History, definitions and diagnosis

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History, definitions and diagnosis

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History, definitions and diagnosis
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The history of Parkinson’s disease
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The ‘shaking palsy’
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The condition that we now know as Parkinson’s disease (PD) was first described systematically in 1817 by the London surgeon and apothecary James Parkinson.[Lees et al., 2009; Pfeiffer et al., 2013]

In his historic essay, Parkinson drew together his observations of several patients who were affected by similar symptoms and disease progression.[Parkinson, 1817] He described their characteristic tremors, gait impairment, stooped posture, and impaired speech, and also included important non-motor symptoms, such as constipation and sleep disorders.[Parkinson, 1817] However, he differed from our modern understanding of PD in believing that the disease did not adversely affect the mind of the patient.[Parkinson, 1817] It is now generally accepted that PD can cause psychiatric problems and cognitive decline, particularly during later phases of the disease.[Lees et al., 2009]

Parkinson’s unique contribution to the field was to propose that, despite clear differences between each patient in terms of their individual symptoms and experiences, they had in fact been suffering from a common underlying condition, which he called ‘paralysis agitans’, or the ‘shaking palsy’.[Parkinson, 1817]

It was not until several decades after James Parkinson published his essay that the shaking palsy was renamed ‘Parkinson’s disease’ as a tribute to the careful and ground-breaking work that he had carried out (see next slide).[Lees et al., 2009; Pfeiffer et al., 2013]

Lees AJ, Hardy J, Revesz T. Parkinson’s disease. Lancet 2009; 373 (9680): 2055–2066.

Parkinson J. An essay on the shaking palsy. London: Sherwood, Neely and Jones, 1817.

Pfeiffer RF, Wszolek ZK, Ebadi M. Parkinson’s Disease, 2nd edition. Boca Raton: CRC Press, 2013.

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Parkinson’s disease
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In 1872, Jean-Martin Charcot identified general slowness of movement (‘bradykinesia’) as a prominent feature of paralysis agitans.[Goetz, 2011] Bradykinesia is now known as one of the characteristic, or ‘cardinal’, features of PD.[Goetz, 2011] Charcot also distinguished between the tremors caused by paralysis agitans and those associated with multiple sclerosis.[Pfeiffer et al., 2013] The description of paralysis agitans was refined accordingly, and the condition was subsequently known as ‘Parkinson’s disease’.[Goetz, 2011; Pfeiffer et al., 2013]

Physicians set about investigating the underlying causes of the disease.[Pfeiffer et al., 2013] Although Charcot considered PD to be a neurosis, or mental health disorder, others looked for non-psychiatric pathologies.[Pfeiffer et al., 2013] An autopsy was carried out on an individual who had suffered from PD, leading eventually to the identification of an abnormality in a part of the brain called the ‘substantia nigra’ as the most likely source of the disease.[Pfeiffer et al., 2013]

In his efforts to treat patients suffering from PD, Charcot tried several anti-cholinergic agents (which reduce the action of the neurotransmitter acetylcholine).[Pfeiffer et al., 2013] Through his observations, he discovered that one anti-cholinergic agent was at least partially effective at controlling symptoms.[Pfeiffer et al., 2013]

Goetz CG. The history of Parkinson’s disease: early clinical descriptions and neurological therapies. Cold Spring Harb Perspect Med 2011; 1 (1): a008862.

Pfeiffer RF, Wszolek ZK, Ebadi M. Parkinson’s Disease, 2nd edition. Boca Raton: CRC Press, 2013.

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The dopamine deficiency hypothesis
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In 1960, scientists showed that brains of PD patients had very low levels of the neurotransmitter dopamine, particularly in the region known as the striatum (comprised of the putamen and the caudate nucleus).[LeWitt & Fahn, 2016; Ehringer & Hornykiewicz, 1998] This ‘dopamine deficiency’ appeared to be caused by a marked loss of neurons in the substantia nigra.[Cheng et al., 2010]

Clinical trials showed that the drug levodopa was effective in relieving PD motor symptoms, increasing recognition that restoring dopamine levels in the brain was likely to be the basis of this mechanism.[LeWitt & Fahn, 2016] In 1970, levodopa was approved by the US Food and Drug Administration, and it was adopted as the main treatment for PD, which is still the case today.[LeWitt & Fahn, 2016]

We now know that the production of other key neurotransmitters, such as serotonin and noradrenaline, is also reduced in many patients with PD.[Pfeiffer et al., 2013; Espay et al., 2014] So, while dopamine deficiency is certainly a major component of the disease, it is only one of several aspects of brain function affected by this degenerative disorder.[Pfeiffer et al., 2013]

Cheng HC, Ulane CM, Burke RE. Clinical progression in Parkinson’s disease and the neurobiology of axons. Ann Neurol 2010; 67 (6): 715–725.

Ehringer H, Hornykiewicz O. Distribution of noradrenaline and dopamine (3-hydroxytyramine) in the human brain and their behavior in diseases of the extrapyramidal system. Parkinsonism Relat Disord 1998; 4 (2): 53–57.

Espay AJ, LeWitt PA, Kaufmann H. Norepinephrine deficiency in Parkinson’s disease: the case for noradrenergic enhancement. Mov Disord 2014; 29 (14): 1710–1719.

LeWitt PA, Fahn S. Levodopa therapy for Parkinson disease. Neurology 2016; 86 (14): S3–S12.

Pfeiffer RF, Wszolek ZK, Ebadi M. Parkinson’s Disease, 2nd edition. Boca Raton: CRC Press, 2013.

Other reference used on slide:
Lees AJ, Hardy J, Revesz T. Parkinson’s disease. Lancet 2009; 373 (9680): 2055–2066.

Tortora GJ, Derrickson B. Principles of Anatomy and Physiology, 12th Edition. John Wiley & Sons, 2009.

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Lewy bodies
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Lewy bodies are mostly comprised of abnormal, misfolded protein, and are found in the nerve cells of most patients with PD.[Lees et al., 2009; Ropper et al., 2014] They were first discovered by Fritz Heinrich Lewy in 1912, although it was not until several years later that the presence of Lewy bodies within the substantia nigra was considered a characteristic feature of PD.[Pfeiffer et al., 2013] The function of Lewy bodies in the pathogenesis of PD is still unclear, as they have been associated with both neuroprotection and toxicity.[Raiss et al., 2016] It may be the case that functionally different Lewy bodies exist, which differ in their localisation and morphology.[Raiss et al., 2016]

Although strongly associated with PD, Lewy bodies are also present in the brains of patients with Alzheimer’s disease and other neurodegenerative disorders.[Pfeiffer et al., 2013] Additionally, Lewy bodies can be detected in a proportion of people who die without having experienced any obvious neurological problems (so called ‘incidental Lewy body disease’).[Lees et al., 2009] The distinguishing feature of PD, however, is that Lewy bodies are located primarily in the basal ganglia region, particularly in the substantia nigra.[Pfeiffer et al., 2013]

Lees AJ, Hardy J, Revesz T. Parkinson’s disease. Lancet 2009; 373 (9680): 2055–2066.

Pfeiffer RF, Wszolek ZK, Ebadi M. Parkinson’s Disease, 2nd edition. Boca Raton: CRC Press, 2013.

Raiss CC, Braun TS, Konings IBM, et al. Functionally different α-synuclein inclusions yield insight into Parkinson’s disease pathology. Sci Reports 2016; 6: 23116.

Ropper AH, Samuels MA, Klein JP. Adams and Victor’s Principles of Neurology, 10th edition. New York: McGraw-Hill Education, 2014.

