orthostatic hypotension,
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inspiratory stridor, and rapid-eye-movement sleep behavior disorder months to years before the first motor symptoms appear21.
Two main clinical presentations are recognized. MSA-P subtype is clinically characterized by predominant parkinsonian features, while in MSA-C cerebellar symptoms prevail.
1.1.4.1 Motor symptoms
Parkinsonian features are characteristics of MSA-P subtype and consist of progressive akinesia and rigidity, postural tremor (though rarely observed at rest), often associated with dystonia and postural instability. Falls are less frequently reported than in PSP. Particularly at the onset of symptoms, the differential diagnosis with Parkinson's disease is arduous, though the poor response to Levodopa in MSA-P is helpful. MSA-P patients usually develop their symptoms fully after 5 years. Although survival rates are similar, patients with MSA-P exhibit faster functional decline22. Conversely, MSA-C is mainly characterized by cerebellar features, consisting of a wide-based gait, uncoordinated limb movements, action tremor, and spontaneous, gaze-evoked, or positional downbeat nystagmus. Spasticity or pyramidal weakness should cast doubts on a diagnosis of multiple-system atrophy, but generalized hyperreflexia, as well as a Babinski sign, may occur in 30 to 50% of cases22. In advanced stages of disease, dysarthria, dysphonia and dysphagia usually occur11.
1.1.4.2 Non-motor symptoms
Early and severe autonomic failure is a key in the MSA diagnostic criteria. Symptoms include severe orthostatic hypotension, defined as a blood pressure decrease of 30 mmHg systolic or 15 mmHg diastolic within 3 minutes after a passive head-up tilt or standing from the recumbent position; erectile dysfunction (less evaluable female sexual dysfunction); urinary dysfunction; respiratory disorders ranging from OSAS up to respiratory failure. These symptoms are generally worse and appear earlier than in Parkinson's disease, facilitating differential diagnosis.
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In addition to dysautonomia, sleep disorders are also frequently observed. In many MSA patients, REM behaviour disorder is the presenting feature of the disease23. A video-polysomnography is recommended to confirm RBD and rule out other sleep problems. Obstructive sleep apnea is more frequent than central sleep apnea, occurring in up to 40% of patients with MSA.
Though hyposmia has been observed in MSA, a pronounced olfactory disorder is not common in this disease and should lead to a diagnosis of idiopathic Parkinson’s disease21.
The causes of death in MSA commonly include bronchopneumonia, urosepsis, or sudden death, which occurs usually at night due to either acute bilateral vocal-cord paralysis or acute disruption of the brain-stem cardiorespiratory drive5.
1.1.5 Diagnostic criteria
Diagnostic criteria of the disease have been established in 1998 and in 2008 (second consensus)7-8.
MSA diagnosis is distinguished in possible, probable, defined. A diagnosis of defined MSA is set only after autoptical finding of GCIs, which are the pathognomonic sign of disease20, associated with nigro-striatal degeneration or olivopontocerebellar ataxia. The onset of the disease is defined by the occurrence of autonomic symptoms (with the exception of erectile dysfunction) and motor symptoms (parkinsonism or ataxia), though the neuropathological damage is likely preceding.
A possible MSA is defined by the appearance of an adult-onset (> 30 years), progressive disease, with parkinsonism, ataxia and dysautonomic disorders, variably associated with other signs including specific neuroimaging findings.
The diagnosis of probable MSA requires the presence of urinary dysfunction or orthostatic hypotension with a decrease in pressure of at least 30 mmHg for systolic and 15 mmHg for diastolic after 3 minutes in orthostatism, together with parkinsonian signs not responding to Levodopa and / or cerebellar ataxia. The diagnosis is helped by the
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presence other clinical features, specific tests for the dysautonomia and neuroimaging findings.
1.1.6 Diagnostic techniques
1.1.6.1 Autonomic testing
Cardiovascular system. Since orthostatic hypotension (OH) is very common in MSA,
and is a key feature of the diagnostic criteria, an assessment of cardiovascular function should always be performed in the suspicion of pathology. The diagnosis of neurogenic OH requires autonomic function testing with continuous BP monitoring to rule out non-neurogenic causes (i.e., OH due to other factors such as volume depletion, anaemia, medications side effects)23. Patients with MSA have neurogenic OH more frequently than those with PD (~70% vs. ~50%). However, despite several reports of abnormalities in the Valsalva maneuver and the heart rate variability during paced deep breathing being worse in patients with MSA than in patients with PD24,25, the differences are not consistent enough to distinguish between both groups26.
Thermoregulatory and sudomotor testing. Decreased sweating is reported in up to 80%
MSA patients, with global anhidrosis in up to 45% of cases23,27. This degree of sweat loss in MSA is greater than in PD and has been classically attributed to a preganglionic lesion27, based on the findings that thermoregulatory sweat test (TST, which measures integrity of both pre- and post-ganglionic neurons) is abnormal in patients with MSA, whereas quantitative sudomotor axon reflex test (QSART, which measures integrity of post-ganglionic sudomotor function) is relatively preserved.
1.1.6.2 Urological evaluation
Assessment of bladder function is useful for the detection of disorders of the autonomic nervous system in an initial phase of disease. Although frequency and urinary urgency are also common in Parkinson's, severe incontinence with loss of urine is not usual. Urodynamic studies showed a wide variety of alterations in MSA. In early stages, detrusor hyperreflexia is commonly present, with abnormal functioning of the urethral
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sphincter, leading to urinary urgency and incontinence. Over the course of the disease, hyperreflexia decreases and generally lead to bladder atony, with an increase in the residual volume of post-urinal urine8. An increased residual urinary volume >100 ml has a positive predictive value of 91.6% and a residual volume < 100 ml has negative predictive value of 67.8% to distinguish MSA vs. PD28.
1.1.6.3 Olfactory function
Significant hyposmia has been found in the majority of patients with PD, with normosmia or mild hyposmia in the majority of patients with MSA29. Olfactory functions tests have very high specificity and moderate sensitivity to distinguish PD from MSA30 and, therefore, should be included in the routine evaluation of patients with suspected MSA. Interestingly, olfaction is a good biomarker to predict which patients will develop MSA or PD/DLB in patients in the premotor phase of the synucleinopathies31 .
