Mild cognitive impairment has been defined as a syndrome of cognitive decline that is greater than would be expected for an individual’s age and level of education. Cognitive deficits are common in Parkinson’s disease, even early in the disease when there may be no cognitive complaints. This article will highlight the clinical features and various management options of MCI in Parkinson’s disease.
Parkinson’s disease (PD) is a neurodegenerative condition that has been defined by its characteristic motor hallmarks of rest tremor, bradykinesia, rigidity, and gait impairment. In addition, non-motor features are increasingly recognised as part of PD. Non-motor signs and symptom of PD include not only cognitive impairment and dementia, but also mood disorders, psychosis, sleep disturbances, and autonomic dysfunction. Mild cognitive impairment in PD (PD-MCI) is a non-motor complication frequently encountered in the course of PD and often a precursor to dementia in PD.1
PD-MCI has been increasingly recognised as a distinct entity and a potential prodromal state to PD dementia (PDD). Mild cognitive impairment is common in non-demented PD patients; however, frequency estimates vary across studies due to methodological differences and lack of uniform diagnostic criteria for PD-MCI. This article will highlight the clinical features and various management options of MCI in Parkinson’s disease.
Mild cognitive impairment (MCI) is an intermediate stage between the expected cognitive decline of normal ageing and the more-serious decline of dementia. It can involve problems with memory, language, thinking and judgment that are greater than normal age-related changes. In general, MCI represents a degree of cognitive impairment that is not normal for age.1 Historically, the criteria for MCI developed from clinical studies of ageing that demonstrated cognitive decline or conversion to dementia in subsets of older participants.2
One of the main reasons for the development of MCI criteria has been the early identification of patients who are at risk of converting to dementia and ultimately helping the advances in therapies that may halt or slow the progression of MCI.1
The criteria for MCI specified the following:3
- A memory complaint that is preferably corroborated and confirmed by an informant.
- An impairment in memory as documented according to appropriate reference values.
- Essentially normal performance in non-memory cognitive domains.
- Generally preserved activities of daily living.
- Not demented.
With the recognition that not all MCI evolved into dementia, these criteria were subsequently revised to incorporate both amnestic and non-amnestic clinical phenotypes of MCI,4 (table 1). The revised and the complementary criteria provide a more global approach to the clinical phenotype of MCI and recognize that aetiologies of MCI are varied and not solely due to Alzheimer’s disease (AD).4,5 In addition, MCI can be attributed to degenerative, vascular, psychiatric, or other medical conditions.1
Table 1. The revised and complementary criteria for MCI clinical diagnosis.
The revised MCI criteria
The Complementary MCI criteria (for the clinical diagnosis)
1) The presence of MCI: Presence of a cognitive complaint, which was not normal for age and represented a decline in cognitive function, but did not represent dementia or impair functional activities.
2) The presence of memory impairment, categorized as yes or no, and thereby as amnestic or non-amnestic MCI, respectively.
3) The number of domains impaired, single or multiple, thereby leading to 4 MCI subtypes. These are amnestic MCI single domain, amnestic MCI multiple domain, non-amnestic MCI single domain, or non-amnestic MCI multiple domain.
1) Concern regarding a change in cognition as reported by the patient, reliable informant, or clinician observation.
2) Impairment in one or more cognitive domains with evidence by impaired cognitive performance greater than the patient’s age and educational background (often considered as scores 1 to 1.5 standard deviations [SD] below appropriate normative data, though specific cutoff scores are not stipulated) or a decline in performance over serial evaluations.
3) Preservation of independence in functional abilities.
4) Insufficient evidence of dementia.
Patients diagnosed with MCI have different patterns of symptoms and there are many possible underlying causes. The first subtype is amnestic MCI, where memory loss is the main symptom. The second subtype is non-amnestic MCI, where memory is not impaired but other thinking abilities such as organising and planning, reasoning, learning or judgement may be affected. However, the clinical phenotype of PD-MCI is heterogeneous with both non-amnestic and amnestic cognitive domains affected and single and multiple-domain impairment.
