Course, Natural History and Prognosis - New slides for Parkinson's disease now available

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Course, Natural History and Prognosis - New slides for Parkinson's disease now available

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Course natural history and prognosis
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The course of Parkinson’s disease
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The journey of Parkinson’s disease
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The clinical effects of Parkinson’s disease (PD) are visually obvious, but the underlying pathology of PD is still not fully understood.[McCann et al., 2016] PD pathology is thought to spread from brain region to brain region over multiple long-distance relays, during long periods of time.[McCann et al., 2016] To spread in this way, between brain regions, the pathology must be transferred from cell to cell; the transfer setting off a series of intracellular changes that progress within the affected cells leading to cell death.[McCann et al., 2016] Several mechanisms have been implicated in the cellular pathology of PD, including mitochondrial dysfunction and impairments in autophagy.[McCann et al., 2016]

McCann H, Cartwright H, Halliday GM. Neuropathology of α-synuclein propagation and Braak hypothesis. Mov Disord 2016; 31 (2): 152–160.

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Clinical symptoms and time course of Parkinson’s disease progression
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The progression of PD is generally slow, taking place over years (often many years).[Kalia & Lang, 2015] While diagnosis tends to occur with the onset of motor symptoms, this can be preceded by a long prodromal phase of 15 years or more.[Goldman & Postuma, 2014] This prodromal phase is typically characterised by a range of non-motor symptoms, including sleep disorders, depression, and constipation.[Goldman & Postuma, 2014] One of the most common symptoms is ‘REM sleep behaviour disorder’, in which affected individuals can become physically, even violently, active during the REM (rapid eye movement) stage of sleep.[Goldman & Postuma, 2014; Kalia & Lang, 2015] 

Additional non-motor symptoms develop following clinical diagnosis and, as the disease progresses, cause increasing disability.[Sung & Nicholas, 2013] Some symptoms, such as postural instability, dysphagia, and dementia, tend to occur in more advanced disease.[Kalia & Lang, 2015]

After several years of levodopa therapy, complications can begin to appear.[Kalia & Lang, 2015] These may include ‘fluctuations’, when patients alternate between periods of good symptom control (ON periods) and poor symptom control (OFF periods).[Kalia & Lang, 2015] The occurrence of these dopa-related response complications remains a major limitation of levodopa as a dopamine replacement therapy.[Kalia & Lang, 2015]
 
 

Kalia LV, Lang AE. Parkinson’s disease. Lancet 2015; 386 (9996): 896–912.

Goldman JG, Postuma R. Premotor and non-motor features of Parkinson’s disease. Curr Opin Neurol 2014; 27 (4): 434–441.

Sung VW, Nicholas AP. Nonmotor symptoms in Parkinson’s disease: expanding the view of Parkinson’s disease beyond a pure motor, pure dopaminergic problem. Neurol Clin 2013; 31 (3 Suppl): S1–16.

Poewe W, Seppi K, Tanner CM, et al. Parkinson disease. Nat Rev Dis Primers 2017; 3: 17013.

Kulisevsky J, Luquin MR, Arbelo JM, et al. Advanced Parkinson’s disease: clinical characteristics and treatment (part 1). Neurologia 2013; 28 (8): 503–521. 

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Thresholds for the appearance of Parkinson’s disease symptoms
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Regions of the brain that are particularly vulnerable to Lewy pathology and degeneration during the earliest phase of PD include the olfactory bulb, a critical component of the sense of smell; the locus coeruleus, which produces noradrenaline and regulates sleep/wake cycles; and the dorsal motor nucleus of the vagus nerve, which is involved in regulating gastrointestinal function.[Dalvi, 2013; Morahed et al., 2003] The early involvement of these brain regions could explain several of the non-motor symptoms of PD that occur during Stages 1 and 2 of the six stages proposed by Braak and colleagues (as shown on the slide).[Braak et al., 2004; Dalvi, 2013]
During Stage 1 of PD, many individuals experience a loss of smell (hyposmia) and/or suffer from constipation.[Dalvi, 2013] In addition, sleep may become disordered or disturbed, accompanied by crying out, punching, or kicking during rapid eye movement (REM) sleep.[Dalvi, 2013; Baumann, 2014] However, some of these features, such as constipation, may not be very specific, as they can also occur in many older, otherwise healthy, people.[Braak et al., 2004]

Stages 3 and 4 mark the transition from prodromal stage to clinically overt PD, as the disease spreads from the brainstem up into the midbrain and forebrain.[Braak et al., 2004] The classic symptoms of PD – bradykinesia, tremor, and muscular rigidity – start to appear as the substantia nigra loses its capacity to produce dopamine, and intrinsic compensatory mechanisms are overwhelmed.[Hawkes et al., 2010; Schapira & Obeso, 2006] Diagnosis typically occurs around this point.[Braak et al., 2004] Gradually, initial clinical symptoms worsen while new ones start to appear.[Hawkes et al., 2010] Resting tremors may begin to affect both sides of the body, rather than just one, and normal balance becomes increasingly difficult to maintain.[Hawkes et al., 2010] 

Baumann C. Sleep-wake disorders in Parkinson’s disease. In: Wolters E, Baumann C (eds). Parkinson Disease and Other Movement Disorders. VU University Press, 2014.

Braak H, Ghebremedhin E, Rüb U, et al. Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 2004; 318 (1): 121–134.

Dalvi A. Premotor symptoms. In: Pahwa R, Lyons KE (eds). Handbook of Parkinson’s Disease, 5th edition. Boca Raton: CRC Press, 2013. 

Hawkes CH, Del Tredici K, Braak H. A timeline for Parkinson’s disease. Parkinsonism Relat Disord 2010; 16 (2): 79–84.