1.1.6.4 Electromyography of the anal sphincter
The EMG of the anal sphincter reveals, in about 80% of cases of MSA, signs of neural degeneration in the nucleus of Onuf with spontaneous muscular activity and polyphasic potentials. These alterations, however, do not allow to discriminate between MSA and other parkinsonisms, as they can also be found in PSP, but also in advanced phases of PD. When excluded other causes of sphincter denervation, this exam allows to distinguish MSA from other forms of cerebellar ataxia, and from idiopathic Parkinson's disease at least 5 years after diagnosis32.
1.1.6.5 Neuroimaging
Standard MRI and quantitative techniques (Volumetry, DWI). Standard MRI
abnormalities include putamen alterations such as atrophy, hypointensity in T2 sequences, marginal "slit-like" hyperintensities, and atrophy and / or hyperintensity of brain stem, middle cerebellar peduncles and cerebellum33. Particularly, two anomalies
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are considered as "typical" of MSA: the marginal "slit-like" hyperintensity of the putamen and the so-called Hot cross-bun sign, i.e. the hyperintensity with a cruciform aspect of pons basis in the T2-w sequences and Diffusion. Actually, neither the two signal changes are pathognomonic of MSA. In fact, the putaminal hyperintensity can also be found in healthy adults and in people with idiopathic Parkinson's disease. The hot cross bun sign indicate a degeneration of the pontocerebellar fibers, but it is an aspecific sign also found in SCA 2134 or leptomeningeal carcinomatosis or vasculitis23. Therefore, the presence of these alterations can help in the differential diagnosis with Parkinson's or with healthy subjects, but their sensitivity is low, and they could not be seen at early stages. Furthermore, they are not specific enough to distinguish MSA from other atypical parkinsonisms. Generally, the two MSA subtypes are not split in neuroradiological studies. However, Bürk et al. compared a population of only MSA-C to subjects with adult idiopathic cerebellar ataxia (ILOCA), and observed a more severe atrophy and signal hyperintensity in MSA-C of pons and cerebellum35.Several MRI algorithms to distinguish MSA-P from PD have been proposed. Usually, they show high specificity but low sensitivity 36,37.
Diffusion-weighted imaging and diffusion tensor imaging. Increased diffusivity of
posterior area of putamen was observed in MSA-P compared to the anterior ones38. Furthermore, even if the putaminal diffusivity was similar between MSA-P and PSP, diffusivity in the middle cerebellar peduncle was higher in MSA-P compared to PSP39. DWI has also proved to be superior in finding supratentorial changes (especially in the putamen) and infratentorial to differentiate between MSA-P and PD40. Putaminal diffusivity in brain magnetic resonance diffusion-weighted imaging (DWI) is increased in patients with the parkinsonian variant of multiple system atrophy (MSA-P) compared to Parkinson disease (PD) patients and a recent meta-analysis confirmed the diagnostic relevance of this method41. Ito et al. compared the differences in diffusivity and fractional anisotropy (FA) between MSA and PD with 3T MRI. The diffusivity values in the pons, cerebellum and putamen were significantly higher, and those of FA lower, in the MSA compared to PD and controls42. Abnormalities of the basal ganglia have also been reported in patients with MSA-P when studied with Magnetization Transfer
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Imaging. Particularly, this technique allowed the distinction between Parkinson's disease from parkinsonism (MSA and PSP), but not among parkinsonisms43.
Volumetry. Quantitative assessment with MR volumetry using region-of-interests (ROI)
in patients with MSA showed atrophy of the putamen, caudate, brainstem and cerebellum44,45. Among these, Quattrone et al. proposed the use of an index called MR Parkinsonism Index (MRPI), based on the observation that the width of the medial cerebellar peduncles is a marker that distinguishes with high sensitivity between MSA and PD, but not between MSA and other parkinsonisms; the pons area measured in the sagittal T1-dependent images is significantly reduced in the MSA-P compared to PD and PSP, and the opposite occurs for the midbrain (more thinned in the PSP). Index is calculated by multiplying the ratio between the midbrain area / pons area (P / M) by the ratio between the width of the medial cerebellar peduncle/ and width of the superior cerebellar peduncle (MCP / SCP), or [(P / M) * (MCP / SCP)]. This ratio was significantly higher in patients with PSP compared to PD and MSA-P, as well as compared to controls46.
Magnetic Resonance Spectroscopy (MRS); Functional brain magnetic resonance imaging (fMRI). So far, MRS of the striatum has not been considered useful in the
differential diagnosis of parkinsonian disorders47. MRS of other brain areas may have better discriminative capacity48.
A study assessing longitudinal fMRI changes over the course of 1-year in PD, MSA, and PSP using a hand-grip-force paradigm showed reduced fMRI signal and more widespread and more pronounced changes in basal ganglia, cerebellum, and motor cortex in patients with MSA and PSP compared to PD49.
Functional imaging. Brain Positron Emission Tomography (PET) with Fluorodeoxyglucose (FDG-PET). FDG-PET studies have shown a reduced metabolism
in the striatum, brainstem and cerebellum in MSA patients, while in Parkinson’s disease the putaminal metabolism is increased and the frontotemporal metabolism reduced. Most studies were performed in the absence of an anatomopathological confirm of the
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diseases and on small series of cases, and the effective sensitivity and specificity of this technique is still to be demonstrated33. Brain single photon emission computed
tomography. Single photon emission computed tomography (SPECT) using
technetium-99m-ethyl cysteinate dimer perfusion showed different perfusion patterns of the putamen in patient with MSA compared to those with PD; however, the diagnostic accuracy was poor (sensitivity 73.3%, specificity 84%)50.
Dopaminergic imaging. Multiple tracers are available, including 18F-Dopa (dopamine
storage capacity), 11C-dihydrotetrabenazine (DTBZ, vesicular monoamine transporter function) for PET, and 123I-β-CIT and 123I-FPCIT (dopamine transporter binding) for SPECT33.