Non-amnestic, single domain impairment predominates in PD-MCI, with executive function as the most frequent cognitive domain affected, though some PD-MCI patients exhibit greater amnestic or cortical-type profiles.6,7 Studies have suggested that patients with amnestic single and multiple domains MCI subsequently progress to Alzheimer’s disease (AD), whereas patients in the other MCI categories, particularly the non-amnestic ones, develop conditions such as frontotemporal dementia, vascular dementia, dementia with Lewy bodies, or depression.2 Thus, MCI represents a heterogeneous clinical syndrome that can be ascribed to different aetiologies.
Cognitive impairment has been frequently reported in non-demented PD using various definitions of MCI and evaluating different cohorts of PD patients.8 The presence of mildly impaired cognition has been noted even in early or newly diagnosed PD.9 Frequency estimates of PD-MCI, however, vary due to factors such as differences in populations studied, exclusion of PD dementia, inclusion of normal control groups, clinical and neuropsychological criteria used, and the number and type of neuropsychological tests or domains assessed.1
In addition, other contributing factors such as PD medications, comorbid psychiatric disorders (eg., depression, apathy), fatigue and sleep disorders, and the motor demands of neuropsychological tests have not always been considered and merit attention when interpreting neuropsychological test performance in PD and defining PD-MCI.1
Epidemiologic studies over the years have used different MCI criteria and have examined different subject populations, with prevalence rates of MCI of 14-18% for persons aged 70 years and older.10 Rates of MCI progression range from about 6-10% per year in community-based studies and 10-15% per year in dementia clinical care centres, both greater than base rates of 1-2% per year.2,11 Higher rates in the dementia centres likely reflect referral bias and a greater likelihood of amnestic MCI in the cohort.
In recent years, several studies have evaluated larger incident PD cohorts in the community, yielding estimates of about 20-35% with PD-MCI. In a population study identifying new cases of parkinsonism in the UK, it was reported that 57/159 (36%) of the incident PD cases were cognitively impaired but not demented.12
There is no single cause of mild cognitive impairment (MCI) and current evidence indicates that MCI often, but not always, arises from a lesser degree of the same types of brain changes seen in Alzheimer's disease or other forms of dementia. PD-MCI has been associated with older age at evaluation, older age at PD onset, male gender, depression, worse motor symptoms, and advanced disease,7 (table 2).
Table 2. General risk factors for MCI
Strong risk factors for MCI
Other risk factors
· Increasing age
· Having a specific form of a gene known as APOE-e4, also linked to Alzheimer's disease — though having the gene does no guarantee that you will experience cognitive decline.
· Male gender
· High blood pressure
· Elevated cholesterol
· Lack of physical exercise
· Infrequent participation in mentally or socially stimulating activities.
Cognitive deficits in non-demented PD have been frequently attributed to neurochemical alterations in dopaminergic, cholinergic, and other systems as well as the neuropathological contributions of limbic and cortical Lewy bodies and neurites, amyloid deposition, neurofibrillary tangles, and cerebrovascular disease.1
Executive dysfunction may reflect frontal lobe impairment, particularly affecting the dorso-lateral prefrontal cortex, resulting from disruptions of fronto-striatal loops, due to either degeneration of dopaminergic nigrostriatal or meso-cortical pathways.13 To date, neuropathological studies of PD-MCI are limited.1 The neuropathological staging of PD by Braak and colleagues, however, supports changes in brain regions involved in cognition in stages in early symptomatic PD (neuropathological stage-3, with changes in melano-neurons in the substantia nigra; projection neurons in magno-cellular nuclei of the basal forebrain).14
The cholinergic deficits in the basal forebrain and prefrontal cortex may be responsible for some of the cognitive deficits in PD.15 Neuropathological stage-4 is represented by involvement of limbic structures including the anteromedial temporal mesocortex, which contribute to memory function.1
In an autopsy series of PD patients, the majority of individuals with either intact cognition or marginal impairment (MMSE scores 25-30) or mildly impaired cognition (MMSE scores 21-24) were classified as neuropathological stage 3 to 4.16, 17