Morahed P, Mitra MT, Chaudhuri KR. Sleep dysfunction. In: Pahwa R, Lyons KE (eds). Handbook of Parkinson’s Disease, 5th Edition. Boca Raton: CRC Press, 2013.

Schapira AH, Obeso J. Timing of treatment initiation in Parkinson’s disease: a need for reappraisal? Ann Neurol 2006; 59 (3): 559–562.

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The therapeutic benefits of modifying the disease course
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While there have been major advances in the management and reduction of PD-related symptoms, there is still no effective way of preventing or slowing the underlying neurodegeneration.[Athauda & Foltynie, 2015; Ferreira et al., 2013] As the disease becomes more extensive during its advanced stages, the ability of drugs and other coping strategies to compensate for the increasing loss of neurological function is severely reduced.[Athauda & Foltynie, 2015] Increasingly poor responses to treatment lead to a worsening quality of life for the patient, and an increased risk of PD-related morbidity and mortality.[Kulisevsky et al., 2013]
Many drugs have shown promise during preclinical studies as potentially protective or restorative of neurological function in PD, yet have failed during the final stages of clinical trials.[Athauda & Foltynie, 2015] Other drugs are in the pipeline but, so far, the efficacy of novel pharmacological interventions in PD is proving to be difficult to predict.[Athauda & Foltynie, 2015] Potential reasons for these failures in detecting clinical benefits of new therapies include the lack of good biomarkers of disease state, the lack of diagnostic biomarkers for PD in general, and the use of clinical rating scales that may lack the sensitivity to detect change within the timeframe of a clinical trial.[Lim & Tan, 2018; Schapira, 2013] 

Athauda D, Foltynie T. The ongoing pursuit of neuroprotective therapies in Parkinson disease. Nat Rev Neurol 2015; 11 (1): 25–40.

Ferreira JJ, Katzenschlager R, Bloem BR. Summary of the recommendations of the EFNS/MDS-ES review on therapeutic management of Parkinson’s disease. Eur J Neurol 2013; 20 (1): 5–15.

Kulisevsky J, Luquin MR, Arbelo JM, et al. Advanced Parkinson’s disease: clinical characteristics and treatment. Part II. Neurologia 2013; 28 (9): 558–583.

Lim SY, Tan AH. Historical perspective: the pros and cons of conventional outcome measures in Parkinson’s disease. Parkinsonism Relat Disord 2018; 46 (Suppl 1): S47–S52.

Schapira AHV. Recent developments in biomarkers in Parkinson disease. Curr Opin Neurol 2013; 26: 395–400.

Schapira AH, Bezard E, Brotchie J, et al. Novel pharmacological targets for the treatment of Parkinson’s disease. Nat Rev Drug Discov 2006; 5 (10): 845–854.
 

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Change in levodopa response over time – ‘wearing-off’
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Levodopa is the major symptomatic therapy for PD and provides benefit to virtually all patients.[Obeso et al., 2000] During the so-called ‘honeymoon’ period, the effects of levodopa tend to be long-lasting and side effects are tolerable.[Obeso et al., 2000] Beyond this ‘honeymoon’ period, however, patients may struggle to maintain good symptom control as the duration of response to levodopa therapy becomes progressively shorter.[Obeso et al., 2000] This problem is known as ‘wearing-off’.

‘Wearing-off’ is a predictable recurrence of PD symptoms that precedes a scheduled dose of levodopa and usually improves with medication.[Bhidayasiri et al., 2015] By contrast, the less predictable fluctuations – sometimes called ‘yo‑yoing’ – are associated with more advanced stages of PD.[Thanvi & Lo, 2004] 

Bhidayasiri R, Hattori N, Jeon B, et al. Asian perspectives on the recognition and management of levodopa ‘wearing-off’ in Parkinson’s disease. Expert Rev Neurother 2015; 15 (11): 1285–1297.

Obeso JA, Rodriguez-Oroz MC, Chana P. The evolution and origin of motor complications in Parkinson’s disease. Neurology 2000; 55 (11 Suppl 4): S13–S20.

Thanvi BR, Lo TC. Long term motor complications of levodopa: clinical features, mechanisms, and management strategies. Postgrad Med J 2004; 80 (946): 452–458.

Schapira AH, Emre M, Jenner P, Poewe W. Levodopa in the treatment of Parkinson’s disease. Eur J Neurol 2009; 16 (9): 982–989.

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Definitions of terms used in Parkinson’s disease
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The slide includes some basic definitions of terms used to describe the course of PD.

Hametner E, Seppi K, Poewe W. The clinical spectrum of levodopa-induced motor complications. J Neurol 2010; 257 (Suppl 2): S268–275.

Kalia LV, Lang AE. Parkinson’s disease. Lancet 2015; 386 (9996): 896–912.

Parkinson Study Group. A randomized placebo-controlled trial of rasagiline in levodopa-treated patients with Parkinson disease and motor fluctuations: the PRESTO study. Arch Neurol 2005; 62 (2): 241–248.

Stacy M, Bowron A, Guttman M, et al. Identification of motor and nonmotor wearing-off in Parkinson’s disease: comparison of a patient questionnaire versus a clinician assessment. Mov Disord 2005; 20 (6): 726–733.

Stacy M, Hauser R. Development of a patient questionnaire to facilitate recognition of motor and non-motor wearing-off in Parkinson’s disease. J Neural Transm (Vienna) 2007; 114 (2): 211–217.
 