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α-synuclein
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Since its discovery in the 1990s, the dysfunction of the protein α-synuclein has emerged as a major factor in the development of PD.[Burré, 2015]

The precise function of α-synuclein has been difficult to determine, but it appears to interact with and affect various proteins at the synapse (the interface that exists between nerve cells).[Burré, 2015]

A key feature of PD is the aggregation – or clumping together – of misfolded α-synuclein into filaments called ‘fibrils’.[Lee & Trojanowski, 2006] This aggregation continues until Lewy bodies are formed, which can ultimately lead to the destruction of the nerve cell.[Lee & Trojanowski, 2006]

The accumulation of α-synuclein in the development of PD means that the condition is often referred to as one of the ‘synucleinopathies’, along with other neurodegenerative disorders (dementia with Lewy bodies and multiple system atrophy).[Burré, 2015] It is hoped that these disorders can be prevented from developing in the first place by limiting the accumulation of α‑synuclein.[Burré, 2015]

Burré J. The synaptic function of α-synuclein. J Parkinson Dis 2015; 5 (4): 699–713.

Lee VM, Trojanowski JQ. Mechanisms of Parkinson’s disease linked to pathological alpha-synuclein: new targets for drug discovery. Neuron 2006; 52 (1): 33–38.

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The cardinal symptoms of Parkinson’s disease
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Parkinsonism
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‘Parkinsonism’ is a collection of four clinical features that are typically, although not exclusively, observed in PD.[Massano & Bhatia, 2012] The features may also be present in patients with other neurological disorders, including progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, and vascular parkinsonism.[Williams & Litvan, 2013]

Together with PD, these disorders are collectively called the ‘parkinsonian syndromes’ and reflect the underlying dysfunction of the basal ganglia region of the brain, or other systemic degeneration.[Williams & Litvan, 2013]

Massano J, Bhatia KP. Clinical approach to Parkinson’s disease: features, diagnosis, and principles of management. Cold Spring Harb Perspect Med 2012; 2 (6): a008870.

Williams DR, Litvan I. Parkinsonian syndromes. Continuum (Minneap Minn) 2013; 19 (5): 1189–1212.

Other reference used on slide:
Chaudhuri KR, Ondo W. Handbook

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Motor symptoms – bradykinesia
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Bradykinesia refers to a slowness of movement.[Pfeiffer et al., 2013] Patients with PD often report feeling clumsy or slow, and this may be misinterpreted by family members as a ‘normal’ part of ageing.[Williams & Litvan, 2013] Bradykinesia can manifest in different ways, but it always appears at some point during PD and inevitably worsens as the disease progresses.[Massano & Bhatia, 2012]

Patients with bradykinesia are often limited in their ability to perform repetitive movements, such as tapping their foot on the floor, or opening and closing the hand.[Massano & Bhatia, 2012] They typically struggle to maintain both speed and range of motion (‘amplitude’).[Massano & Bhatia, 2012] Symptoms tend to be asymmetrical, affecting one side more than the other, so when walking patients with bradykinesia may display reduced arm swing on the more affected side.[Massano & Bhatia, 2012; Williams & Litvan, 2013] Initiation of movement can also be difficult (e.g., when starting to walk),[Massano & Bhatia, 2012] and sometimes patients pause mid-movement, causing them to appear frozen.[Williams & Litvan, 2013]

Earlier and more subtle signs of bradykinesia may include reductions in spontaneous movement, such as facial expressions (‘hypomimia’), as well as less non-verbal communication through gesticulation.[Williams & Litvan, 2013] The voice may become increasingly soft (‘hypophonia’), and handwriting smaller and more laboured (‘micrographia’).[Massano & Bhatia, 2012; Wagle Shukla et al., 2012]

Massano J, Bhatia KP. Clinical approach to Parkinson’s disease: features, diagnosis, and principles of management. Cold Spring Harb Perspect Med 2012; 2 (6): a008870.

Pfeiffer RF, Wszolek ZK, Ebadi M. Parkinson’s Disease, 2nd edition. Boca Raton: CRC Press, 2013.

Wagle Shukla A, Ounpraseuth S, Okun MS, et al. Micrographia and related deficits in Parkinson’s disease: a cross-sectional study. BMJ Open 2012; 2 (3): e000628

Williams DR, Litvan I. Parkinsonian syndromes. Continuum (Minneap Minn) 2013; 19 (5): 1189–1212.

Other reference used on slide:
Ellis T, Cavanaugh JT, Earhart GM, et al. Which measures of physical function and motor impairment best predict quality of life in Parkinson’s disease? Parkinsonism Relat Disord 2011; 17 (9): 693–697.

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Motor symptoms – muscular rigidity
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The muscular rigidity or stiffness associated with parkinsonism – sometimes called ‘extrapyramidal rigidity’ – is a key feature of the syndrome.[Massano & Bhatia, 2012; Williams & Litvan, 2013]

During the earlier stages of PD, rigidity may manifest solely as pain and can be easily misinterpreted as a musculoskeletal problem, such as a frozen shoulder or degenerative spinal pain.[Williams & Lees, 2009; Williams & Litvan, 2013] As PD progresses, movement can become either inconsistent and jerky (‘cogwheel’ rigidity) or consistently stiff throughout the range of movement (‘lead pipe’ rigidity).[Williams & Litvan, 2013] However, this stiffness should always be independent of the velocity of movement, clearly distinguishing it from spasticity, in which resistance is greatest during early acceleration and then gives way (‘clasp knife’ phenomenon).[Williams & Litvan, 2013]

Massano J, Bhatia KP. Clinical approach to Parkinson’s disease: features, diagnosis, and principles of management. Cold Spring Harb Perspect Med 2012; 2 (6): a008870.

Williams DR, Litvan I. Parkinsonian syndromes. Continuum (Minneap Minn) 2013; 19 (5): 1189–1212.

Williams DR, Lees AJ. How do patients with parkinsonism present? A clinicopathological study. Intern Med J 2009; 39 (1): 7–12.

Other reference used on slide:
Pfeiffer RF, Wszolek ZK, Ebadi M. Parkinson’s Disease, 2nd edition. Boca Raton: CRC Press, 2013.

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Motor symptoms – resting tremor
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Tremors are a common and highly-visible symptom of PD, typically present when the patient is fully at rest.[DeMaagd & Philip, 2015] The shaking action tends to be a rhythmic, medium-frequency oscillation.[Massano & Bhatia, 2012] It starts when the particular body part is relaxed and supported by a surface, disappears with active movement, and then returns again once movement has ceased (re-emergent tremor).[Massano & Bhatia, 2012] Whilst this pattern is normally a tell-tale symptom of parkinsonism, it is not unknown for some patients with PD to present with tremors during active movement (action tremor).[DeMaagd & Philip, 2015] 

Tremor occurs mostly in the upper and lower limbs, as well as the tongue and jaw, while head tremor is less common.[Massano & Bhatia, 2012] The classic form of resting tremor in patients with PD is the so-called ‘pill-rolling’ action, during which the thumb repeatedly rubs against the index finger.[Massano & Bhatia, 2012] Fingers may also repeatedly flex and extend in a tapping-like movement.[Massano & Bhatia, 2012]

DeMaagd G, Philip A. Parkinson’s disease and its management. Pharmacol Therapeut 2015; 40 (8): 504–510.

Massano J, Bhatia KP. Clinical approach to Parkinson’s disease: features, diagnosis, and principles of management. Cold Spring Harb Perspect Med 2012; 2 (6): a008870.

Other reference used on slide
Pfeiffer RF, Wszolek ZK, Ebadi M. Parkinson’s Disease, 2nd edition. Boca Raton: CRC Press, 2013.