Cognitive dysfunction in non-demented PD encompasses a broad spectrum of clinical deficits and severity, affecting both non-amnestic and amnestic domains. The cognitive dysfunction typically includes slowed processing, difficulty with multi-tasking or planning, decreased attention and concentration, and word finding disturbances.1 Various impairments of cognitive domains such as executive function, psychomotor speed, visuospatial abilities, language, and memory have been noted in non-demented PD patients. The executive function, which encompasses the ability to plan, initiate, and regulate goal-directed behaviour and relies on frontal-striatal circuitry including prefrontal regions such as the dorsolateral prefrontal cortex and its connections to the basal ganglia, is a prominent feature not only in the “subcortical dementia” syndrome in PD but also in non-demented PD.13,18 In addition, PD patients may exhibit difficulty in learning novel information as demonstrated by impaired free recall performance which may improve with semantic cues or recognition tasks.19,20
In general, people with MCI are still able to carry out their normal daily activities, but do have these common complaints: Losing things often; forgetting to go to events or appointments; having more trouble coming up with words than other people of the same age. In addition, movement difficulties and problems with the sense of smell have also been linked to MCI. The rate of progression of MCI to dementia may be affected by a variety of factors including degree of cognitive impairment, genetic risk (eg., apolipoprotein E [APOE] epsilon 4 carrier status), changes on neuroimaging or cerebrospinal fluid (CSF) abnormalities (eg., low beta-amyloid 1-42 peptide or elevated total tau or phosphorylated tau levels).1 The changes on neuroimaging may include volume loss of the mesial temporal lobe or whole brain on structural magnetic resonance imaging [MRI], hypometabolism in temporoparietal areas on fludeoxyglucose F 18-positron emission tomography [PET], or increased amyloid binding using carbon-11 Pittsburgh Compound B scans.1
Mild cognitive impairment in Parkinson’s disease (PD-MCI) is a clinical diagnosis. It rests upon the concept that MCI, in general and specific to PD, refers to a clinical syndrome of cognitive impairment in the absence of dementia.1 Several studies of MCI in PD have utilised established MCI criteria or modified versions of these with items often modified pertain to the presence of memory complaints, preservation of activities of daily living, and degree of memory impairment according to different reference values.3,4 However, the established MCI criteria do not specify how many neuropsychological tests or which tests should be used, what cognitive domains and how many should be examined.1 Studies illustrate that the use of different cut-off scores (ranging from 0.5 to 2 SD below normative data) greatly influence frequency estimates of PD-MCI.
The process of diagnosing or ruling out MCI may involve some or all of the following: taking a thorough medical history, assessing independent function and daily activities, observations from a family member or carer, brief cognitive screening tests, neurological examination, mood evaluation, basic laboratory tests, and neuropsychological testing to assess multiple types of cognitive abilities. Several global cognitive scales have been proposed as screening tests for PD-MCI, including the Montreal Cognitive Assessment (MoCA), Parkinson Neuro-psychometric Dementia Assessment (PANDA), PD-Cognitive Rating Scale (PD-CRS), and Scales for Outcomes in Parkinson’s disease-cognition (SCOPA-COG) among others; most of these tests take about 10-30 minutes to administer.21
The MoCA, which was originally developed to screen for MCI in the general population, can assess orientation, executive function, attention, concentration, naming, verbal abstraction, and visuo-constructive abilities. Although the MoCA performed better in detecting PDD, it had an acceptable sensitivity (0.83), but low specificity (0.53) using a cut-off of 26-27/30 in detecting MCI in one PD study.22 In one study of PD patients, of whom 21/114 (18%) had PD-MCI, the MoCA and standardized MMSE demonstrated excellent discrimination of PDD from non-demented PD and PD-MCI from cognitively normal PD; the MoCA in particular performed well, with an optimal screening cut-off for PD-MCI of <26/30 having 90% sensitivity, 75% specificity, and a negative predictive value of 95%.23. Biomarkers have been recently incorporated into research MCI criteria with an emphasis on the early detection of and interventions for dementia.1