- Presynaptic. In patients with probable MSA-P, the function of the dopaminergic presynaptic system is severely impaired. Similarly to PDs, the putaminal uptake of 18F-dopa is reduced by 50% and correlates with the severity of the motor disorder; compared to PD, the caudate nucleus uptake is more compromised in MSA-P patients51. Otsuka et al. reported the PET findings in MSA (P and C) and PD patients, showing that 18F-dopa uptake of putamen and caudate was compromised in both groups (MSA vs. PD), but the caudate-putamen index (CPI), reflecting the differences in uptake between caudate and putamen divided by caudate uptake, was significantly lower in MSA patients, allowing a distinction between MSA and PD52. However, other studies did not confirm these findings53.
- Postsynaptic. MSA patients had a reduction in the density of dopamine D2 receptors in the putamen, in contrast with PDs in which it is normal or increased. However, since there is a wide overlap range between the two populations, and some MSA patients showed a normal receptor density, this methodology cannot be considered specific enough to discriminate between the two conditions54.
Cardiac sympathetic neuroimaging. 123I-methaloxybenzylguanidine (MIBG) is an
analogue of norepinephrine which is stored in sympathetic nerve terminals. Multiple studies of cardiac imaging with [123I] MIBG SPECT in patients with Parkinson's
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disease have shown a decrease in dopamine uptake, indicating a post-ganglionic sympathetic cardiac dysfunction even when the cardiovascular reflexes remain intact. Conversely, MSA patients showed a normal sympathetic myocardial innervation55. However, the specificity of the examination is limited since some PDs in the initial phase are normal, and that myocardial SPECT is not specific enough to distinguish between the various atypical parkinsonisms33.
Transcranial sonography. Recent studies have shown a hyperechogenicity of the
substantia nigra in 80% of PD patients and in 10% of atypical parkinsonians (MSA-PSP); conversely, a hyperechogenicity of the lentiform nucleus (unilateral or bilateral) is found in 70% of patients with MSA or PSP, and in 25% of PD. Therefore, a hyperechogenicity of the lenticular nucleus with normal substantia nigra could be quite specific for a diagnosis of atypical parkinsonism, especially when in combination with other diagnostic modalities. Unfortunately, not in all subjects the ultrasound method can be applied; moreover, the hyperechogenicity of the parenchyma is difficult to quantify and it is dependent on the operators capacity56.
1.1.7 Differential diagnosis
Differential diagnosis of MSA of both subtypes should be first considered with other extrapyramidal conditions, and particularly with Parkinson's disease and other atypical parkinsonisms.
The poor responsiveness to Levodopa, combined with the presence of disautonomic symptoms and, in the case of MSA-C, the prevailing ataxic component, could address the diagnosis yet on clinical examination, while neuroimaging (see previous paragraphs) can further contribute to differential diagnosis. During the early stage of disease, when some key features may be missing, it is often very arduous to distinguish between MSA and PSP or CBD, even when applying neuroimaging or other ancillary investigations. Dementia or visual hallucinations are not consistent with a diagnosis of multiple-system atrophy; these symptoms in the presence of parkinsonism and autonomic failure should prompt consideration of dementia with Lewy bodies8.
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Given the prominent cerebellar symptoms, other cerebellar ataxias with adulthood onset should be ruled out in diagnosis of MSA-C. These ataxias could be of acquired (toxic, paraneoplastic, infectious), hereditary (dominant as cerebellar or recessive spinal attaxes, of a rarer onset in old age) or sporadic origin. A correct family and personal history, together with the observation of the disease course and a careful neurological and instrumental examinations, might be of help in the differential diagnosis. Some difficulties arise from the differentiation with the so-called ILOCA form, adulthood ataxias with idiopathic etiology whose clinical and neuro-radiological characteristics, including the presence of dysautonomia and extracerebellar signs, often show an overlap with MSA -C, also making the distinction in two pathological entities doubtful. However, ILOCA would show a slower progression and less clinical impairment (prognosis estimated approximately 12 years), compared to MSA-C (5-7 years)34. Given the presence of dysautonomia, MSA should be differenced from "Pure Autonomic Failure "(PAF), a rare disease belonging to the spectrum of Lewy body diseases and characterized by severe and gradually progressive dysautonomia, with anhidrosis, orthostatic hypotension, neurological bladder. Since in early stage there may be a clinical overlap, a cut-off of 5 years is fixed for the discrimination between the two. However, REM and respiratory sleep disorders are usually rare in PAF compared to MSA; furthermore, myocardial scintigraphy with MIBG is often impaired in PAF, similarly to PD21.
1.1.8 Treatment
So far, MSA therapy is only symptomatic and mostly targets towards the treatment of extrapyramidal and dysautonomic signs and symptoms.
Levodopa, usually reported as ineffective in MSA, has instead shown initial benefit in some patients (up to 40%) during the first years of illness, but not subsequently22. Levodopa withdrawal occasionally causes abrupt and sometimes irreversible worsening of motor abnormalities, also in patients with no motor response; therefore, complete discontinuation of Levodopa treatment is not recommended for patients who do not have major side effects. Dopamine agonists are less likely to provide a motor benefit in
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MSA but may be tried in cases of Levodopa-induced dystonia; evidence for the effectiveness of amantadine, a selective antagonist of NMDA receptors, is controversial. Rasagiline has shown a neuroprotective effect in transgenic mice and could be promising in preventing disease progression11.
The treatment of orthostatic hypotension is based on an adequate intake of fluids or a diet rich in salt; pyridostigmine and midodrine are also used in the United States. Urinary incontinence can be treated with anticholinergic drugs, but they are often poorly tolerated for side effects, including urinary retention. Finally, antidepressant may be employed for laughter and spastic crying and benzodiazepines for the RBD disorder. The sialorrhea can be reduced by schopolamine and the tremor by beta-blockers or primidone, besides anti-parkinsonian drugs. Physiokinesitherapy and speech therapy are recommended11.