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Motor symptoms – postural instability
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During the progression of PD, the postural reflexes become increasingly impaired as the brain struggles to integrate sensory information about the relative position of various body parts.[Rinalduzzi et al., 2015] Since this integration is necessary to maintain balance during movement, the loss of the postural reflexes is one of the more disabling symptoms of PD and one of those least responsive to treatment.[Rinalduzzi et al., 2015]

Whereas the cardinal features of PD – bradykinesia, resting tremor, and rigidity – are mainly ascribed to the loss of dopaminergic neurons, those involving posture, balance, and gait are largely secondary to the degeneration of non-dopaminergic pathways, and significantly contribute to impairment and disability in patients with advanced PD.[Magrinelli et al., 2016]

Postural instability occurs in approximately 50% of PD patients within five years of diagnosis.[DeMaagd & Philip, 2015] The loss of postural reflexes is a particularly important symptom of PD because it increases the risk of injuries from falling.[Massano & Bhatia, 2012] This can have serious consequences for the ability of a patient to live independently, and can lead to social isolation.[Rinalduzzi et al., 2015]

DeMaagd G, Philip A. Parkinson’s disease and its management. Pharmacol Therapeut 2015; 40 (8): 504–510.

Magrinelli F, Picelli A, Tocco P, et al. Pathophysiology of motor dysfunction in Parkinson’s disease as the rationale for drug treatment and rehabilitation. Parkinsons Dis 2016; 2016: 9832839.

Massano J, Bhatia KP. Clinical approach to Parkinson’s disease: features, diagnosis, and principles of management. Cold Spring Harb Perspect Med 2012; 2 (6): a008870.

Rinalduzzi S, Trompetto C, Marinelli L, et al. Balance dysfunction in Parkinson’s disease. BioMed Res Int 2015; 2015: 434683.

Other reference used on slide:
Williams DR, Litvan I. Parkinsonian syndromes. Continuum (Minneap Minn) 2013; 19 (5 Movement Disorders): 1189–1212.

 

 

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Motor symptoms – gait impairment
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Postural instability and gait impairments are universally features of advanced PD.[Massano & Bhatia, 2012; Williams & Litvan, 2013] Examination of gait in patients with PD involves asking the patient to stand, unaided, from a seated position, then walk approximately ten metres, turn around, walk back, and sit down again.[Williams & Litvan, 2013] Depending on the level of gait impairment, patients may walk with shortened steps, walk hesitantly, take several steps to turn around, or their gait may freeze.[Williams & Litvan, 2013]

Massano J, Bhatia KP. Clinical approach to Parkinson’s disease: features, diagnosis, and principles of management. Cold Spring Harb Perspect Med 2012; 2 (6): a008870.

Williams DR, Litvan I. Parkinsonian syndromes. Continuum (Minneap Minn) 2013; 19 (5 Movement Disorders): 1189–1212.

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The non-motor symptom complex of Parkinson’s disease
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PD has traditionally been regarded as a motor disorder.[Massano & Bhatia, 2012] However, physicians are increasingly realising the need to recognise non-motor symptoms, both for diagnostic and management purposes, to try to improve patients’ quality of life.[Massano & Bhatia, 2012]

Many non-motor symptoms, for example psychosis and excessive daytime sleepiness, are due to the effects of the PD itself as well as PD medications.[Lim & Lang, 2010; Sung & Nicholas, 2013] Some of the non-motor symptoms of PD can be managed effectively with appropriate treatment.[Sung & Nicholas, 2013] For example, depression may respond well to antidepressants, and constipation may be resolved with laxatives.[Sung & Nicholas, 2013]

However, some non-motor symptoms are more difficult to manage, e.g., dementia or apathy.

Lim SY, Lang AE. The nonmotor symptoms of Parkinson’s disease – an overview. Mov Disord 2010; 25 (Suppl 1): S123–130.

Massano J , Bhatia KP. Clinical approach to Parkinson’s disease: features, diagnosis, and principles of management. Cold Spring Harb Perspect Med 2012; 2 (6): a008870.

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.

Other references used on slide:
Chaudhuri KR, Ondo W. Handbook of Movement Disorders. London: Current Medicine Group, 2009.

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

 

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Clinical symptoms and time course of Parkinson’s disease progression
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The development of PD is generally slow and progressive.[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 and poor symptom control.[Kalia & Lang, 2015] In fact, the occurrence of motor response complications (fluctuations and dyskinesias) is one of the main limitations of oral 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.

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Diagnosis of Parkinson’s disease
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Diagnosis occurs at symptom presentation
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A correct diagnosis of PD allows appropriate forms of therapy and counselling to be made available to the patient.[Berardelli et al., 2013]

As discussed previously, the progression of PD can be subtle at first, manifesting as relatively minor issues, such as experiencing difficulty rising from a chair.[DeMaagd & Philip, 2015] Typically, younger individuals with PD show less rigidity and bradykinesia compared with older adults, which may delay the accurate diagnosis of their condition.[DeMaagd & Philip, 2015; Suchowersky et al., 2006]

Diagnosis of PD most commonly occurs on presentation of one or more of the cardinal symptoms, such as bradykinesia, resting tremor, or rigidity.[DeMaagd & Philip, 2015] In the early stages of the disease, the response to dopaminergic therapy is sustained.[Thanvi & Lo, 2004] In the later stages of PD, the loss of neurons in the substantia nigra plus other (e.g., post-synaptic) factors mean that the beneficial effects of each dose of dopamine precursor (levodopa in its formulations) become progressively more short-lived.[Thanvi & Lo, 2004]

Berardelli A, Wenning GK, Antonini A, et al. EFNS/MDS-ES/ENS recommendations for the diagnosis of Parkinson’s disease. Eur J Neurol 2013; 20 (1): 16–34.

DeMaagd G, Philip A. Parkinson’s disease and its management. Pharmacol Therapeut 2015; 40 (8): 504–510.

Suchowersky O, Reich S, Perlmutter J, et al.; Quality Standards Subcommittee of the American Academy of Neurology. Practice parameter: diagnosis and prognosis of new onset Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006; 66 (7): 968–975.

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

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Causes of secondary parkinsonism
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The symptoms of parkinsonism can be caused by a wide range of conditions, including infections; exposure to toxic chemicals; drug side effects; brain tumours; repeated head trauma; and metabolic disorders.[Tolosa et al., 2006] ‘Secondary parkinsonism’ is caused by something other than truly ‘idiopathic’ PD.[Tolosa et al., 2006] Accurate diagnosis of such cases is therefore critical to provide the correct treatment and prognosis for the patient.[Tolosa et al., 2006]

Drug-induced parkinsonism can often be reversed simply by identifying and withdrawing the drug responsible.[DeMaagd & Philip, 2015] Drugs leading to secondary parkinsonism include certain antipsychotic medications and antiemetics (to reduce nausea or vomiting).[DeMaagd & Philip, 2015]

DeMaagd G, Philip A. Parkinson’s disease and its management. Pharmacol Therapeut 2015; 40 (8): 504–510.

Tolosa E, Wenning G, Poewe W. The diagnosis of Parkinson’s disease. Lancet Neurol 2006; 5 (1): 75–86.

Other reference used on slide:
Jang H, Boltz DA, Webster RG, Smeyne RJ. Viral parkinsonism. Biochim Biophys Acta 2009; 1792 (7): 714–721.

Çoban A, Küçükali CFI, Bilgiç B, et al. Evaluation of incidence and clinical features of antibody-associated autoimmune encephalitis mimicking dementia. Behav Neurol 2014; 2014: 935379.