Biomarkers for PD-MCI including CSF(CSF beta-amyloid levels, CSF total tau or phosphorylated tau levels), genetics (polymorphism) and neuroimaging are currently under study, though at present, many studies are limited by small samples and a lack of uniform PD-MCI definitions, detailed neuropsychological evaluation, and longitudinal follow-up.1 Several genetic biomarkers have been explored in PD patients with cognitive dysfunction including polymorphisms related to dopamine regulation and tau proteins. Small clinical studies suggest that there are two distinct cognitive syndromes in PD, the fronto-striatal and posterior cortical deficits.1 These two types may have different prognoses or risk for developing dementia.24 Structural and metabolic neuroimaging may provide another potential biomarker for PD-MCI. Using voxel-based morphometry (VBM) analyses of brain MRI, PD-MCI patients had reduced gray matter in the left frontal and bilateral temporal lobe regions, compared to PD without MCI. However, these differences did not remain significant after corrections for multiple comparisons and patient groups were small in size.25
The management of MCI is generally symptomatic and there are very few pharmacologic or non-pharmacologic options for the management of PD-MCI. To date, clinical research trials and therapeutic interventions specifically for PD-MCI are limited.1
Cholinesterase inhibitors have emerged as a potentially useful therapeutic option for cognitive impairment in PD with the potential of positive impact on global assessment, cognitive function, behavioural disturbance, and activities of daily living. However, the evidence on the use of cholinesterase inhibitors in PD-MCI patients is limited. It has been suggested that Rivastigmine may result in a clinically meaningful benefit in approximately 15% of cases, with improvements in cognition and activities of daily living, though there are significant trade-offs between efficacy and adverse effects.26 Rasagiline, a selective monoamine oxidase type-B inhibitor, was assessed in a multi-center study in non-demented PD patients.27 The rasagiline-treated group showed significant improvement in some cognitive tasks relevant to executive function and attention, compared to the placebo group. However, no benefits were seen in memory, language, and visuospatial functions.27 Dopaminergic medications such as levodopa or dopamine agonists may have variable effects on cognition, with improvement in executive function tasks in some PD patients and in others, worsening or no effect.28
Treatment of comorbid conditions such as depression, anxiety, apathy, and sleep dysfunction may play a role in treating MCI in PD. In addition, non-PD medications with the potential to impair cognition or cause confusion (e.g., centrally-acting medications for pain, bladder function, sleep) should be avoided or used sparingly.1
Non-pharmacological treatment options may also play a valuable role and this method of therapy showed promise as a primary and secondary prevention strategy for cognitive decline across a range of neurodegenerative diseases. Generally, cognitive rehabilitation in PD patients has shown significant, albeit modest improvement in cognitive domains. Several preliminary studies suggest that cognitive rehabilitation with computerised programs improves neuropsychological performance on various cognitive scales and tests, though more rigorous studies are needed.29 Non-demented PD patients who underwent cognitive rehabilitation or training have been found to improve performance in tests of attention, information processing speed, memory, visuospatial and visuo-constructive abilities, semantic verbal fluency, and executive functions .In addition, they have also displayed improvements in performance on the Stroop test (a neuropsychological tool to evaluate executive functions) and reduced cortical activation patterns visible on functional MRI (fMRI).30
Mild cognitive impairment in PD is a frequent non-motor complication that affects significant number of PD patients, though studies differ in methodologies used to assess its prevalence. PD patients with MCI, especially the subtype involving memory problems, are more likely to develop dementias than people without MCI. However, PD-MCI does not always lead to dementia. Cognitive impairment in PD is not only a late-stage feature of the disease, but may be evident in early or newly diagnosed PD patients. Although single domain impairment with non-amnestic deficits predominates in PD-MCI, the cognitive profile of PD-MCI is heterogeneous with a mix of non-amnestic and amnestic deficits and single and multiple-domains affected.