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1.2 Progressive supranuclear palsy
Progressive supranuclear palsy (PSP) is traditionally considered an atypical parkinsonism. However, during the past decade, PSP was found to encompass a range of clinical phenotypes involving behavioural, language, and movement abnormalities57. The classic movement disorder clinical phenotype was firstly described as a distinct nosological entity by Steele et al. in 196458. Onset is usually around 60 years-old and clinical features include progressive postural instability and frequent falls, parkinsonism not-responsive to Levodopa treatment, dysarthria and dysphagia, supranuclear paralysis of vertical gaze and fronto-temporal cognitive disorders. Since it is neuropathologically characterized by neuro-fibrillary deposits and aggregates of 4R-P-tau protein in neurons and in the glia of the basal ganglia and brainstem, it is included among tau-protein disorders, such as corticobasal degeneration, Pick's disease, frontotemporal dementia and Alzheimer's disease59.
1.2.1 Epidemiology
The estimated prevalence of PSP is around 5-7 cases per 100000. In a population study conducted in the United Kingdom the peak prevalence was about 18 cases per 100000 between the ages of 70-74 years60. When considering other PSP phenotypes in addition to PSP-RS, prevalence was 18 cases per 100000 across all ages61.
1.2.2 Neuropathology
The neuropathological key features of PSP are the abundant neuro-fibrillary tangles and/or neuropil filaments, particularly in the striatum, pallidum nucleus, subthalamic nucleus, substantia nigra, oculomotor regions, periaqueductal gray matter, superior colliculus, pons basis, dentate nucleus and prefrontal cortex. The aggregates of tau are uniformly present in the astrocytes. In the healthy adult brain, there are six different tau isoforms with different microtubule-binding domains, and the ratio of tau isoforms with 3-R and 4-R domains is 1: 1. In PSP, the altered tau is composed of aggregates of 4-R
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isoforms (E10 +), accumulating in abnormal filaments in the cells and glia of subcortical and cortical regions59.
The characteristic glial lesion is the tufted astrocyte. They are seen especially in the precentral gyrus, striatum and superior colliculus, being more variable in the thalamus, subthalamic nucleus and red nucleus yet rare or absent in the lower brainstem62.
In addition, oligodendroglial tau inclusions called coiled bodies is very frequent in PSP. Coiled bodies tend to be parallel to the distribution of neuropil threads and can be numerous in white matter tracts in the basal ganglia, thalamus and brainstem.
Neurochemical studies have shown that degenerative processes in the PSPs involve dopaminergic neurons of the nigrostriatal dopaminergic system, innervating the striatum, but also cholinergic and GABA-ergic efferent neurons from the striatum and from other basal ganglia and brainstem nuclei, thus explaining the transient and / or lacking efficacy of treatment with Levodopa63.
1.2.3 Pathogenesis
The cause of PSP is unknown, but it is hypothesized that genetic, environmental, oxidative and inflammatory factors participate in its development.
The locus most strongly linked with risk of PSP is the gene for the microtubule-associated protein tau (MAPT)57. Genetic studies, including genome-wide association studies, have identified both an inversion polymorphism and haplotype-specific MAPT polymorphisms that affect the risk of PSP64. Rarely, familial forms of PSP have been identified. Although a causative mutation has not been identified for most familial cases, mutations in the MAPT gene have been identified as pathological in several families with autosomal dominant pattern of disease inheritance, including some families with pathologically confirmed PSP57.
Oxidative stress could play a pivotal role in cell death and disease progression; in fact, serious oxidative damage and lipoperoxidation are found in subthalamic nucleus, substantia nigra, prefrontal cortex of PSP patients compared to healthy subjects65.
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Among the environmental factors that may contribute to the development of disease, toxic inhibitors of the mitochondrial complex I (quinoline, roteinoids), discovered in some tropical plants and herbal teas to which indigenous peoples of the West Indies are exposed, have been considered. These substances, as shown also in studies on mice and primates, could be risk factors for the development of PSP and, even at much lower concentrations, can also be found in the diet of western populations (cheese, milk, eggs, cocoa)66.
1.2.4 Diagnostic criteria
Differential diagnosis at the onset of symptoms is arduous, since clinical presentation may overlap with other parkinsonian pathologies; it has been estimated that only a half of the patients receive a correct diagnosis at onset. To facilitate the recognition of the disease, diagnostic criteria of PSP have been coded by The National Institute of Neurological Disorders and Stroke (NINDS) in 199667 and a revision has been operated recently68. New criteria have established the following diagnostic categories:
- “Definite PSP”, which can only be diagnosed by neuropathological examination
- “Probable PSP” , diagnosed in the presence of a combination of clinical features considered to be highly specific, though they may be not very sensitive
- “Possible PSP” is diagnosed in the presence of clinical features that increase sensitivity, but at the possible cost of decreased specificity.
- Conditions “suggestive of PSP” represent subtle early signs of PSP, but do not meet the threshold for possible or probable PSP.
“Core” clinical features for diagnosis include oculomotor disturbances, particularly vertical gaze palsy, postural instability, akinesia and cognitive impairment. Other clinical clues and imaging findings may support the diagnosis.
1.2.5 Clinical presentation and PSP phenotypes
Clinical presentation of disease is extremely heterogeneous and various phenotypes have been described and included in the diagnostic criteria57,68-70.
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Richardson syndrome (PSP-RS). PSP-RS is the classical and firstly described
phenotype. Common features include postural instability (sometimes described as that of a drunken sailor), frequent drops with retropulsion, vertical gaze palsy (mostly downward) and saccades slowing. Other signs include symmetrical extrapyramidal features such as rigidity and akinesia, rest tremor (rare), and hypophonia. Motor disorders are associated with cognitive and personality changes such as depression, abulia, irritability, emotional lability (often over 2 years). Among the non-specific ocular symptoms, dry eye, photophobia, and blurred vision can be observed. Eyelid abnormalities may be evident, as the number of blinks with consequent corneal or epiphora irritation is reduced. Dysarthria and dysphagia are also common. Overall, these symptoms lead to a functional decline over 3-4 years, and people become wheelchair-bound. The average survival is described around about 5-8 years, with death mainly due to respiratory complications71.
PSP-P (Parkinsonism). Differently from the classic Steele-Richardson presentation, the
subgroup of PSP-P patients has predominantly bradykinesia, asymmetric rigidity, possible rest tremor, often in absence of abnormal ocular movement and frequent falls, at least at the onset. Initial response to Levodopa may be moderate, but followed by a non-responsiveness after a few years. PSP-P and Richardson syndrome are more easily distinguished in the first two years from onset, since after some time there may be a clinical overlap. The differential diagnosis with Parkinson's disease is particularly difficult. In PSP-P, however, the progression of the disease is faster, the axial symptoms are prominent and the response to Levodopa is poor. Compared to Richardson's syndrome, the prognosis is slightly better (3 years longer)70,71.