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Differential diagnosis
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The diagnosis of PD is largely determined by medical history, clinical examination, and response to treatment; there is currently no reliable biochemical, imaging or genetic test that provides a definitive diagnosis.[Jankovic, 2008; Williams & Litvan, 2013] However, laboratory tests are used in differential diagnosis of other health problems.[DeMaagd & Philip, 2015]

Clinicians tend to diagnose PD incorrectly in approximately 25% of cases.[Tolosa et al., 2006] A correct diagnosis of PD may be delayed as many of the could, at first, be confused with the normal process of ageing, or other comorbidities.[DeMaagd & Philip, 2015] Even when motor symptoms appear, an erroneous diagnosis of Alzheimer’s disease, dementia with Lewy bodies (DLB), or drug-induced parkinsonism might easily be made.[Tolosa et al., 2006]

DLB has similar clinical and neuropathological features to PD, but may be distinguished by the presence of cognitive impairment and hallucinations (unrelated to therapy) early during the disease process.[Litvan et al., 1998]

There are many other conditions that present with symptoms similar to those of PD, and patients may therefore require expert evaluation to confirm a diagnosis.[DeMaagd & Philip, 2015]

DeMaagd G, Philip A. Parkinson’s disease and its management. Pharmacol Therapeut 2015; 40 (8): 504–510.

Litvan I, MacIntyre A, Goetz CG, et al. Accuracy of the clinical diagnoses of Lewy body disease, Parkinson disease, and dementia with Lewy bodies: a clinicopathologic study. Arch Neurol 1998; 55 (7): 969–978.

Jankovic J. Parkinson’s disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 2008; 79: 368–376.

Tolosa E, Wenning G, Poewe W. The diagnosis of Parkinson’s disease. Lancet Neurol 2006; 5 (1): 75–86.

Williams DR, Litvan I. Parkinsonian syndromes. Continuum (Minneap Minn) 2013; 19 (5): 1189–1212.

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Differential diagnosis – Wilson’s disease (1)
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References

Wilson’s disease (WD) is a disorder of copper metabolism, and was first identified in 1912.[Bandmann et al., 2015] Clinically, WD can cause neurologic, psychiatric, and hepatic problems.[Bandmann et al., 2015] The symptoms can include tremor, dystonia and/or parkinsonism, which makes confirmation of the diagnosis of WD, and therefore ruling out PD, important.[Bandmann et al., 2015] The main tests for diagnosis of neurologic/neuropsychiatric WD are: slit lamp examination by an ophthalmologist, plasma levels of ceruloplasmin, 24-hour urine copper assay, and brain MRI scan.[Hedera, 2017] Diagnosis of WD is increasingly done by genetic testing for mutations in the ATP7B gene.[Bandmann et al., 2015]

Bandmann O, Weiss KH, Kaler SG. Wilson’s disease and other neurological copper disorders. Lancet Neurol 2015; 14 (1): 103–113.

Hedera. Update on the clinical management of Wilson’s disease. Appl Clin Genet 2017; 10: 9–19.

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Differential diagnosis – Wilson’s disease (2)
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One of the key challenges in the clinical management of Wilson’s disease (WD) is early and accurate diagnosis.[Hedera, 2017] A delay in the diagnosis of WD can lead to worsening of the neurologic and hepatic symptoms, and a worse prognosis.[Hedera, 2017] The average delay between the onset of symptoms and accurate diagnosis is roughly one year, which is potentially why some patients experience an irreversible deterioration in their health.[Hedera, 2017]

Because WD is a disorder of copper metabolism, the gold-standard treatment is chelation of the excess copper that builds up, using drugs or other chemical agents.[Hedera, 2017] There are various new therapies on the horizon or in clinical trials, including cell-based and gene-based approaches.[Hedera, 2017]

Hedera. Update on the clinical management of Wilson’s disease. Appl Clin Genet 2017; 10: 9–19.

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Differential diagnosis – Wilson’s disease Kayser–Fleischer rings
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In Wilson’s disease (WD), the presence of Kayser–Fleischer rings and reduced serum ceruloplasmin can be sufficient to confirm a diagnosis of WD.[Bandmann et al., 2015] However, Kayser–Fleischer rings are not present in every patient with WD (even those with a neurologic/neuropsychiatric presentation), so their absence cannot be used to rule out a diagnosis.[Bandmann et al., 2015]

Bandmann O, Weiss KH, Kaler SG. Wilson’s disease and other neurological copper disorders. Lancet Neurol 2015; 14 (1): 103–113.

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Differential diagnosis – multiple system atrophy (MSA)
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Multiple system atrophy (MSA) is an adult-onset, fatal disease, with a constellation of autonomic, cerebellar, and pyramidal symptoms, including parkinsonism.[Niccolini & Politis, 2016; Wenning et al., 1994] Pathologically, MSA is characterised by α-synuclein-positive inclusion bodies that form in glial cells of affected brain regions, including the striatonigral and/or olivopontocerebellar systems.[Niccolini & Politis, 2016; Wakabayashi & Takahashi, 2006]

Niccolini F, Politis M. A systematic review of lessons learned from PET molecular imaging research in atypical parkinsonism. Eur J Nucl Med Mol Imaging 2016; 43 (12): 2244–2254.

Wakabayashi K, Takahashi H. Cellular pathology in multiple system atrophy. Neuropathology 2006; 26 (4): 338–345.

Wenning GK, Ben Shlomo Y, Magalhães M, et al. Clinical features and natural history of multiple system atrophy. An analysis of 100 cases. Brain 1994; 117 (Pt 4): 835–845.

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Differential diagnosis – progressive supranuclear palsy (PSP)
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Progressive supranuclear palsy (PSP) is a fatal neurodegenerative condition, with a typical survival time of seven years.[Niccolini & Politis, 2016; Golbe, 2014] PSP can present with parkinsonism symptoms.[Niccolini & Politis, 2016] Pathologically, PSP is characterised by accumulation of tau proteins (four-repeat tau) that form filaments and neurofibrillary tangles within the brains of affected individuals.[Niccolini & Politis, 2016; Spillantini & Goedert, 2013]

Golbe LI. Progressive supranuclear palsy. Semin Neurol 2014; 34 (2): 151–159.

Niccolini F, Politis M. A systematic review of lessons learned from PET molecular imaging research in atypical parkinsonism. Eur J Nucl Med Mol Imaging 2016; 43 (12): 2244–2254.

Spillantini MG, Goedert M. Tau pathology and neurodegeneration. Lancet Neurol 2013; 12: 609–622.

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Differential diagnosis – corticobasal degeneration (CBD)
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References

Corticobasal degeneration (CBD) is a rare, fatal, neurodegenerative condition.[Niccolini & Politis, 2016] The features of CBD include asymmetrical rigidity, parkinsonism, dystonia, myoclonus, apraxia, cortical sensory loss, and an ‘alien hand’.[Kouri et al., 2011] Pathologically, CBS is characterised by plaques formed of tau protein (four-repeat tau) that form within striatal neurones and glial cells.[Kouri et al., 2011]

Kouri N, Whitwell JL, Josephs KA, et al. Corticobasal degeneration: a pathologically distinct 4R tauopathy. Nat Rev Neurol 2011; 7 (5): 263–272.

Niccolini F, Politis M. A systematic review of lessons learned from PET molecular imaging research in atypical parkinsonism. Eur J Nucl Med Mol Imaging 2016; 43 (12): 2244–2254.

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Parkinson’s disease diagnostic criteria
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UK Parkinson Society Brain Bank clinical diagnostic criteria (1992)
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References

The UK Parkinson Society Brain Bank Clinical Criteria were created more than 25 years ago, yet they remain the most commonly used criteria for clinical diagnosis of PD.[Hughes et al., 1992; Postuma et al., 2015]

For a diagnosis of parkinsonism (not necessarily idiopathic PD), the criteria require the presence of bradykinesia and at least one other classic motor symptom of PD: muscular rigidity, 4–6 Hz resting tremor, or postural instability not caused by primary visual, vestibular, cerebellar, or proprioceptive dysfunction.[Hughes et al., 1992]

Once parkinsonism has been confirmed, the diagnosis can be further refined to determine whether or not the patient has PD or another form of parkinsonism.[Hughes et al., 1992] This is achieved by finding either supportive positive criteria (e.g., response to levodopa therapy, progressive symptoms) or exclusion criteria (e.g., head injury, repeated strokes, cerebellar symptoms).[Hughes et al., 1992]

Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: A clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992; 55 (3): 181–184.