Studies incorporating CSF, genetics, and neuroimaging may provide clues to the pathogenesis of PD-MCI and have potential utility as biomarkers of PD-MCI and PDD, but further research is needed. Widely-accepted assessment tools for PD-MCI are still lacking, however; to optimise the diagnosis of PD-MCI in clinical practice, valid and short screening tools are necessary. The MoCA, using a cut-off of <26, is a short, user-friendly test to evaluate cognitive impairment in PD. However, there is not a specific cut-off score to distinguish MCI-PD from PDD. There are very few pharmacologic or non-pharmacologic options for the management of PD-MCI. Uniform definitions and diagnostic criteria of PD-MCI will facilitate comparisons across multiple centres and PD populations, provide well-characterised groups for clinical research trials, and identify cognitive changes at early stages.
Nabil Aly, Consultant physician, University Hospital Aintree, Liverpool
Michelle Smith, PD Specialist Nurse, University Hospital Aintree, Liverpool
- Goldman JG and Litvan I . Mild Cognitive Impairment in Parkinson’s disease. Minerva Med. 2011 Dec; 102(6): 441–459.
- Petersen RC, Roberts RO, Knopman DS, Boeve BF, Geda YE, Ivnik RJ, Smith GE and Jack CR. Mild cognitive impairment: ten years later. Arch Neurol. 2009 Dec;66(12):1447–55.
- Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol. 1999 Mar; 56(3):303–8.
- Winblad B, Palmer K, Kivipelto M, Jelic V, Fratiglioni L, Wahlund LO, Nordberg A, Bäckman L, Albert M, Almkvist O, et al. Mild cognitive impairment--beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. J Intern Med. 2004 Sep; 256(3):240–6.
- Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, Gamst A, Holtzman DM. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011 May;7(3):270–9.
- Williams-Gray CH, Foltynie T, Brayne CE, Robbins TW, Barker RA. Evolution of cognitive dysfunction in an incident Parkinson’s disease cohort. Brain. 2007 Jul;130(Pt 7):1787–98.
- Aarsland D, Bronnick K, Williams-Gray C, Weintraub D, Marder K, Kulisevsky J, Burn D, Barone P, Pagonabarraga J, Allcock L, Santangelo G, Foltynie T, Janvin C, Larsen JP, Barker RA, Emre M. Mild cognitive impairment in Parkinson disease: a multicentre pooled analysis. Neurology. 2010 Sep 21;75(12):1062–9.
- Janvin C, Aarsland D, Larsen JP, Hugdahl K. Neuropsychological profile of patients with Parkinson’s disease without dementia. Dement Geriatr Cogn Disord. 2003;15(3):126–31.
- Aarsland D, Bronnick K, Janvin C, et al. Frequency and profile of mild cognitive impairment (MCI) in Parkinson’s disease: a multicentre meta-analysis of neuropsychological data. Movement Disorders. 2009;24(Suppl 1):S.
- Lopez OL, Jagust WJ, DeKosky ST, Becker JT, Fitzpatrick A, Dulberg C, Breitner J, Lyketsos C, Jones B, Kawas C, Carlson M, Kuller LH. Prevalence and classification of mild cognitive impairment in the Cardiovascular Health Study Cognition Study: part 1. Arch Neurol. 2003 Oct;60(10):1385–9.
- Busse A, Hensel A, Guhne U, Angermeyer MC, Riedel-Heller SG. Mild cognitive impairment: long-term course of four clinical subtypes. Neurology. 2006 Dec 26; 67(12):2176–85.
- Foltynie T, Brayne CE, Robbins TW, Barker RA. The cognitive ability of an incident cohort of Parkinson’s patients in the UK. The CamPaIGN study. Brain. 2004 Mar; 127(Pt 3):550–60.
- Dubois B, Pillon B. Cognitive deficits in Parkinson’s disease. J Neurol. 1997 Jan;244(1):2–8.
- Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K. Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res. 2004 Oct; 318(1):121–34.
- Tiraboschi P, Hansen LA, Alford M, Sabbagh MN, Schoos B, Masliah E, Thal LJ, Corey-Bloom J. Cholinergic dysfunction in diseases with Lewy bodies. Neurology 2000 Jan 25; 54(2):407–11.