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Drug-induced dyskinesias in Parkinson’s disease
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Levodopa-induced dyskinesias cover a broad clinical spectrum of different types of involuntary movements, ranging from chorea affecting the limbs, trunk, and head, slow dystonic movements, fixed dystonic postures, or (more rarely) myoclonus or ballism.[Hametner et al., 2010; Thanvi et al., 2007] Levodopa-induced dyskinesias can be broadly classified into three main categories:[Hametner et al., 2010] 

  • ON dyskinesias, appearing when motor capacity is at its greatest
  • biphasic dyskinesias, heralding the onset and end of the ON period
  • OFF period dyskinesias, typically featuring dystonic elements.

Hametner E, Seppi K, Poewe W. The clinical spectrum of levodopa-induced motor complications. J Neurol 2010; 257 (Suppl 2): S268–275. 

Thanvi B, Lo N, Robinson T. Levodopa‐induced dyskinesia in Parkinson’s disease: clinical features, pathogenesis, prevention and treatment. Postgrad Med J 2007; 83 (980): 384–388.

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Relationship between levodopa administration and motor fluctuations
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As the extent of neurodegeneration in the substantia nigra becomes greater, its capacity to produce dopamine diminishes to the point where patients require larger doses of levodopa to maintain normal function.[Jenner, 2013] 

Motor complications, such dyskinesia and motor fluctuations, can greatly worsen the quality of life during mid to late PD.[Chapuis et al., 2005] One of the key priorities for the management of PD during this time is to optimise the administration of dopaminergic medication, minimising time spent in ‘OFF’ states (e.g., akinesia) or experiencing dyskinesias.[Connolly & Lang, 2014] 

Since a patient may lack the ability to store dopamine during more advanced PD, the maintenance of dopamine levels requires multiple doses of dopaminergic medication each day, typically orally, which results in an oscillating, pulsatile form of therapy (as opposed to a more consistent ‘drip feed’).[Chapuis et al., 2005] This pattern of administration increases the likelihood of peak-dose dyskinesias, which occur when levodopa levels are high, and ‘OFF’ states, which occur when levodopa levels are low.[Chapuis et al., 2005] ‘OFF’ states can be particularly severe during the night and early morning (see slide).[Chapuis et al., 2005]
 

Chapuis S, Ouchchane L, Metz O, et al. Impact of the motor complications of Parkinson’s disease on the quality of life. Mov Disord 2005; 20 (2): 224–230.

Connolly BS, Lang AE. Pharmacological treatment of Parkinson disease: a review. JAMA 2014; 311 (16): 1670–1683.

Jenner P. Wearing off, dyskinesia, and the use of continuous drug delivery in Parkinson’s disease. Neurol Clin 2013; 31 (3 Suppl): S17–S35.

Stacy M. Medical treatment of Parkinson disease. Neurol Clin 2009; 27 (3): 605–631.

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Prodromal Parkinson’s disease
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MDS research criteria for prodromal Parkinson’s disease
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The Movement Disorder Society (MDS) research criteria for identification of prodromal PD were designed solely for research purposes since, for now at least, the lack of effective treatments that are able to halt the progression of prodromal PD makes their clinical use unwarranted.[Berg et al., 2015] Ethical considerations may prevent the disclosure of a potentially distressing diagnosis in a non-clinical context, particularly if the research participant has not yet sought medical treatment for their symptoms, if present.[Berg et al., 2015]

When used correctly, the MDS criteria have at least 80% accuracy in diagnosing prodromal PD.[Berg et al., 2015] A total score is calculated, which combines background risk, including environmental exposures and genetic traits, and the results of diagnostic markers, such as clinical symptoms (constipation, sleep disorder, impaired sense of smell, etc.) and biomarkers.[Berg et al., 2015]

Berg D, Postuma RB, Adler CH, et al. MDS research criteria for prodromal Parkinson’s disease. Mov Disord 2015; 30 (12): 1600–1611.

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Distribution of α-synuclein pathology in Parkinson’s disease
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The Lewy pathology and aggregated α-synuclein proteins associated with PD are not confined to the central nervous system (CNS); they can also be found in the peripheral nervous system at various sites around the body, such as the skin, gastrointestinal tract, and salivary glands.[Tolosa & Vilas, 2015] The cause of these α-synuclein deposits is still unknown, as is the extent to which they reflect damage or loss of function in these areas.[Fasano et al., 2015; Tolosa & Vilas, 2015]
The relatively recent discovery of peripheral α-synuclein pathology could have profound consequences for the development of a useful biomarker of PD – one that could be measured during the pre-clinical or prodromal stages of the disease.[Tolosa & Vilas, 2015] Peripheral α-synuclein (i.e., that found outside the CNS) is easier to sample (in a skin or gut biopsy) than brain tissue.[Tolosa & Vilas, 2015] If viable, such a biomarker would not only be able to detect PD early, but it could also be used to distinguish the disease from similar forms of parkinsonism, such as multiple system atrophy.[Tolosa & Vilas, 2015; Wood, 2016] At present, however, researchers have yet to agree on a biopsy procedure that yields the most reliable diagnosis.[Tolosa & Vilas, 2015] 

Fasano A, Visanji NP, Liu LW, et al. Gastrointestinal dysfunction in Parkinson’s disease. Lancet Neurol 2015; 14 (6): 625–639. 

Tolosa E, Vilas D. Peripheral synuclein tissue markers: a step closer to Parkinson’s disease diagnosis. Brain 2015; 138 (8): 2120–2122.

Wood H. Parkinson disease: peripheral α-synuclein deposits – prodromal markers for Parkinson disease? Nat Rev Neurol 2016; 12 (5): 249.