PSP with Progressive Gait Freezing (PSP-PGF). The first description of a syndrome
with pure akinesia dates back to 1974 in two patients with freezing of walking and writing, without anomalies of eye movements72. The clinical features of this syndrome include: progressive gait disturbance with start hesitation and subsequent freezing of gait, sometimes also involving difficulties with initiating or completing speech or writing, without tremor, rigidity, dementia, eye movement abnormalities during the first
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5 years of the disease; no benefit from Levodopa. Disease duration is estimated longer than the other subtypes73.
PSP-CBS (Cortico-basal syndrome). CBS is the most common presentation of
cortico-basal degeneration. Clinically and genetically, there is a consistent overlap between cortico-basal degeneration and PSP neuropathology57. PSP-CBS is characterized by progressive and asymmetric apraxia, cortical sensory deficit, including alien limb, bradykinesia non-responsive to Levodopa. It is a rare presentation of PSP disease; in a sample of 160 PSP patients, only 5 showed these features. None of them subsequently developed instability or falls, or dysarthria-dysphagia. Increased saccadic latency prevailed on the saccadic slowing74.
PSP- speech language (nfv PPA). Non-fluent variant of Primary Progressive Aphasia
(nfv PPA) is a language disorder characterized by non-fluent spontaneous speech, with hesitations, agrammatism, phonemic errors that require considerable effort in the production of speech (apraxia of speech). This disorder may be associated with frontotemporal dementia or cortico-basal degeneration70. However, a small percentage of patients with nfvPPA had neuropathological characteristics which were typical of PSP pathology, particularly those patients with predominantly apraxia of language at onset (on the contrary, a minor apraxia of the language seems more related to the FTD)75.
PSP with Frontal presentation. PSP-F refers to patients presenting with features of
behavioural variant of fronto-temporal dementia years before developing a PSP-RS phenotype. These symptoms include early and progressive deterioration of personality, social comportment, behaviour (such as apathy, rigidity, disinhibition, and hyperorality), and cognition. PSP-F is very rare and should be autopsy-proven57.
PSP with predominant cerebellar ataxia. PSP-C is a very rare phenotype in which
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In autopsy-proven cases, clinical characteristics were similar to MSA-C but the absence of dysautonomia did not allow to meet MSA diagnostic criteria57.
PSP with mixed pathology. Rarely, other neuropathological hallmark may underlie a
typical PSP clinical presentation. Among these, Alzheimer’s disease pathology, Parkinson’s disease pathology, TDP-43 deposition, argyrophilic grain disease, or cerebrovascular disease have been described57.
1.2.6 Diagnostic techniques
1.2.6.1 Neuroimaging
Standard MRI. Standard MRI, even if with some limitations, can contribute in
differential diagnosis of PSP vs other APD or Parkinson’s disease and is included as an ancillary investigation in the diagnostic criteria. Atrophy of the midbrain, present in 75-80% of PSP patients, and of superior cerebellar peduncles is considered a useful marker in differentiating PSP from other APDs46,76. As The use of MRPI (magnetic resonance parkinsonism index, see MSA paragraph) yielded sensitivity of 100% and specificity of 99·2–100·0% for PSP-RS77. The pons:midbrain ratio, as calculated from conventional MRI, had high specificity and sensitivity for the diagnosis of pathologically confirmed PSP. Other indirect signs of midbrain atrophy include atrophy of the lenticular nucleus, (putamen and pallidum nucleus). The atrophy of the rostral tegment, the pons basis and the cerebellum that can be observed in the sagittal sections of the MRI (so-called penguin or hummingbird sign) is observed in a large proportion of PSP patients, especially RS78, as well as the morning glory sign, a particular MR finding of mesencephalic atrophy with concavity of the lateral margin of the midbrain tegment (resembling the lateral edge of the Morning Glory flower). Less data is available on the extent of mesencephalic atrophy between PSP subgroups76.
Functional imaging. The SPECT study of presynaptic dopaminergic function, with
18F-dopa and with 18F-dopamine transporter (DAT) tracers, shows great sensitivity in recognizing parkinsonian atypical syndromes, but low specificity in discriminating
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between them and from PD. Postsynaptic dopamine dysfunction is also common in PSP-RS but of unclear value in distinguishing between alternate parkinsonisms. An FDG-PET study has recently shown a marked midbrain, thalamic and frontal cortex hypometabolism in PSP-RS patients, and a putaminal hypometabolism in PSP-P79. In the MDS-PSP criteria, demonstration of predominant midbrain hypometabolism is sufficient to qualify for an “imaging supported diagnosis” label68,80.
Transcranial sonography. Recent studies have found specific alterations in MSA and
PSP, but not in PD or Lewy bodies dementia. Particularly, the normoecogenicity of the substantia nigra is characteristic of PSP, while it appears hyperechogenic in PD. In addition, a hyperechogenicity of the lenticular nucleus is typical of MSA and PSP, but not of PD, and dilatation of the third ventricle (> 10 mm), associated with hyperechogenicity of the lenticular nucleus, can discriminate PSP from PD with positive predictive value of 89%56.
1.2.6.2 CSF and blood biomarkers
Various attempts have been carried out to identify CSF biomarkers that would prove useful in accurate diagnosis of PSP, but no definitive results have been obtained. In particular, the quantification of alpha-synuclein in the liquor has been used in differentiating PD from MSA and PSP, but was not useful in discriminating among APDs. The concentration of tau protein is normal or reduced in PSP in respect to controls57. Measurement of neurofilament light chain concentrations has been applied in CSF and blood with promising results. In both, concentration was found higher in PSP patients in respect to healthy controls and Parkinson’s disease57.
1.2.6.3 Other techniques
Polysomnographic studies have shown a decrease in total sleep time, an increase in awakening and progressive loss of REM sleep. These alterations have been attributed to the degeneration of brainstem structures which are crucial for the genesis of a normal sleep pattern.