- Braak H, Rub U, Jansen Steur EN, Del Tredici K, de Vos RA. Cognitive status correlates with neuropathologic stage in Parkinson disease. Neurology. 2005 Apr 26;64(8):1404–10.
- Adler CH, Caviness JN, Sabbagh MN, Shill HA, Connor DJ, Sue L, Evidente VG, Driver-Dunckley E, Beach TG.Heterogeneous neuropathological findings in Parkinson’s disease with mild cognitive impairment. Acta Neuropathol. 2010 Dec; 120(6):827–8.
- Emre M. Dementia associated with Parkinson’s disease. Lancet Neurol. 2003 Apr;2(4):229–37.
- Stebbins GT, Gabrieli JD, Masciari F, Monti L, Goetz CG. Delayed recognition memory in Parkinson’s disease: a role for working memory? Neuropsychologia. 1999 Apr;37(4):503–10.
- Filoteo JV, Rilling LM, Cole B, Williams BJ, Davis JD, Roberts JW. Variable memory profiles in Parkinson’s disease. J Clin Exp Neuropsychol. 1997 Dec;19(6):878–88.
- Kulisevsky J, Pagonabarraga J. Cognitive impairment in Parkinson’s disease: tools for diagnosis and assessment. Mov Disord. 2009 Jun 15;24(8):1103–10.
- Hoops S, Nazem S, Siderowf AD, Duda JE, Xie SX, Stern MB, Weintraub D. Validity of the MoCA and MMSE in the detection of MCI and dementia in Parkinson disease. Neurology. 2009 Nov 24;73(21):1738–45.
- Dalrymple-Alford JC, MacAskill MR, Nakas CT, Livingston L, Graham C, Crucian GP, Melzer TR, Kirwan J, Keenan R, Wells S, Porter RJ, Watts R, Anderson TJ. The MoCA: well-suited screen for cognitive impairment in Parkinson disease. Neurology. 2010 Nov 9;75(19):1717–25.
- Seto-Salvia N, Clarimon J, Pagonabarraga J, Pascual-Sedano B, Campolongo A, Combarros O, Mateo JI, et al. Dementia risk in Parkinson disease: disentangling the role of MAPT haplotypes. Arch Neurol. 2011 Mar;68(3):359–64.
- Beyer MK, Janvin CC, Larsen JP, Aarsland D. A magnetic resonance imaging study of patients with Parkinson’s disease with mild cognitive impairment and dementia using voxel-based morphometry. J Neurol Neurosurg Psychiatry. 2007 Mar;78(3):254–9.
- Maidment !, Fox C, and Boustani M. “Cholinesterase inhibitors for Parkinson's disease dementia,” Cochrane Database of Systematic Reviews 2006, issue 1, Article ID CD004747.
- Hanagasi HA, Gurvit H, Unsalan P, Horozoglu H, Tuncer N, Feyzioglu A, Gunal DI, Yener GG, Cakmur R, Sahin HA, Emre M. The effects of rasagiline on cognitive deficits in Parkinson’s disease patients without dementia: A randomized, double-blind, placebo-controlled, multicenter study. Mov Disord. 2011 Aug 15;26(10):1851-8.
- Cools R, Barker RA, Sahakian BJ, Robbins TW. Enhanced or impaired cognitive function in Parkinson’s disease as a function of dopaminergic medication and task demands. Cereb Cortex. 2001 Dec;11(12):1136–43.
- Paris AP, Saleta HG, de la Cruz Crespo Maraver M, Silvestre E, Freixa MG, Torrellas CP, et al. Blind randomized controlled study of the efficacy of cognitive training in Parkinson’s disease. Mov Disord. 2011 Jun;26(7):1251–8.
- Nombela C, Bustillo P J, Castel P. F, Sanchez L, Medina V, and Herrero M T. Cognitive rehabilitation in Parkinson’s disease: evidence from neuroimaging. Frontiers in Neurology 2011, vol. 2(82):1-11.