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The gastrointestinal system and Parkinson’s disease
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Neurons found in the enteric (gut) nervous system (ENS) require dopamine.[Rao & Gershon, 2016] Without dopamine, these neurons cannot properly control gastrointestinal motility.[Rao & Gershon, 2016] Animal studies have suggested that the ENS may be vulnerable to degeneration during PD, and the finding of Lewy pathology in gut biopsy samples taken from patients with PD supports this.[Rao & Gershon, 2016] It may, therefore, be useful to measure levels of α-synuclein in the gut as a method of potentially diagnosing PD during its early stages.[Rao & Gershon, 2016] 

A gut-derived biomarker may be particularly valuable if, as some studies have suggested, PD develops first in the ENS and then moves up into the brainstem via nerve fibres.[Rao & Gershon, 2016] Experimental data using rodents have recently demonstrated (as a proof of concept) that the application of a toxin to the gastrointestinal system can lead to neurodegeneration in the central nervous system, including the brain.[Rao & Gershon, 2016] This ‘gut–brain’ hypothesis is further supported by epidemiological data that indicate a reduced risk of PD in individuals who had undergone truncal vagotomy, an operation that severs the vagus nerve connecting the ENS to the brain.[Svensson et al., 2015]
 

Rao M, Gershon MD. The bowel and beyond: the enteric nervous system in neurological disorders. Nat Rev Gastroenterol Hepatol 2016; 13 (9): 517–528.

Svensson E, Horváth-Puhó E, Thomsen RW, et al. Vagotomy and subsequent risk of Parkinson’s disease. Ann Neurol 2015; 78 (4): 522–529. 

Lema Tomé CM, Tyson T, Rey NL, et al. Inflammation and α-synuclein’s prion-like behavior in Parkinson’s disease – is there a link? Mol Neurobiol 2013; 47 (2): 561–574.

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The stages of Parkinson’s disease
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Motor symptoms can define three stages of Parkinson’s disease
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During the early phase of PD, symptoms are mild-to-moderate and can be treated effectively with levodopa therapy.[Reichman et al., 2015] Over time, such treatment can become more complicated as the levodopa is required at higher doses and at shorter intervals.[Jenner, 2015]
The middle of the disease course is characterised by the onset of motor fluctuations brought about by ‘wearing off’ or ‘OFF’ states.[Jenner, 2015; Reichman et al., 2015] From this point onwards, it becomes increasingly difficult for a patient to maintain a stable level of mobility similar to that observed during early PD.[Jenner, 2015] 

Unfortunately, it is difficult to predict which patients will develop motor complications and fluctuations, although evidence suggests that younger age at PD onset, and greater exposure to levodopa, might make such complications more likely.[Kadastik-Eerme et al., 2017; Jenner, 2015] 
During later stages of PD, the management of symptoms becomes further complicated by numerous non-motor symptoms, such as dementia, that are severely troublesome to the patient yet respond only partially, if at all, to dopaminergic medication.[Jenner, 2015; Reichman et al., 2015]
 

Jenner P. Treatment of the later stages of Parkinson’s disease – pharmacological approaches now and in the future. Transl Neurodegener 2015; 4: 3.

Kadastik-Eerme L, Taba N, Asser T, Taba P. Factors associated with motor complications in Parkinson’s disease. Brain Behav 2017; 7 (10): e00837.

Reichman H, Barone P, Poewe W. Progression of Parkinson’s disease and unmet needs in mid- to late-stage patients. Eur Neurol Rev 2015; 10 (2): 182–188.

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Early stage Parkinson’s disease
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During early PD, patients may experience one or more motor symptoms.[PDF, 2017] Some patients live with mild symptoms for many years whereas others develop moderate/advanced PD more quickly.[PDF, 2017] Therefore, the precise length of the ‘early/mild’ stage is hard to determine.[PDF, 2017]
Medication may not be required, but patients who do receive treatment usually respond well to appropriate therapy.[PDF, 2017] If dopaminergic treatment is initiated at this early stage, patients experience a period during which their symptoms are effectively controlled.[PDF, 2017] The duration of this ‘honeymoon’ period can last from several months to several years, depending on the total dose and duration of levodopa treatment and personal factors, such as age at PD onset, gender, and body weight.[Jenner, 2015]

Jenner P. Treatment of the later stages of Parkinson’s disease – pharmacological approaches now and in the future. Transl Neurodegener 2015; 4: 3.

Parkinson’s Disease Foundation website. http://www.pdf.org/en/progression_parkinsons. Accessed February 2017.

Goetz CG, Poewe W, Rascol O, et al. Movement Disorder Society Task Force report on the Hoehn and Yahr staging scale: status and recommendations. Mov Disord 2004; 19 (9): 1020–1028.

Hoehn MM, Yahr MD. Parkinsonism: onset, progression, and mortality. Neurology 1967; 17 (5): 427–442.

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Mid stage Parkinson’s disease
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The mid stage of PD is characterised by the appearance of disabling symptoms and a progressive impairment in the ability to carry out activities of daily living (ADL).[PDF, 2017] Patients start to display a decreased response to first-line therapy.[PDF, 2017]

From mid-stage disease onwards, the focus of treatment generally shifts towards achieving an optimal balance between reduction of motor symptoms and minimising dyskinesia and other complications.[Reichman et al., 2015] Many patients experience a ‘non-troublesome’ amount of dyskinesia at this point, which does not necessarily require treatment, while other elements of motor function are adequately maintained.[Jenner, 2015]
 

Jenner P. Treatment of the later stages of Parkinson’s disease – pharmacological approaches now and in the future. Transl Neurodegener 2015; 4: 3.

Parkinson’s Disease Foundation website. http://www.pdf.org/en/progression_parkinsons. Accessed February 2017.

