Atypical Parkinsonian Disorders: Reviewing the Complex Web of Proteinopathies
α-synuclein is the main protein implicated in Parkinson disease, as well as dementia with Lewy bodies and multiple system atrophy.
The term “parkinsonian disorders” encompasses a broad spectrum of heterogeneous neurodegenerative diseases that share core symptoms of parkinsonian syndrome. Diagnosis of Parkinson disease (PD) — by far the most prevalent — is often confounded by the common clinical overlap of atypical parkinsonian disorders (APDs), such as progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal degeneration (CBD), and dementia with Lewy bodies, as well as several rare disorders that are grouped among APDs.
Each of these phenotypically distinct diseases manifests a number of specific clinical features with overlapping symptoms that have limited treatments and no cures. In recent years, the symptomatic approach to parkinsonian disorders has hit a wall, yet at the same time, an explosion in genetic and radiographic research has begun to tease apart PD from APDs and to further distinguish the multiple overlapping syndromes involved.1-3
Designation by Proteinopathy
Idiopathic PD was linked to dysfunction of α-synuclein proteins in the brain in the late 1990s.4,5 Since then, other parkinsonian disorders were found to share a common mechanism of protein aggregation and the formation of inclusions in the brain and spinal cord. These were designated “proteinopathies,” according to the primary protein involved. For dementia with Lewy bodies, MSA, and PD, α-synuclein is the main protein (α-synucleinopathies), whereas in PSP and CBD, it is the tau protein (tauopathies).6,7 The tau protein is considered dominant in Alzheimer disease (AD), although α-synuclein pathology is also present.
A second feature of proteinopathies is the misfolding of specific molecules, originally observed in the α-synuclein protein specific to PD and AD, and later shown in the molecular pathology of tau proteins underlying diseases such as amyotrophic lateral sclerosis and AD.8,9
Clinical Distinctions Between PD and APDs
The most prominent differences between PD and APD are in their responses to levodopa, which is highly effective in managing motor signs of PD and to some degree in MSA, but has low or no efficacy in APD.10
Although similar to PD, MSA (characterized by akinesia and rigidity) is much less responsive to levodopa and progresses more rapidly. Prognosis is worsened by autonomic failure at the time of diagnosis. Parkinsonian tremor is rare in MSA, and tends to be posturally or activity induced rather than resting type when it does occur. Ocular motor dysfunction manifests as suppression of vestibular-ocular reflexes and nystagmus, as well as impairment of smooth-pursuit eye movements and saccades. Pyramidal signs are common, as is cognitive impairment in later stages.6,10
Early olfactory dysfunction — which may be a prodromal feature of PD and is often mildly present in MSA — is generally rare in APDs.10 APDs also include a number of cerebellar symptoms and extrapyramidal signs unique to each syndrome that are rarely seen in idiopathic PD.
Frontotemporal lobar degeneration (FTLD) is a newer designation for disorders previously called “Parkinson-plus” syndromes, including frontotemporal dementia, CBD, and at least 15 variations of PSP that have been shown to share different pathology from the α-synuclein mechanisms underlying PD and MSA.6,10 A recent study by Coyle-Gilchrist et al6 indicated a similar incidence, prevalence, and risk for mortality among all 3 syndromes, with a peak prevalence between the ages of 65 and 69. Diagnostic criteria for FTLD have been substantially revised in the past decade, helping to further define these conditions5,10-12:
- Frontotemporal dementia is the most commonly diagnosed form of FTLD, characterized by behavioral signs of disinhibition, apathy, inertia, and impulsivity, as well as a loss of empathy, judgment, and self-control. In semantic variants of primary progressive aphasia, language skills are significantly affected.
- CBD is the least common of FTLD syndromes. It generally presents with a great variation of motor symptoms, resulting in less than a 50% accuracy of diagnosis. The most common symptoms include rigidity, bradykinesia, and dystonia. A hallmark sign is alien limb phenomenon, usually of the arm, but also of the foot.
The classic and most common form of PSP is Richardson-Steele syndrome, first identified in 1963,13 which was recently found to account for 24% of cases.14 More than 15 subtypes make up the remainder of PSP cases, with variations defined by primary motor symptoms such as ocular motor dysfunction, postural instability, pure akinesia, and primary progressive freezing of gait. Other subtypes are defined by cortical dysfunction, such as the frontal lobe.
The main distinguishing feature of APDs is a poor clinical response to levodopa, the mainstay of PD treatment. This feature alone necessitates a better understanding of APDs to treat these diseases effectively. Matching clinical signs to subclasses of proteinopathies is an important goal of clinical trials, which can then better target specific constellations of symptoms to the many APD variants.
Further investigations of proteinopathy are underway, targeted at halting or slowing protein aggregation before clinical manifestations occur. In a 2017 review, Longhena et al2 wrote that, “numerous studies have shown that small molecule-based approaches may be potentially the most promising for halting protein aggregation in neurodegenerative diseases. Indeed, several of these compounds have been found to interact with intrinsically disordered proteins and promote their clearing in experimental models.”
- Dąbrowska M, Schinwelski M, Sitek EJ, et al. The role of neuroimaging in the diagnosis of the atypical parkinsonian syndromes in clinical practice. Neurol Neurochir Pol. 2015;49(6):421-431.
- Longhena F, Spano P, Bellucci A. Targeting of disordered proteins by small molecules in neurodegenerative diseases [published online October 1, 2017]. Handb Exp Pharmacol. doi: 10.1007/164_2017_60
- Fogel BL, Clark MC, Geschwind DH. The neurogenetics of atypical parkinsonian disorders. Semin Neurol. 2014;34(2):217-224.
- Baba M, Nakajo S, Tu PH, et al. Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson's disease and dementia with Lewy bodies. Am J Pathol. 1998;152(4):879-884.
- Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. Alpha-synuclein in Lewy bodies. Nature. 1997;388(6645):839-840.
- Coyle-Gilchrist IT, Dick KM, Patterson K, et al. Prevalence, characteristics, and survival of frontotemporal lobar degeneration syndromes. Neurology. 2016;86(18):1736-1743.
- Alafuzoff I, Hartikainen P. Alpha-synucleinopathies. Handb Clin Neurol. 2017;145:339-353.
- Grad LI, Fernando SM, Cashman NR. From molecule to molecule and cell to cell: prion-like mechanisms in amyotrophic lateral sclerosis. Neurobiol Dis. 2015;77:257-265.
- Lewis J, Dickson DW. Propagation of tau pathology: hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies. Acta Neuropathol. 2016;131(1):27-48.
- Deutschländer AB, Ross OA, Dickson DW, Wszolek ZK. Atypical parkinsonian syndromes: a general neurologist's perspective [published online August 12, 2017]. Eur J Neurol. doi: 10.1111/ene.13412
- Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain. 2011;134:2456-2477.
- Armstrong MJ, Litvan I, Lang AE, et al. Criteria for the diagnosis of corticobasal degeneration. Neurology. 2013;80(5):496-503.
- Richardson JC, Steele J, Olszewski J. Supranuclear ophthalmoplegia, pseudobulbar palsy, nuchal dystonia and dementia. A clinical report on eight cases of “heterogenous system degeneration.” Trans Am Neurol Assoc. 1963;88:25-29.
- Respondek G, Stamelou M, Kurz C, et al. The phenotypic spectrum of progressive supranuclear palsy: a retrospective multicenter study of 100 definite cases. Mov Disord. 2014;29:1758–1766.