Postuma RB, Berg D, Stern M, et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord 2015; 30 (12): 1591–1601.

Other reference used on slide:
Edwards M, Bhatia K, Quinn N, Swinn L. Parkinson’s Disease and Other Movement Disorders, 2nd edition. Oxford University Press, 2016.

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NINDS criteria (2008)
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References

The National Institute of Neurological Disorders and Stroke (NINDS) diagnostic criteria have proposed three levels of diagnostic confidence: ‘definite’, ‘probable’, and ‘possible’.[Gelb et al., 1999; Jankovic, 2008] Only ‘possible’ and ‘probable’ can be assigned to a living patient, as a definitive diagnosis requires post mortem examination of brain tissue.[Gelb et al., 1999; Jankovic, 2008]

A ‘possible’ level of confidence requires at least two features of parkinsonism from Group A to be present (of which at least one should be either bradykinesia or resting tremor) and the absence of any exclusion criteria from Group B.[Gelb et al., 1999; Jankovic, 2008] Either substantial and sustained response to levodopa or a dopamine agonist has been documented, or the patient has not had an adequate trial of levodopa or a dopamine agonist.[Gelb et al., 1999; Jankovic, 2008]

A ‘probable’ level of confidence requires at least three features of parkinsonism from Group A and the absence of any exclusion criteria from Group B.[Gelb et al., 1999; Jankovic, 2008] The patient should also have shown a substantial and sustained response to levodopa therapy.[Gelb et al., 1999; Jankovic, 2008]

A ‘definite’ level of confidence is the same as for ‘probable’ but with additional histopathological confirmation from post mortem examination of the brain of the affected individual.[Gelb et al., 1999; Jankovic, 2008]

The NINDS criteria are widely used, but have been criticised for not including any preclinical/prodromal symptoms that might facilitate diagnosis during the early stages of PD.[Berg et al., 2014]

Berg D, Postuma RB, Bloem B, et al. Time to redefine PD? Introductory statement of the MDS task force on the definition of Parkinson’s disease. Mov Disord 2014; 29 (4): 454–462.

Gelb DJ, Oliver E, Gilman S. Diagnostic criteria for Parkinson’s disease. Arch Neurol 1999; 56 (1): 33–39.

Jankovic J. Parkinson’s disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 2008; 79: 368–376.

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Problems with the definitions of PD
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References

The task force set up by the Movement Disorder Society identified several problems with the accepted criteria at the time.[Berg et al., 2014] These problems included the lack of an agreed-upon ‘gold standard’ criteria by which patients could be diagnosed, disagreement about whether dementia should be an exclusion criterion, how the various subtypes of PD should be accounted for, and when exactly PD begins.[Berg et al., 2014]

PD passes inevitably through some type of prodromal phase, and there are currently no 100% reliable means to identify prodromal PD.[Berg et al., 2014] Therefore, the task force proposed that diagnosis of PD should be ‘probabilistic’; probable prodromal PD would refer to a high likelihood (for example >80%; sufficiently certain for neuroprotective trials), whereas possible prodromal PD would refer to a lower, but still substantial, likelihood of neurodegenerative α-synucleinopathy (for example 30%–80%).[Berg et al., 2014]

Berg D, Postuma RB, Bloem B, et al. Time to redefine PD? Introductory statement of the MDS task force on the definition of Parkinson’s disease. Mov Disord 2014; 29 (4): 454–462.

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MDS clinical diagnostic criteria (2015) – clinically established Parkinson’s disease
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References

The Movement Disorder Society (MDS) clinical diagnostic criteria were created to standardise the diagnosis of PD, making it both accurate and reproducible.[Postuma et al., 2015] The MDS criteria provide expert guidance for clinicians, particularly those with less experience in the field of PD, by setting out clear and unambiguous clinical diagnostic criteria.[Postuma et al., 2015]

The MDS method is similar to the UK Parkinson Society Brain Bank Clinical Criteria in that it first requires a diagnosis of parkinsonism, which can then be either supported or excluded by additional criteria.[Postuma et al., 2015] As with the UK Parkinson Society Brain Bank Clinical Criteria, there is a category of absolute exclusion criteria, such as an absence of a response to levodopa therapy, supranuclear gaze palsy or cerebellar signs.[Postuma et al., 2015] There are also additional ‘red flag’ criteria which, if present, require counterbalancing by additional supportive evidence of PD.[Postuma et al., 2015]

A diagnosis of clinically-established PD requires the absence of any absolute exclusion criteria, along with at least two supportive criteria, and no red flags.[Postuma et al., 2015]

Postuma RB, Berg D, Stern M, et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord 2015; 30 (12): 1591–1601.

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MDS clinical diagnostic criteria (2015) – clinically probable Parkinson’s disease
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References

A diagnosis of ‘clinically-probable’ PD requires the absence of any absolute exclusion criteria along with sufficiently counter-balanced supportive criteria.[Postuma et al., 2015] Up to two ‘red flags’ are allowed, but should be offset by an equal number of supportive criteria.[Postuma et al., 2015]

Postuma RB, Berg D, Stern M, et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord 2015; 30 (12): 1591–1601.

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MDS research criteria for prodromal Parkinson’s disease (2015)
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References

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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Parkinson’s disease biomarkers
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A biomarker…
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References

Biomarkers are characteristics that provide an objective measure of an underlying biological process, such as how a patient is responding to treatment.[Lesko & Atkinson, 2001; Sharma et al., 2013] This can be useful for both clinical and regulatory purposes.[Lesko & Atkinson, 2001] A biomarker that can reliably demonstrate the efficacy of a treatment may provide a valuable surrogate endpoint, which can be used to supplement clinical evidence of a response.[Lesko & Atkinson, 2001]

An ideal biomarker is clinically relevant; precise in its ability to predict risk; robust and reliable; non-invasive, so that it can be measured without harm to the patient; and sufficiently cost-effective to be used as part of routine care.[Lesko & Atkinson, 2001; Sharma et al., 2013] Biomarkers with all of these characteristics are very rare, however, and compromise on one or more factors is often necessary.[Lesko & Atkinson, 2001]

One example of a widely used biochemical biomarker is plasma cholesterol, which provides an approximate indicator of future cardiovascular disease risk.[Atkinson et al., 2012] It is hoped that a similar biomarker – simple, reliable, and cost-effective – can be developed to predict the likelihood of someone developing PD.[Sharma et al., 2013]

Atkinson AJ, Huang S-M, Lertora JJL, Markey SP (eds). Principles of Clinical Pharmacology, 3rd edition. San Diego: Elsevier, 2012.

Lesko LJ, Atkinson AJ. Use of biomarkers and surrogate endpoints in drug development and regulatory decision making: criteria, validation, strategies. Annu Rev Pharmacol Toxicol 2001; 41: 347–366.

Sharma S, Moon CS, Khogali A, et al. Biomarkers in Parkinson’s disease (recent update). Neurochem Int 2013; 63 (3): 201–229.