Reichman H, Barone P, Poewe W. Progression of Parkinson’s disease and unmet needs in mid- to late-stage patients. Eur Neurol Rev 2015; 10 (2): 182–188.

Goetz CG, Poewe W, Rascol O, et al. Movement Disorder Society Task Force report on the Hoehn and Yahr staging scale: status and recommendations. Mov Disord 2004; 19 (9): 1020–1028.

Hoehn MM, Yahr MD. Parkinsonism: onset, progression, and mortality. Neurology 1967; 17 (5): 427–442.

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Late stage Parkinson’s disease
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In the advanced stages of PD, the patient experiences continuing symptom progression, worsening of function, and fluctuations in the response to therapy.[PDF, 2017] Patients require a high level of care and assistance with most daily activities, particularly those involving mobility and coordination.[PDF, 2017] They may also start to experience impaired cognitive function, which is often associated with delusions and hallucinations.[PDF, 2017] Postural instability worsens, leading to a greater risk of falls and associated fractures.[Kulisevsky et al., 2013a]

As symptoms proliferate and become more severe, the drugs required to manage them become increasingly complex.[Kulisevsky et al., 2013b] Optimal control of symptoms can be difficult without inducing severe complications, and eventually many patients fail to respond to therapy, or become unable to tolerate their medication.[Kulisevsky et al., 2013a] Consequently, patients experience periods of time with uncontrolled motor symptoms, such as gait disorders, dysphagia (difficulty swallowing), and dysarthria (difficulty speaking).[Kulisevsky et al., 2013a] 

Parkinson’s Disease Foundation website. http://www.pdf.org/en/progression_parkinsons. Accessed February 2017.

Kulisevsky J, Luquin MR, Arbelo JM, et al. Advanced Parkinson’s disease: clinical characteristics and treatment (part 1). Neurologia 2013a; 28 (8): 503–521. 

Kulisevsky J, Luquin MR, Arbelo JM, et al. Advanced Parkinson’s disease: clinical characteristics and treatment (part II). Neurologia 2013b; 28 (9): 558–583.

Goetz CG, Poewe W, Rascol O, et al. Movement Disorder Society Task Force report on the Hoehn and Yahr staging scale: status and recommendations. Mov Disord 2004; 19 (9): 1020–1028.

Hoehn MM, Yahr MD. Parkinsonism: onset, progression, and mortality. Neurology 1967; 17 (5): 427–442.

Sinemet® (carbidopa, levodopa). Summary of Product Characteristics. Merck Sharp & Dohme Limited, October 2017.

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Identifying biomarkers of Parkinson’s disease progression using observational cohorts
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Observational cohorts of Parkinson’s disease progression
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A cohort study is simply an observational study whereby a defined set of individuals are followed over a period of time.[Song & Chung, 2010] A review, published in 2017, identified 44 cohort studies in Parkinson’s Disease, some of which are described on the slide.[Heinzel et al. 2017]
 

Heinzel S, Lerche S, Maetzler W, Berg D. Global, yet incomplete overview of cohort studies in Parkinson’s disease. J Parkinsons Dis 2017; 7 (3): 423–432.

Song JW, Chung KC. Observational studies: cohort and case-control studies. Plast Reconstr Surg 2010; 126 (6): 2234–2242.

Malek N, Swallow DMA, Grosset KA, et al. Tracking Parkinson’s: study design and baseline patient data. J Parkinsons Dis 2015; 5 (4): 947–959.

Neurodegeneration research website. http://www.neurodegenerationresearch.eu/cohort/the-mayo-clinic-study-of-.... Accessed July 2018.

NorthShore website. https://www.northshore.org/neurological-institute/research-innovation/th.... Accessed July 2018.

OPDC website. http://opdc.medsci.ox.ac.uk/theme-1-clinical-cohorts. Accessed July 2018.

Parkinson’s disease Luxembourg website. https://www.parkinson.lu/index.php/en/research/pd-cohort-help-pd. Accessed July 2018.

PPMI website. PPMI-info.org. Accessed July 2018.

Roberts RO, Geda YE, Knopman DS, et al. The Mayo Clinic study of aging: design and sampling, participation, baseline measures and sample characteristics. Neuroepidemiology 2008; 30 (1): 58–69.

Szewczyk-Krolikowski K, Tomlinson P, Nithi K, et al. The influence of age and gender on motor and non-motor features of early Parkinson’s disease: initial findings from the Oxford Parkinson Disease Center (OPDC) discovery cohort. Parkinsonism Relat Disord 2014; 20 (1): 99–105.

The Parkinson’s Progression Markers Initiative (PPMI). Study Protocol. October 2015.

Tracking Parkinson’s website. https://www.trackingparkinsons.org.uk/home/about/. Accessed July 2018.

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Mayo Clinic Olmsted Study of Aging (MCSA)
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Olmsted County is an ideal place for epidemiological research for several reasons.[Roberts et al. 2008]

  • Most residents seek care within the community from one of two providers – the Mayo Clinic and Olmsted Medical Center.
  • Both healthcare providers use a unit medical record that includes all inpatient and outpatient information for every patient.
  • Medical record information can be easily retrieved using patient identifiers through the records-linkage system of the Rochester Epidemiology Project.

 
Participants were randomly selected from the Olmsted county population using a sex- and age-stratified sampling scheme.[Roberts et al. 2008] Individuals with a confirmed diagnosis of dementia were not contacted for participation.[Roberts et al. 2008] Publications using data from this study have suggested that physical activity decreases the risk of dementia, and that APOE ε4 status increases the risk of incident MCI.[Krell-Roesch et al. 2018; Pankratz et al. 2015]

Krell-Roesch J, Feder NT, Roberts RO, et al. Leisure-time physical activity and the risk of incident dementia: the mayo clinic study of aging. J Alzheimers Dis 2018; 63 (1): 149–155.