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The brain evoked potentials (BAERS) and blink reflexes are usually normal in PSP. The EMG of the anal sphincter can be useful in differentiating PSP from PD, but from MSA59.
1.2.7 Treatment
Treatment for individuals suspected to have PSP remains symptomatic and supportive, with ongoing clinical trials striving to identify disease-modifying therapies often targeting the underlying tau pathology80.
Patients may show a benefit with Levodopa treatment, especially in PSP-P phenotype, but this success is generally transient and has no effect on disease prognosis. Amantadine is sometimes tried with limited supportive evidence. Botulinum toxin injections can be used for focal dystonias including apraxia of eyelid opening80.
There are no accepted treatments for cognitive symptoms, but small series of cases suggest a potential role for cholinesterase inhibitors.
The development of disease-modifying therapeutic approaches targeting tau or mitochondrial dysfunction is promising, but to date they have failed in demonstrating efficacy on PSP.
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1.3 Corticobasal degeneration
The first description of "corticodentatonigra degeneration with neuronal acromasia" as a distinct nosological entity dates back to 196781. Only later it was renamed corticobasal
degeneration. Subsequent clinical and pathological studies have later revealed that the originally described clinical features of CBD may actually be neuropathologically related to other diseases. Consequently, the term CBD is confusing, and currently the term corticobasal syndrome (CBS), indicating the clinical presentation typical of CBD, is preferred, while the term CBD should be used only when hystopathological confirmation is available82. Neuropathological characteristic of CBD is the presence of widespread deposits of 4 microtubule-binding domains hyperphosphorylated tau protein (4R) in neurons and glia (in the latter as astrocytic plaques) in specific brain areas83.
1.3.1 Epidemiology
The age of onset of CBD is about 60 years-old, without differences of gender84. The average duration of illness is about 6.6 years, with a range between 2 and 12.5 (SD 2.4)85. It is estimated that, antemortem , CBD is diagnosed in a percentage ranging between 25% and 56% of cases86.
1.3.2 Pathogenesis
Macroscopically, CBD is characterized by frontotemporal cortical atrophy. The asymmetry of brain involvement may be less marked than clinically observable, although present. The substantia nigra often appears depigmented, but this is less pronounced in patients with prevalent and severe cognitive symptoms. Histologically, neuronal loss and gliosis are more observable on superficial cortical layers. "Ballooned" neurons, characterized by swelling of the pericar, dispersion of the Nissl substance, eccentrically localized nuclei and occasional cytoplasmic vacuoles, are found in affected cortical areas. Ballooned neurons can also be observed in other diseases, such as Pick's disease, Alzheimer's disease, PSP, motor neuron disease and Creutzfeld-Jakob disease, but the quantity and distribution are diagnostic in CBD. In addition, the
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presence of oligodendroglial tau inclusions called coiled bodies are common in CBD, but are much more frequent in PSP than CBD62,87.
The astrocytic plaques, the hallmark features of disease, represent tau accumulation in the distal segments of astrocytes with minimal accumulation in the cell body, creating a central clear zone. They are more numerous in cortex, but can also be seen in caudate and putamen and less often in thalamus and midbrain tectum; they do not contain amyloid and are also distinguished from the astrocytes observable in the PSP, thus resulting characteristic of CBD62.
Neuropathological criteria for the diagnosis of CBD were also established by the "The Office of Rare Diseases of the National Institutes of Health" (USA). Major criteria include: focal neuronal loss (fronto-parieto-temporal); neuronal loss in the substatntia nigra; neuronal and glial tau-positive lesions (astrocytic plaques and filaments) in the white and gray matter. Among the supporting criteria: cortical atrophy, with possible spongiosis; ballooned neurons; tau-positive spirals in olygodendrocytes88.
1.3.3 Clinical presentation
The Corticobasal Syndrome is usually characterized by akinetic-rigid parkinsonism, dystonic and myoclonic movements, associated with cortical symptoms such as ideomotor apraxia, alien limb phenomena, aphasia or sensory neglect62.
Asymmetric rigidity and apraxia. The cardinal symptoms of CBS are represented by
progressive rigidity and asymmetric apraxia. Symptoms typically begin in a limb (without right-left predilection) which, at the clinical evaluation, might be rigid and dystonic; both rigidity and spasticity can be present. Usually apraxia appears later (although sometimes, if extrapyramidal symptoms prevail, this may not be adequately assessed). Generally, stiffness and apraxia progress to a limb (usually the superior) over a two-year period, and then extends either to the contralateral or to the lower82.
Alien limb. There is uncertainty in the definition of alien limb, as sometimes it is also
applied to severe coreo atetosis or severe cortical deficit. Usually, the limb is perceived as having its own life and the movement is only spontaneous, but not voluntary82.
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Cortical sensory impairment. This symptom ranges from the compromission of the
sense of position to the agrafesthesia and asterognosia82.
Myoclonus. It usually begins distally in one limb and progresses proximally. Frequency
and amplitude increase with tactile stimulation and action.
Dystonia. Often an onset symptom, generally starting at one of the upper limbs mostly
during walking, without pain. The cause underlying dystonia is perhaps either the damage to the striatum, or degeneration of the motor cortex82.
Tremor. This symptom is usually seen during the action, while it is less frequent at rest.
The classic PD tremor (4-6 Hz) is rare in CBS.
Not-responsiveness to Levodopa. No amelioration of symptoms has been reported, so
the Levodopa administration could at least be a method for a differential diagnosis with PD (but not from other parkinsonisms).
Dementia. An impairment in various cognitive domain is observable at the onset of
CBS. Neuropsychological tests usually show attention/concentration deficits in executive functions, verbal fluency, language and visual-spatial functions. In contrast, learning and memory are rarely affected at an early stage. Aphasia, apraxia and hemineglect can also be observed. A Gerstmann's syndrome in CBS has been described, with acalculia, agraphia, agnosia, right-left disorientation; other symptoms in CBS include visual agnosia, alexia, and sensory aphasia.
Neuropsychiatric symptoms. Depression, apathy and "frontal" behaviour have been
reported in CBS. In contrast, the occurrence of hallucinations points towards a diagnosis of Lewy bodies dementia89.