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The Biomarkers Definitions Working Group has defined a biomarker (or a biological mark) as...
References

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

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Biomarkers for PD
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References

Biomarkers are useful for aiding an accurate diagnosis when clinical symptoms are complex and difficult to interpret, such as in PD.[Miller & O’Callaghan, 2015] For PD, this can be particularly the case during the early, prodromal phase when cardinal features (bradykinesia, muscle rigidity, resting tremor) that strongly suggest a diagnosis of PD are not yet apparent.[Miller & O’Callaghan, 2015] During this time, misdiagnosis may occur, so a reliable diagnostic biomarker that can identify PD before a significant amount of damage has occurred would be invaluable.[Miller & O’Callaghan, 2015]

Predictive and diagnostic biomarkers also help scientists to carry out more research during the early stages of a disease, which at the moment can be challenging in PD due to the difficulty of identifying true cases using only clinical examination.[Miller & O’Callaghan, 2015] By studying the disease in its early development, researchers would be more likely to develop therapies in the future that actually prevent neuron loss, rather than merely treating the resulting symptoms.[Miller & O’Callaghan, 2015]

 

Miller DB, O’Callaghan JP. Biomarkers of Parkinson’s disease: present and future. Metabolism 2015; 64 (3 Suppl 1): S40–46.

Other reference used on slide:
Sharma S, Moon CS, Khogali A, et al. Biomarkers in Parkinson’s disease (recent update). Neurochem Int 2013; 63 (3): 201–229.

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Cerebrospinal fluid biomarkers
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References

The cerebrospinal fluid (CSF) is closely associated with the extracellular space in the brain, so many of the biochemical processes that occur in the brain should be detectable in the CSF.[Jiménez-Jiménez et al., 2014]

A great deal of research has attempted to find a robust CSF biomarker that is able to distinguish PD from healthy controls.[Andersen et al., 2017] Many substances have been associated with a greater risk of PD, or found in lesser or greater amounts in patients with PD than in healthy controls.[Andersen et al., 2017] However, at present, no biomarker has been found that can diagnose PD with sufficient precision.[Andersen et al., 2017]

Most useful PD biomarkers identified to date have been limited in their diagnostic ability; for example, because α-synuclein is present in the CSF of patients with PD, it may be a useful biomarker to distinguish PD from healthy controls.[Jiménez-Jiménez et al., 2014] Yet, the biomarker would still be unable to differentiate between idiopathic PD (the most common form) and other forms of α-synucleinopathy.[Schapira, 2013; Jiménez-Jiménez et al., 2014]

The role of CSF biomarkers therefore remains limited and highly specific.[Schapira, 2013] As yet, there is no one biomarker – or even collection of biomarkers – that can provide a simple ‘yes/no’ PD diagnosis with sufficiently high precision to be used in a clinical context.[Andersen et al., 2017; Jiménez-Jiménez et al., 2014; Schapira, 2013]  

Andersen AD, Binzer M, Stenager E, Gramsbergen JB. Cerebrospinal fluid biomarkers for Parkinson’s disease – a systematic review. Acta Neurol Scand 2017; 135 (1): 34–56.

Jiménez-Jiménez FJ, Alonso-Navarro H, García-Martín E, Agúndez JAG. Cerebrospinal fluid biochemical studies in patients with Parkinson’s disease: toward a potential search for biomarkers for this disease. Front Cell Neurosci 2014; 8: 369.

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

Other reference used on slide:
Sharma S, Moon CS, Khogali A, et al. Biomarkers in Parkinson’s disease (recent update). Neurochem Int 2013; 63 (3): 201–229.

 

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Biomarkers for prodromal Parkinson’s disease
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References

The term ‘prodromal PD’ describes individuals for whom the symptoms and signs of PD are present, but they are insufficient to define disease.[Berg et al., 2015] These are typically non-motor symptoms, such as hyposmia (impaired sense of smell), mood disorders, and sleep disorders and/or subtle motor features.[Mahlknecht et al., 2015]

A biomarker that provides diagnostic information when patients first presents with prodromal PD symptoms might allow them to receive treatment and counselling for the disorder.[Mahlknecht et al., 2015; Miller & O’Callaghan, 2015]

Genetic markers of PD risk have been useful for research purposes, but have not yet provided a biomarker suitable for clinical use.[Mahlknecht et al., 2015] However, sophisticated analysis is now available whereby a patient’s cumulative genetic risk – i.e., the total effect of many genes – can be calculated as a polygenic risk score.[Escott-Price et al., 2015] Such a score may prove useful in distinguishing patients whose PD is most likely to have the largest or smallest genetic component.[Escott-Price et al., 2015] Identifying these individuals would allow researchers to gain a better understanding of the role played by genes in PD.[Escott-Price 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.

Escott-Price V, Nalls MA, Morris HR, et al.; International Parkinson’s Disease Genomics Consortium. Polygenic risk of Parkinson disease is correlated with disease age at onset. Ann Neurol 2015; 77 (4): 582–591.

Mahlknecht P, Seppi K, Poewe W. The concept of prodromal Parkinson’s disease. J Parkinsons Dis 2015; 5 (4): 681–697.

Miller DB, O’Callaghan JP. Biomarkers of Parkinson’s disease: present and future. Metabolism 2015; 64 (3 Suppl 1): S40–46.

Other reference used on slide:
Cooper CA, Chahine LM. Biomarkers in prodromal Parkinson disease: a qualitative review. J Int Neuropsychol Soc 2016; 22 (10): 956–967.

 

 

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The pitfalls of biomarker research
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References

Ideally, methods of collecting and analysing biomarkers need to be standardised to enable valid comparison of data from one study to another, as differences in procedures used can markedly affect the data.[Andersen et al., 2017]

International guidelines for the sampling and storage of cerebrospinal fluid have been available since 2009, and these ensure that samples obtained for large biobanks from multiple sites are all handled in the same way.[Teunissen et al., 2009] The guidelines outline best practice methods for collecting biomarker samples in order to improve the comparability of data between studies.[Teunissen et al., 2009]

Andersen AD, Binzer M, Stenager E, Gramsbergen JB. Cerebrospinal fluid biomarkers for Parkinson’s disease – a systematic review. Acta Neurol Scand 2017; 135 (1): 34–56.

Teunissen CE, Petzold A, Bennett JL, et al. A consensus protocol for the standardization of cerebrospinal fluid collection and biobanking. Neurology 2009; 73 (22): 1914–1922.

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Imaging techniques
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References

As with biomarkers, there is no definitive imaging method that can accurately diagnose PD on its own.[Schapira, 2013] However, imaging can be used to exclude other causes of symptoms (differential diagnosis).[Miller & O’Callaghan, 2015]

Imaging can provide important information about the brain structure and function in brains affected by PD.[Miller & O’Callaghan, 2015] Importantly, imaging is non-invasive and can therefore be used repeatedly to assess changes over time.[Schapira, 2013; Miller & O’Callaghan, 2015] Some imaging methods require highly specialised and expensive equipment, however, so they may not be widely available for routine diagnostics as part of clinical care.[Miller & O’Callaghan, 2015]

Miller DB, O’Callaghan JP. Biomarkers of Parkinson’s disease: present and future. Metabolism 2015; 64 (3 Suppl 1): S40–46.

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

Other reference used on slide:
Chaudhuri KR, Ondo W. Handbook of Movement Disorders. London: Current Medicine Group, 2009.

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Specific imaging techniques
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References

Transcranial sonography (TCS) is considered to be one of the more promising imaging techniques as it is widely available and is more cost-effective than other methods, such as single-photon emission computed tomography (SPECT).[Miller & O’Callaghan, 2015; Schapira, 2013]

In more than 90% of patients with PD, TCS reveals abnormally high-density tissue in the substantia nigra region of the brain, as compared with only 9% of healthy individuals.[Spiegel et al., 2006] This finding appears to be stable during the course of the disease, and is thought to reflect increased amounts of iron.[Miller & O’Callaghan, 2015; Spiegel et al., 2006] However, it does not necessarily reflect the degeneration of presynaptic dopaminergic nerve terminals – i.e., the rate of disease progression.[Spiegel et al., 2006]

TCS has been shown to have a good level of accuracy in patients with PD, and is most likely to be used in clinical practice for providing additional diagnostic information during the early stages of PD.[Miller & O’Callaghan, 2015]

 

Miller DB, O’Callaghan JP. Biomarkers of Parkinson’s disease: present and future. Metabolism 2015; 64 (3 Suppl 1): S40–S46.