Pankratz VS, Roberts RO, Mielke MM, et al. Predicting the risk of mild cognitive impairment in the mayo clinic study of aging. Neurology 2015; 84 (14): 1433–1442.

Roberts RO, Geda YE, Knopman DS, et al. The Mayo Clinic study of aging: design and sampling, participation, baseline measures and sample characteristics. Neuroepidemiology 2008; 30 (1): 58–69.

Neurodegeneration research website. http://www.neurodegenerationresearch.eu/cohort/the-mayo-clinic-study-of-.... Accessed July 2018.

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PRoBaND – Tracking Parkinson’s
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In the PRoBaND study, treatment-naïve and treated patients aged 18–90 years were eligible for inclusion.[Malek et al. 2015] All participants were assessed for LRRK2 and GBA mutation carrier status, and participants with early-onset PD were also screened for PARK2 and PINK1 mutations.[Malek et al. 2015]

Malek et al. Tracking Parkinson’s: study design and baseline patient data. J Parkinsons Dis 2015; 5 (4): 947–959.

Tracking Parkinson’s website. https://www.trackingparkinsons.org.uk/home/about/. Accessed July 2018.

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Oxford Parkinson’s Disease Centre (OPDC)
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Participants were recruited from 11 neurology clinics across a defined area of Southern England between September 2010 and September 2014.[Lawton et al. 2015; Szewczyk-Krolikowski et al. 2014] Healthy controls were recruited from spouses and friends of PD participants.[Szewczyk-Krolikowski et al. 2014] Participants in the at-risk group were defined as first-degree relatives of PD patients, and a smaller group of patients with REM (rapid eye movement) behaviour sleep disorder (RBD) diagnosed by polysomnography.[Szewczyk-Krolikowski et al. 2014] Data from this study suggest that there may be five sub-groups of patients with recently diagnosed PD:[Lawton et al. 2015]

  1. mild motor and non-motor disease
  2. poor posture, gait, cognition, smell, and postural hypotension
  3. severe tremor
  4. poor psychological well-being, RBD, and sleep
  5. severe motor, non-motor, and cognitive disease, with poor psychological well-being.

Lawton M, Baig F, Rolinski M, et al. Parkinson’s disease subtypes in the Oxford Parkinson Disease Centre (OPDC) discovery cohort. J Parkinsons Dis 2015; 5 (2): 269–279. 

Szewczyk-Krolikowski K, Tomlinson P, Nithi K, et al. The influence of age and gender on motor and non-motor features of early Parkinson’s disease: initial findings from the Oxford Parkinson Disease Center (OPDC) discovery cohort. Parkinsonism Relat Disord 2014; 20 (1): 99–105.

Heinzel S, Lerche S, Maetzler W, Berg D. Global, yet incomplete overview of cohort studies in Parkinson’s disease. J Parkinsons Dis 2017; 7 (3): 423–432.

OPDC website. http://opdc.medsci.ox.ac.uk/theme-1-clinical-cohorts. Accessed July 2018.

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What is the Parkinson’s disease progression marker initiative (PPMI)?
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References

The Parkinson Progression Marker Initiative (PPMI) is a comprehensive, observational, international study designed to identify PD progression biomarkers.[PPMI, 2011] The aim of the study is to improve the understanding of the causes of PD, and to provide tools to enhance future clinical trials of potential therapies.[PPMI, 2011] 

The PPMI cohort comprises approximately 400 recently diagnosed patients with PD and 200 healthy control participants.[PPMI, 2011] These individuals have been followed over several years, during which a wide range of clinical, imaging, and biological biomarkers have been measured using standardised methods at 33 sites across the USA, Europe, and Australia.[PPMI, 2018] 

By comparing the biomarkers of patients with PD to those of ‘healthy’ control participants, researchers hope to be able to identify markers that predict important clinical outcomes in PD, such as early cognitive decline.[Skogseth et al., 2015]

Parkinson Progression Marker Initiative. The Parkinson Progression Marker Initiative (PPMI). Prog Neurobiol 2011; 95 (4): 629–635.

PPMI website. PPMI-info.org. Accessed July 2018.

Skogseth RE, Bronnick K, Pereira JB, et al. Associations between cerebrospinal fluid biomarkers and cognition in early untreated Parkinson’s disease. J Parkinsons Dis 2015; 5 (4): 783–792. 

The Parkinson’s Progression Markers Initiative (PPMI). Study Protocol. October 2015.

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Patient enrolment in the PPMI trial
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The Parkinson Progression Marker Initiative (PPMI) comprises a mix of individuals with PD, along with healthy controls.[PPMI, 2018] All 600 participants will have their genomes analysed to identify the extent to which certain genes are associated with PD or specific PD-related outcomes.[PPMI, 2018]
The majority of participants with PD who have enrolled into the study (n=423) are known as de novo patients, meaning that they have, thus far, not taken any medication.[PPMI, 2018] Recruiting untreated patients allows researchers to explore the nature of PD, before symptoms are alleviated using drug therapies.[PPMI, 2018]
One of the PPMI cohorts (n=64) includes patients initially diagnosed with PD but who have shown no evidence of reduced dopamine-related activity in the brain, and these individuals are classified as having ‘scans without evidence of dopaminergic deficit’ or ‘SWEDD’.[PPMI, 2018] These patients have been followed over a shorter 2-year period, with the aim of comparing them to more typical patients with PD who show dopamine deficiency, as well as with healthy control participants.[PPMI, 2018]

PPMI website. PPMI-info.org. Accessed July 2018.