Oculomotor apraxia. Variable degrees of oculomotor apraxia, observed as a slowing in
initiating ocular movements (especially saccades) are reported in almost all patients.
Other characteristics. These include: dysarthria, asymmetric hyperreflexia, Babinski
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1.3.4 Phenotypes and diagnostic criteria
Since a neuropathologically proven CBD may manifest with great heterogeneity, a classification of the different phenotypes (syndromes) of CBD disease has been proposed by Armstrong et al83. These phenotypes include: probable CBS, possible CBS, frontal behavioural-spatial syndrome, nonfluent/agrammatic variant of primary progressive aphasia, progressive supranuclear palsy syndrome.
Regarding the diagnostic criteria for CBD, two definitions have been proposed. Probable sporadic CBD comprises restrictive criteria aimed at the exclusion of other diseases presenting with similar features; Possible CBD emphasizes clinical presentations consistent with CBD but ones that may also overlap with other t-based pathologies83.
1.3.5 Causes of corticobasal syndrome
Neuropathologically confirmed CBD accounts for approximately 55% of cases with CBS. Other possible causes of CBS (clinically diagnosed) are represented in 28% of cases by tauopathies such as PSP and Pick disease. Furthermore, mutations in the gene encoding the microtubule-associated protein tau (MAPT) may be associated with CBS, as well as mutations in the gene encoding for progranulin, associated with tau-negative FTD disease. Similarly, neurofilaments inclusion body disease (NIBD) has a phenotypic expression variability that also includes CBD. The presence of a familiar history suggests a genetic transmission, while a short course of disease points toward other diseases (Creutfeld-Jakob, NIBD, FTD). A PSP-like presentation or non-fluent progressive aphasia suggests a taupathy87.
1.3.6 Diagnostic techniques
1.3.6.1 Neuroimaging
MRI studies typically show asymmetric cortical atrophy in the frontoparietal regions. In addition, hyperintensity in the precentral gyrus contralateral to the affected limb and atrophy of the putamen, with enlargement of the third and lateral ventricle, may be present90. Conversely, the temporal and occipital lobes are usually less involved.
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Kitagaki et al. found marked asymmetry of the hemispheric volumes, and hypothesized that parasagittal and paracentral atrophy could be a hallmark of CBD91.
Spectroscopic MR images showed a reduced NA / Cre ratio in the semioval centre, and a significant reduction of the NA / Cho ratio in the lentiform nucleus and parietal cortex. These findings could indicate a possible involvement of the white matter in addition to gray92. In a voxel-based MRI morphometric study, the cerebral volumes of subjects with clinically probable CBD were compared with those of probable PSP; CBD showed greater parieto-frontal cortical atrophy compared to PSPs and healthy controls, whereas PSPs had greater atrophy in the brainstem when compared to CBD and controls. Both groups had a greater atrophy of the basal ganglia compared to the controls93.
Recent FDG-PET studies in patients with autopsy confirmed CBD showed an hypometabolism of the parietal lobe, an area that was not seen to be affected in PSP. Hence, parietal hypometabolism may be a biomarker of CBD pathology94,95.
1.3.6.2 CSF biomarkers
Although several attempts have been made, there are currently no CSF biomarkers that can confirm or rule out a diagnosis of CBD. Tau protein dosage is not specific enough to discriminate CBD from other tau-related parkinsonisms such as PSP89.
1.3.6.3 Genetics
There are very few genetic studies in cases of CBD. In one, a higher occurrence of the haplotype tau H1, the same increased in the PSP, has been found. In another study, a higher incidence of ApoE4 in CBDs was observed compared to controls, but to a lesser extent than AD. However, larger studies are needed to confirm these findings89.
1.3.7 Treatment
At present, there is no specific treatment for CBD. In the absence of approved pharmacological treatments for PSP and CBD, management should be based on
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relieving symptoms and assisting patients with their activities of daily living. Advanced care planning and non-pharmacological supportive therapies remain paramount in the management of CBD. L-DOPA and amantadine are not proven to be effective. Botulinum toxin is helpful in reducing dystonia and in managing sialorrhoea and is particularly useful for eyelid dysmotility96.The use of anticholinesterase drugs for cognitive disorders has been tested, but with doubtful efficacy96.
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2 Role of the study of Ocular Movements in Atypical
Parkinsonisms
The examination of eye movements is a valuable tool for investigating, in a non-invasive and repeatable way, the functional integrity of different brain structures involved in oculomotor control and cognitive processes. Oculomotor abnormalities might have a considerable value in localizing a cerebral dysfunction, as the alterations are associated with an impairment of a particular cerebral anatomical structure. In this regard, the study of specific oculomotor abnormalities in atypical parkinsonisms, which are related to cerebellar, brainstem, basal ganglia and, as recently recognized, frontal lobes and cortical structures involvement, is of pivotal interest97.
Eye movements can be globally divided into two categories, each with a specific role. The first, including the oculo-vestibular reflex (VOR) and the optokinetic nystagmus, is responsible for maintaining the stability of images on the retina during head rotations, full field motion and locomotion. Although anomalies of these functions have been reported, most oculomotor changes (and therefore investigations) in APDs specifically address the second category of gaze shifting, which includes the saccadic system and the pursuits.
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2.1 Saccadic system
The saccade is the fastest ocular movement, aimed at moving the fovea towards an object of interest. Saccades can be divided in reflexive (saccades directed towards a suddenly appeared target) and voluntary (i.e. the saccade internally guided towards the remembered location of a visual target or as part of a context specific task). Diverse cortical and subcortical brain areas have been identified as involved in the saccadic control98.
The cortical areas related to saccadic movements in humans include: the Frontal eye field (FEF), which is located in the precentral gyrus and sulcus, close to the intersection with the superior frontal sulcus; the Supplementary eye field (SEF), which lies anterior to the additional motor area, in the upper part of the paracentral sulcus; the pre-SEF, located anterior to the SEF; the Parietal eye field (PEF), lying on the intraparietal sulcus; the dorsolateral prefrontal cortex (DLPC), which lies in the lateral dorsal surface of the frontal lobe, before the FEF; the posterior parietal cortex (PPC).