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

Spiegel J, Hellwig D, Möllers MO, et al. Transcranial sonography and [123I]FP-CIT SPECT disclose complementary aspects of Parkinson’s disease. Brain 2006; 129 (5): 1188–1193.

Other references used on slide:
Ali K, Morris HR. Parkinson’s disease: chameleons and mimics. Pract Neurol 2015; 15 (1): 14–25.

Chaudhuri KR, Ondo W. Handbook of Movement Disorders. London: Current Medicine Group, 2009.

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University of Pennsylvania Smell Identification Test (UPSIT)
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References

Olfactory dysfunction, known as hyposmia, is very common in patients with PD, and can be an early symptom.[Bohnen et al., 2008] The University of Pennsylvania Smell Identification Test (UPSIT) was developed at the University of Pennsylvania, to be a valid and useful test of disorders of the chemical senses.[Doty et al., 1984]

The UPSIT consists of 4 booklets containing 10 odorants apiece, 1 odorant per page.[Doty et al., 1984] The stimuli are embedded in 10–50 μm diameter microencapsulated crystals located on brown strips at the bottom of each page.[Doty et al., 1984] Above each odorant strip is a multiple-choice question with 4 alternative responses for each item (see the example on the slide).[Doty et al., 1984] The patient is required to answer 1 of the 4 alternatives, even if no smell is perceived.[Doty et al., 1984] The range of odours were chosen to span a range of pleasant and unpleasant smells.[Doty et al., 1984]

Scores on the UPSIT scale have been correlated with the degree of neurodegeneration in some areas of the brain linked to PD (specifically hippocampal regions).[Bohnen et al., 2008]

Bohnen NI, Gedela S, Herath P, et al. Selective hyposmia in Parkinson disease: association with hippocampal dopamine activity. Neurosci Lett 2008; 447 (1): 12–16.

Doty RL, Shaman P, Kimmelman CP, Dann MS. University of Pennsylvania Smell Identification Test: a rapid quantitative olfactory function test for the clinic. Laryngoscope 1984; 94 (2 Pt 1): 176–178.

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Scales commonly used in Parkinson’s disease research
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MDS Unified Parkinson’s Disease Rating Scale (MDS-UPDRS)
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References

Staging tools, such as the Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), are useful for assessing the progression of PD and helping to guide decisions relating to the clinical management of the disease.[Goetz et al., 2008; DeMaagd & Philip, 2015]

The MDS-UPDRS consists of four parts, two of which focus on activities of daily living (ADL):

  1. ‘Non-motor ADL’ assesses the impact of non-motor symptoms on the patient’s ability to carry out everyday activities independently.[Goetz et al., 2008] It assesses problems relating to cognitive function, sleep, mood, psychosis, fatigue, constipation, and urinary problems.[Goetz et al., 2008]
  2. ‘Motor ADL’ assesses the impact of motor symptoms on the patient’s ability to carry out everyday activities independently.[Goetz et al., 2008] It assesses problems relating to speech; chewing and swallowing; eating; dressing; hygiene; handwriting; hobbies and other activities; turning in bed; tremor; getting up from a bed or deep seat; walking and balance; freezing; and falls.[Goetz et al., 2008]
  3. ‘Motor examination’ is a clinical assessment of motor function, including speech, muscle rigidity, facial expression, hand and leg movements, toe and finger tapping, gait, tremor, and posture.[Goetz et al., 2008] 
  4. ‘Motor complications’ covers the presence and severity of motor complications, such as fluctuations, OFF-state dystonia, and other dyskinesias.[Goetz et al., 2008]

DeMaagd G, Philip A. Parkinson’s disease and its management. Pharmacol Therapeut 2015; 40 (8): 504–510.

Goetz CG, Tilley BC, Shaftman SR, et al.; Movement Disorder Society UPDRS Revision Task Force. Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov Disord 2008; 23 (15): 2129–2170.

Other reference used on slide:
Goetz CG, Fahn S, Martinez-Martin P, et al. Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS): process, format, and clinimetric testing plan. Mov Disord 2007; 22 (1): 41–47.

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Hoehn & Yahr scale
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References

Another well-known staging tool is that developed by Hoehn and Yahr, which has been used since the late 1960s.[Hoehn & Yahr, 1967] The Hoehn & Yahr scale originally allocated the degree of impairment experienced by the patient to five stages (although these have since been expanded to include two more) ranging from ‘no symptoms’ to a wheelchair- or bed-bound state.[Hoehn & Yahr, 1967; Jankovic, 2003]

While the Hoehn & Yahr scale is particularly useful for comparing populations of patients with PD, it is relatively insensitive to changes in clinical state over time and so tends not to be used for monitoring the responses of individual patients to therapy.[Jankovic, 2003]

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

Jankovic J. Pathophysiology and assessment of parkinsonian symptoms and signs. In: Pahwa R, Lyons K, Koller WC (eds). Handbook of Parkinson’s Disease, 3rd edition. New York: CRC Press, 2003.

Other reference used on slide:
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.

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Schwab & England ADL (SEADL)
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References

The purpose of the Schwab & England Activities of Daily Living (SEADL) scale is to assess the independence and speed with which an individual affected by PD is able to carry out daily activities.[Schwab & England, 1969] The rating is performed by an examiner, who interviews the patient.[Perlmutter, 2009] Frequently, there is a collateral source too – such as a spouse or family member.[Perlmutter, 2009]

Perlmutter JS. Assessment of Parkinson disease manifestations. Curr Protoc Neurosci 2009; (10): 10.1.

Schwab RS, England AC. Projection technique for evaluating surgery in Parkinson’s disease. In: Gillingham FJ, Donaldson IML (eds). Third Symposium on Surgery on Parkinson’s Disease. Edinburgh: Churchill Livingstone, 1969.

Other reference used on slide:
Jankovic J. Pathophysiology and assessment of parkinsonian symptoms and signs. In: Pahwa R, Lyons K, Koller WC (eds). Handbook of Parkinson’s Disease, 3rd edition. New York: CRC Press, 2003.

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Non-Motor Symptoms Questionnaire (NMSQuest/NMSQ)
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References

The Non-Motor Symptoms Questionnaire (NMSQuest) was designed by a multi-disciplinary group of experts, including patient group representatives, for use as a screening tool for non-motor symptoms.[Chaudhuri et al., 2006] It specifically focuses on non-motor symptoms in order to initiate further investigation.[Chaudhuri et al., 2006]

The NMSQuest is a valid instrument for use in the PD population,[Chaudhuri et al., 2006] and has been used to study the spectrum of non-motor symptoms and their prevalence – showing that non-motor symptoms are very common across all stages of PD.[Martinez-Martin et al., 2007]

Chaudhuri KR, Martinez-Martin P, Schapira AH, et al. An international multicentre pilot study of the the first comprehensive self-completed non motor symptoms questionnaire for Parkinson’s disease: the NMSQuest study. Mov Disord 2006; 21 (7): 916 –923.

Martinez-Martin P, Schapira AHV, Stocchi F, et al. Prevalence of nonmotor symptoms in Parkinson’s disease in an international setting; study using nonmotor symptoms questionnaire in 545 patients. Mov Disord 2007; 22 (11): 1623–1629.