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Preliminary results of the PPMI study
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As a result of the Parkinson Progression Marker Initiative (PPMI), several promising biomarkers have been identified.[PPMI, 2018]
A comparison of cerebrospinal fluid (CSF) was carried out between, (a) patients with PD suffering from mild cognitive impairment at the time of enrolment, (b) patients with PD who were cognitively intact, and (c) healthy control participants who were cognitively intact.[Skogseth et al., 2015] A lower level of α-synuclein in CSF was associated with poorer overall cognition, particularly in relation to executive–attentional domains.[Skogseth et al., 2015] This suggests that α-synuclein might play a role in the development of cognitive impairment in PD.[Skogseth et al., 2015]

Kang and colleagues evaluated CSF biomarkers specifically in de novo participants with PD – i.e., those who had not yet received any medication for their disorder.[Kang et al., 2013] They found several biomarkers associated with PD (amyloid-β, total-tau, phosphorylated tau181, and α-synuclein).[Kang et al., 2013] The authors proposed that these biomarkers could potentially be used to facilitate a diagnosis of PD during its early stages.[Kang et al., 2013]

Kang JH, Irwin DJ, Chen-Plotkin AS, et al.; Parkinson’s Progression Markers Initiative. Association of cerebrospinal fluid β-amyloid 1-42, t-tau, p-tau181, and α-synuclein levels with clinical features of drug-naive patients with early Parkinson disease. JAMA Neurol 2013; 70 (10): 1277–1287.

PPMI website. PPMI-info.org. Accessed July 2018.

Skogseth RE, Bronnick K, Pereira JB, et al. Associations between cerebrospinal fluid biomarkers and cognition in early untreated Parkinson’s disease. J Parkinsons Dis 2015; 5 (4): 783–792. 

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Parkinson’s disease prognosis
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Parkinson’s disease prognosis
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Despite the severe disability that it causes in many people, PD is not considered to be a fatal condition.[Parkinson’s UK, 2017]  
The figure on the slide shows the course of PD in five groups of patients who developed the disease at different ages, from the youngest (24–53 years, left) to the oldest (73–80 years, right).[Kempster et al., 2010]

As shown in the figure, a younger onset of PD is typically associated with a longer disease course, compared with those who develop the disease later in life.[Kempster et al., 2010] While the rate of progression can vary greatly between individuals during the earlier stages of PD, the late stage tends to be characterised by a more fixed and rapid progression as the disease spreads into the cortical regions of the brain.[Kempster et al., 2010]
 

Kempster PA, O’Sullivan SS, Holton JL, et al. Relationships between age and late progression of Parkinson’s disease: a clinico-pathological study. Brain 2010; 133 (Pt 6): 1755–1762.

Parkinson’s UK website. www.parkinsons.org.uk. Accessed Feb 2017.

Eggers C, Pedrosa DJ, Kahraman D, et al. Parkinson subtypes progress differently in clinical course and imaging pattern. PLoS One 2012; 7 (10): e46813.

Fernandes GC, Socal MP, Schuh AF, Rieder CR. Clinical and epidemiological factors associated with mortality in Parkinson’s disease in a Brazilian cohort. Parkinsons Dis 2015; 2015: 959304.

Williams-Gray CH, Mason SL, Evans JR, et al. The CamPaIGN study of Parkinson’s disease: 10-year outlook in an incident population-based cohort. J Neurol Neurosurg Psychiatry 2013; 84 (11): 1258–1264.

Wolters E, de Munter H, Steinbusch. Parkinson’s disease. In: Wolters & Baumann (eds). Parkinson Disease and Other Movement Disorders. VU University Press, 2014.

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Long-term prognosis – the Sydney multicentre study
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While PD is not considered to be a fatal disease, its symptoms do increase the risk of potentially fatal comorbidities.[Hely et al., 2005; Parkinson’s UK, 2017] Patients with PD who enrolled in the Sydney multicentre study were found to have almost twice the risk of death 15 years later, as compared to the general population.[Hely et al., 2005] More than one quarter of all patients (27%) in the study died from pneumonia.[Hely et al., 2005] 

The main causes of disability in the Sydney multicentre study at both 15 and 20 years of follow-up were: falls, choking, autonomic disturbance, neuropsychiatric symptoms, and dementia.[Hely et al., 2005; Hely et al., 2008] Dementia was more prevalent at 20 years than at 15 years (83% versus 48%, respectively).[Hely et al., 2005; Hely et al., 2008] Unfortunately, none of these symptoms respond well to dopaminergic therapy.[Hely et al., 2005]
 

Hely MA, Morris JG, Reid WG, Trafficante R. Sydney multicenter study of Parkinson’s disease: non-L-dopa-responsive problems dominate at 15 years. Mov Disord 2005; 20 (2): 190–199.

Hely MA, Reid WG, Adena MA, et al. The Sydney multicenter study of Parkinson’s disease: the inevitability of dementia at 20 years. Mov Disord 2008; 23 (6): 837–844.

Parkinson’s UK website. www.parkinsons.org.uk. Accessed Feb 2017.

Coelho M, Marti M, Tolosa E, et al. Late-stage Parkinson’s disease: the Barcelona and Lisbon cohort. J Neurol 2010; 257: 1524–1532.