FEF lesions appear to be associated with an increase in the latency of reflexive, predictive and memory-guided saccades (where amplitude is also altered). Both FEF and DLPC are involved in the control of antisaccades: particularly, DLPC would contribute to the inhibition of the reflexive saccade, while FEF to the genesis of the voluntary antisaccade. Inactivation of these two areas, respectively, induces an increase in the latency of the antisaccades (lesion of FEF) and an increase of the errors in the antisaccades (lesion of DPLC). DPLC would also be associated with working memory, and its impairment costs more errors in the memory-guided task. SEF alteration would be associated with deficits in the execution of saccadic sequences and memory-guided saccades. The parietal regions are more involved in the genesis of reflexive saccades99.
The frontal and parietal cortices project directly to the superior colliculus and the frontal areas project indirectly to the basal ganglia through a pathway including the caudate nucleus and the pars reticulate of substantia nigra (SNpr). The frontal areas also project, through the pontine nuclei, to the dorsal vermis and fastigial nuclei in the cerebellum98. The cerebral cortex and basal ganglia neurons related to saccade genesis are distributed
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in a topographic fashion that correlates with the amplitude and specific direction of the saccade (i.e. by stimulating a region of the FEF a saccade of corresponding amplitude and direction is obtained); conversely, brainstem and cerebellar neurons have a temporal encoding (i.e. their maximum discharge temporally correlates with the maximum saccadic speed)98.
SNpr has an inhibitory effect on the superior colliculus, facilitating fixation. The caudate nucleus, during the preparation of the saccade, inhibits the SNpr, therefore releasing the colliculus and permitting the execution of the movement. The colliculus, divided into a rostral part (fixation neurons) and a dorsal part (retinotopic map for the position of the target in space) indicated target position to the frontal areas in order to perform an appropriate movement to reach it. The cerebellum (in particular the dorsal oculomotor vermis and the caudal portion of the fastigial nucleus) is responsible for the control of saccadic accuracy and monitors the movement in terms of metric and dynamics, adjusting the amplitude of the saccade on-line and reducing its position error. Finally, the burst cells located on brainstem produce the needed discharge for the saccade initiation, modulated by the cerebellum, while the omnipause neurons normally inhibit the burst neurons in order to avoid spurious saccades and to maintain fixation when a saccade is not needed. The omnipause neurons maintain an inhibitory tonic discharge on the bursts neurons but become inactivated when preparing a new saccade98.
2.2 Saccadic parameters
Relationship between amplitude, peak velocity and duration. Each saccade shows a relationship between amplitude, speed and duration, namely the larger the saccade, the higher the peak velocity (the maximum speed recorded in the movement) and the longer the duration. This fundamental relationship is called the main sequence. However, even the largest saccade lasts not more than 100 ms, less than the response time of the visual system. Consequently, the saccade is a ballistic movement in which accuracy depends on internal neural monitoring, and not on visual feedback.
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Direction (trajectory). The vertical and horizontal saccades are generated by populations of premotor neurons differently located (respectively in the midbrain for the vertical, in the pons for the horizontal movements). For this reason, it is important to measure both vertical and horizontal movements and obliques.
Accuracy. Ideally, a saccade should move the eye so that the fovea reaches precisely the point of interest at the end of the movement. Hypometria occurs when the movement does not reach the target (undershoot), hypermetria when it exceeded the target (overshoot). In normal subjects, slight hypometria can be observed, especially for large movements (> 10 deg); greater hypometria, or hypermetria, are observed in cerebellar impairment. Particularly, hypermetria is linked to fastigial alterations.
Latency (reaction time). This term indicates the interval between the presentation of the target and the beginning of the saccadic movement, whose measurement is useful in order to understand the cortical and subcortical aspects of the saccadic programming. In fact, latency reflects the processing of visual information, target selection and motor programming98.
2.3 Saccadic paradigms
Reflexive Saccades. In natural conditions, we execute numerous reflexive saccades towards different stimuli. In the laboratory, a reflexive saccade can be elicited when a new stimulus is presented after the fixation target has disappeared (often introducing a gap period in which no stimulus is present). In this case, also very low latency express saccades might be observed (about 100 ms of latency).
Voluntary saccades. These can be tested with an overlap paradigm, in which the central fixation stimulus remains throughout the experiment, and “overlaps” with the new lateral target, to which the subject is invited to look.
Memory-guided saccades. In this task, the subjects are invited to perform a saccade towards a remembered location, where a target had appeared for a few seconds before. It is therefore employed in the evaluation of frontal lobes or basal ganglia impairment, in which an alteration of the working memory could be observed. The programming of
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the memory-guided saccades relies on various brain areas. TMS studies have postulated that PPC is involved in the processing of visuospatial information about 300 ms after the presentation of the target; both DLPC areas are involved during the memorization phase (about 1 s after the presentation of the target); the FEF plays a role in the genesis of the memory-guided saccade, perhaps with the contribution of PEF. Specific parameters taken into account include: the number of errors (i.e. saccade not performed or incorrect); the latency of the movement; the accuracy of the movement.
Predictive saccades. In natural conditions, we perform a series of eye movements, including saccades, to anticipate or search for a target in a particular place. In the laboratory, predictive saccades are induced by targets that move between two positions at regular intervals. The SNPR-caudate complex seems to be involved in the genesis of voluntary movements that require predictive behaviour or learning; predictive saccades are indeed impaired in patients with Parkinson's disease or bilateral lesions of the lentiform nucleus.
Antisaccadic paradigm. An important part of the saccadic movement consists in suppressing unwanted movements towards new targets, when considered irrelevant. This behaviour can be reproduced in the laboratory with the antisaccadic task, in which the subject is required to suppress the saccade (prosaccade) towards a new target that appears in the periphery of the visual field and to perform a movement of equal amplitude (antisaccade) towards the opposite side. In some tasks, after a short period, a target that confirms the exact position appears, to evaluate the accuracy of the movement. Normal subjects usually make some mistakes in the task, but the error percentage reduces with practice. FEF alterations increase the latency of the antisaccade, while DLPC lesions increase the number of errors in the task. Specific parameters usually considered are the number of errors, the latency and accuracy of the correct antisaccade, the latency between the errors and the correction.