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Non-Motor Symptom Scale (NMSS)
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References

The Non-Motor Symptom Scale (NMSS) was designed to address the problem, at the time, that there was no validated clinical tool to assess the progress of non-motor symptoms, or track their response to potential treatment.[Chaudhuri et al., 2007] The 30-item NMSS was developed as a quick (10–15 minutes), easy to administer scale of non-motor symptoms, where the patient with PD is scored for both severity and frequency.[Chaudhuri et al., 2007]

When the NMSS was tested in patients with PD, its scores correlated with the severity of PD symptoms assessed using the Hoehn & Yahr scale, NMSQuest, and MDS-UPDRS Part I (which also measures non-motor symptoms) and, importantly, other health-related quality of life assessments.[Chaudhuri et al., 2007; Martinez-Martin et al., 2015] Development of instruments of this kind, which specifically analyse non-motor symptoms, allows for the evidence-based treatment of the non-motor symptom complex of PD.[Chaudhuri et al., 2007]

Chaudhuri KR, Martinez-Martin P, Brown RG, et al. The metric properties of a novel non-motor symptoms scale for Parkinson's disease: results from an international pilot study. Mov Disord 2007; 22 (13): 1901–1911.

Martinez-Martin P, Chaudhuri KR, Rojo-Abuin JM, et al. Assessing the non-motor symptoms of Parkinson’s disease: MDS-UPDRS and NMS Scale. Eur J Neurol 2015; 22: 37–43.

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Parkinson’s Disease Sleep Scale (PDSS)
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References

Sleeping difficulties are an extremely common feature of PD, with almost all patients reporting sleep problems.[Chaudhuri et al., 2002] Sleep can often be light and fragmented due to increased skeletal muscle activity, disturbed breathing, and physical exertions during REM sleep.[Askenasy, 1993] Patients may also experience nocturia (waking up during the night to urinate), restlessness, insomnia, muscle cramps, tremor, akinesia, or early morning dystonia.[Chaudhuri et al., 2002; Swick, 2012]

The Parkinson’s Disease Sleep Scale (PDSS) is a simple bedside screening instrument for evaluating sleep disturbances in PD.[Chaudhuri et al., 2002] It addresses eight important elements of sleep quality:[Chaudhuri et al., 2002]

  1. overall quality of night’s sleep
  2. sleep onset and maintenance insomnia
  3. nocturnal restlessness
  4. nocturnal psychosis
  5. nocturia (waking up during the night to urinate)
  6. nocturnal motor symptoms
  7. sleep refreshment
  8. daytime dozing.

Askenasy JJ. Sleep in Parkinson’s disease. Acta Neurol Scand 1993; 87 (3): 167–170.

Chaudhuri KR, Pal S, DiMarco A, et al. The Parkinson’s Disease Sleep Scale: a new instrument for assessing sleep and nocturnal disability in Parkinson’s disease. J Neurol Neurosurg Psychiatry 2002; 73: 629–635.

Swick TJ. Parkinson’s disease and sleep/wake disturbances. Parkinsons Dis 2012; 2012: 205471.

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RBD Screening Questionnaire (RBDSQ)
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References

Rapid eye movement (REM) sleep behaviour disorder (RBD) is clinically characterised by the intermittent loss of normal skeletal muscle atonia during REM sleep with the appearance of elaborate motor activity associated with dream mentation.[Stiasny-Kolster et al., 2007] RBD can be a very early symptom of PD, early detection of which is clinically relevant.[Stiasny-Kolster et al., 2007]

The REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ) was developed to assess the prominent features of RBD, and was validated by comparing individuals with established RBD against a control group.[Stiasny-Kolster et al., 2007] The use of the RBDSQ has been validated in patients with PD, but – like any questionnaire – it does have a false negative rate, where cases of RBD will be missed.[Stiasny-Kolster et al., 2007; Stiasny-Kolster et al., 2015]

Stiasny-Kolster K, Mayer G, Schäfer S, et al. The REM Sleep Behavior Disorder Screening Questionnaire—a new diagnostic instrument. Mov Disord 2007; 22 (16): 2386–2393.

Stiasny-Kolster K, Sixel-Döring F, Trenkwalder C, et al. Diagnostic value of the REM Sleep Behavior Disorder Screening Questionnaire in Parkinson’s disease. Sleep Med 2015; 16 (1): 186–189.

Other reference used on slide:
Postuma RB, Arnulf I, Hogl B, et al. A single-question screen for rapid eye movement sleep behavior disorder: a multicenter validation study. Mov Disord 2012; 27 (7): 913–916.

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Quality of life scales
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References

Validated questionnaires that assess quality of life are particularly meaningful as they provide an assessment of health and wellbeing from the perspective of the patient.[Schrag et al., 2000]

The choice of therapy should always aim to optimise the quality of life over the whole expected lifespan of an individual.[NCCCC, 2006] Assessments should take into account the impact of both motor and non-motor symptoms as, particularly during the advanced stages of PD, non-motor symptoms may have a greater impact on quality of life.[Schrag et al., 2000]

National Collaborating Centre for Chronic Conditions. Parkinson’s disease: national clinical guideline for diagnosis and management in primary and secondary care. London: Royal College of Physicians, 2006.

Schrag A, Jahanshahi M, Quinn N. What contributes to quality of life in patients with Parkinson’s disease? J Neurol Neurosurg Psychiatry 2000; 69 (3): 308–312.

Other references used on slide:
de Boer AG, Wijker W, Speelman JD, de Haes JC. Quality of life in patients with Parkinson’s disease: development of a questionnaire. J Neurol Neurosurg Psychiatry 1996; 61 (1): 70–74.

Calne SM, Mak E, Hall J, et al. Validating a quality-of-life scale in caregivers of patients with Parkinson’s disease: Parkinson’s Impact Scale (PIMS). Adv Neurol 2003; 91: 115–122.

Jenkinson C, Fitzpatrick R, Peto V, et al. The Parkinson's Disease Questionnaire (PDQ-39): development and validation of a Parkinson’s disease summary index score. Age Ageing 1997; 26 (5): 353–357.

Marinus J, Ramaker C, van Hilten JJ, Stiggelbout AM. Health related quality of life in Parkinson’s disease: a systematic review of disease specific instruments. J Neurol Neurosurg Psychiatry 2002; 72 (2): 241–248.

Marras C, Lang AE. Outcome measures for clinical trials in Parkinson’s disease: achievements and shortcomings. Expert Rev Neurother 2004; 4 (6): 985–993.

Welsh M, McDermott MP, Holloway RG; Parkinson Study Group. Development and testing of the Parkinson’s disease quality of life scale. Mov Disord 2003; 18 (6): 637–645.

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Cognitive scales used in PD research
Slide information
References

Several scales are used for the assessment of cognitive function in PD, although not all are specific for PD patients.[Mahieux et al., 1995; Kulisevsky et al., 2013] The Mini-Mental Parkinson test is a brief screening test for cognition in PD patients, which is derived from the non-PD specific Mini-Mental State Examination (MMSE).[Mahieux et al., 1995]

The Montreal Cognitive Assessment (MoCA) is a brief cognitive screening tool with high sensitivity and specificity for detecting MCI as currently conceptualised in patients performing in the normal range on the MMSE.[Nasreddine et al., 2005]

Kulisevsky J, Fernández de Bobadilla R, et al. Measuring functional impact of cognitive impairment: validation of the Parkinson’s Disease Cognitive Functional Rating Scale. Parkinsonism Relat Disord 2013; 19 (9): 812–817.

Mahieux F, Michelet D, Manifacier MJ, et al. Mini-Mental Parkinson: first validation study of a new bedside test constructed for Parkinson’s disease. Behav Neurol 1995; 8: 15–22.

Nasreddine ZS, Phillips NA, Bédirian V. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 2005; 53 (4): 695–699.

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