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The influence of comorbidities on prognosis of Parkinson’s disease
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PD occurs predominantly in elderly people, who commonly have co-morbidities.[von Campenhausen et al., 2005; Macleod et al., 2016] A recent study, which followed patients with PD over a 12-year period, concluded that having a higher level of comorbidity during the earlier stages of PD (0–4 years from diagnosis/recruitment) increased the likelihood of early death.[Macleod et al., 2016] Beyond 4 years, however, the amount of comorbidity in the population appeared to make little difference.[Macleod et al., 2016] Deaths that occur during early-stage PD are most often caused by other factors (e.g., cardiovascular disease) rather than PD itself, since PD symptoms during this period tend to be mild, easily-controlled, and unlikely to have severe adverse effects on health.[Macleod et al., 2016]

The study also recommended the Charlson Comorbidity Index (CCI)[Charlson et al., 1987] as the most appropriate tool for measuring comorbidity in patients with PD; it is quicker to use and produces more consistent results than other currently available assessment methods.[Macleod et al., 2016]

Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987; 40 (5): 373–383.

Macleod AD, Goddard H, Counsell CE. Co-morbidity burden in Parkinson’s disease: comparison with controls and its influence on prognosis. Parkinsonism Relat Disord 2016; 28: 124–129. 

von Campenhausen S, Bornschein B, Wick R, et al. Prevalence and incidence of Parkinson’s disease in Europe. Eur Neuropsychopharmacol 2005; 15 (4): 473–490.

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Cognitive impairment and dementia in Parkinson’s disease
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The presence of mild cognitive impairment in PD is associated with subsequent dementia.[Janvin et al., 2006] Indeed, patients with PD have an almost six-fold increased risk of developing dementia, as compared with healthy controls.[Aarsland et al., 2001] Cognitive impairment reduces overall quality of life and may ultimately require an affected individual to be placed in a nursing home.[Janvin et al., 2006]

A community-based study carried out in Cambridgeshire, UK, recruited new cases of PD and followed them over several years to identify factors associated with the later development of dementia.[Williams-Gray et al., 2007] In addition to older age, risk factors included a non-tremor-dominant motor phenotype, more severe motor symptoms, and poorer performance on various cognitive function tests (semantic fluency; pentagon copying; spatial recognition memory; and executive function).[Williams-Gray et al., 2007] Patients with a non-tremor-dominant motor phenotype were >4 times more likely to develop dementia than tremor-dominant patients, perhaps reflecting the faster progression of PD in the former group.[Aarsland et al., 2004; Williams-Gray et al., 2007]

Aarsland D, Andersen K, Larsen JP, et al. Risk of dementia in Parkinson’s disease: a community-based, prospective study. Neurology 2001; 56 (6): 730–736.

Aarsland D, Andersen K, Larsen JP, et al. The rate of cognitive decline in Parkinson disease. Arch Neurol 2004; 61: 1906–1911.

Janvin CC, Larsen JP, Aarsland D, Hugdahl K. Subtypes of mild cognitive impairment in Parkinson’s disease: progression to dementia. Mov Disord 2006; 21 (9): 1343–1349.

Williams-Gray CH, Foltynie T, Brayne CE. Evolution of cognitive dysfunction in an incident Parkinson’s disease cohort. Brain 2007; 130 (Pt 7): 1787–1798.

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Braak stage and cognitive status of patients with Parkinson’s disease
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Cognitive function appears to decrease steadily as PD progresses through the six Braak stages.[Braak et al., 2005] A Dutch study collected cognitive function data from patients with PD.[Braak et al., 2005] The investigators carried out autopsies on the brains of study participants to evaluate the extent of neurodegeneration and Lewy pathology.[Braak et al., 2005] They found that greater levels of neuropathology – defined in terms of Braak stages – were significantly correlated with Mini-Mental State Examination (MMSE – a test of cognitive functioning) test scores from 12–18 months prior to the patient’s death.[Braak et al., 2005] The average MMSE score consistently decreased from Braak stages 3 to 6, indicating that the risk of developing dementia in PD increases as the disease progresses.[Braak et al., 2005]

The study also suggested that neurodegeneration in the neocortex is not strictly necessary to develop symptoms of dementia; some individuals will experience cognitive decline before the disease spreads to the cortical regions of the brain.[Braak et al., 2005]

Braak H, Rüb U, Jansen Steur ENH, et al. Cognitive status correlates with neuropathologic stage in Parkinson disease. Neurology 2005; 64 (8): 1404–1410.

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Clinical approach during late stage Parkinson’s disease
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References

During late-stage PD, the ability of patients to control their symptoms diminishes as their dopaminergic medication becomes less effective.[Kulisevsky et al., 2013; Hussain et al., 2013] This lack of symptom control can potentially cause severe mental and physical disability due to the array of motor and non-motor symptoms that develop during late-stage PD.[Kulisevsky et al., 2013; Hussain et al., 2013] These symptoms can be a source of emotional distress to both the patient and their caregivers.[Boersma et al., 2014; Kulisevsky et al., 2013; Hussain et al., 2013] 

Although clinicians may be tempted to provide additional therapies to existing regimens in order to combat late-stage symptoms, one of the goals of treating advanced PD is actually to simplify overall treatment.[Kulisevsky et al., 2013] The aim here is to reduce some of the adverse effects of drug therapies, such as drowsiness, confusion, agitation, and hallucinations.[Kulisevsky et al., 2013]

Boersma I, Miyasaki J, Kutner J, Kluger B. Palliative care and neurology: time for a paradigm shift. Neurology 2014; 83 (6): 561–567.

Kulisevsky J, Luquin MR, Arbelo JM, et al. Advanced Parkinson’s disease: clinical characteristics and treatment. Part II. Neurologia 2013; 28 (9): 558–583.

Hussain J, Adams D, Campbell C. End-of-life care in neurodegenerative conditions: outcomes of a specialist palliative neurology service. Int J Palliat Nurs 2013; 19 (4): 162–169.

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