Neuropsychological Dysfunction in Early PD and in Those at Risk for PD: A Shift in Perspective

That neuropsychological declines accompany PD without dementia has been appreciated for some time. Studies in the 1980s and 1990s, though informing of the typical or “average” frontal-subcortical pattern of PD cognitive impairment, included patients with normal and mildly impaired cognition in PD groups without dementia, and confused early and mild disease (Levin & Katzen, Reference Levin and Katzen1995), thus potentially underestimating the extent of dysfunction and obscuring cognitive heterogeneity. Especially in the last 5 years there has been a shift in perspective, such that studies have attempted to isolate subgroups of PD with and without cognitive dysfunction (Figure 1) and to define the types of deficits observed.

Fig. 1 Schematic of shift in the conceptualization of Parkinson's disease (PD) without dementia and its progression to dementia.

Recent studies have attempted to elucidate extent and nature of cognitive impairments at or near the time of PD diagnosis. Three studies have shown that approximately one third of patients with PD have cognitive decrements on formal neuropsychological testing already at or near the time of PD diagnosis, even though they used a variety of tests and impairment criteria. In the CamPaIGN cohort (Foltynie, Brayne, Robbins, & Barker, Reference Foltynie, Brayne, Robbins and Barker2004) it was found that 36% of 159 newly diagnosed PD patients (mean age = 70.6 years; mean age at diagnosis = 70.3 years; mean UPDRS motor score = 26/108) had cognitive impairment defined by one or more of: MMSE (<24/30), CANTAB modified Tower of London (ToL; <8/14) and pattern recognition (PRM; <16/24). Among those persons with MMSE ≥ 24 who completed both other tasks (n = 134), 10% were impaired on the ToL only, 9% were impaired on PRM only, and 12% were impaired on both tasks (31% overall, non-dementia impairment rate).

A study of 115 newly diagnosed PD patients with MMSE ≥ 24 (mean age = 66.2 years; mean disease duration 18.8 months; mean UPDRS motor score = 17), used a wide-ranging neuropsychological test battery (Muslimovic, Post, Speelman, & Schmand, Reference Muslimovic, Post, Speelman and Schmand2005). By defining impairment as a score ≥2 SD below age appropriate norms, 24% of patients were impaired on at least three tests, and 39% were impaired on at least two tests (100% of patients had impairments on one or more tests). Most common were impairments on tests of attention and executive functions, consistent with the report that executive dysfunction (defined by poor performance on letter, category, and/or alternating verbal fluency) are common (41%) in PD (Kulisevsky, Pagonabarraga, Pascual-Sedano, Garcia-Sanchez, & Gironell, Reference Kulisevsky, Pagonabarraga, Pascual-Sedano, Garcia-Sanchez and Gironell2008). Another study (Elgh et al., Reference Elgh, Domellof, Linder, Edstrom, Stenlund and Forsgren2009) evaluated eight domains of cognition and defined impairment in a domain as more than 50% of single test results in a domain being ≥1.5 SD below normative means. Among 88 patients (MMSE ≥ 24; mean age = 68.1 years; mean UPDRS motor score 24; disease duration and age at diagnosis not provided), 30% had impairments in one or more domains of cognition. Overall, although studies have defined cognitive impairments on the basis of different tests and cutoff scores in PD patients near time of diagnosis, they have yielded fairly comparable estimates of the prevalence of cognitive changes.

Findings of cognitive changes near the time of PD diagnosis raise the question whether subtle cognitive decrements occur before PD diagnosis. One study examined cognition in persons defined as “at risk” for PD (Hawkins et al., Reference Hawkins, Jennings, Marek, Siderowf and Stern2010). Using a sample of persons 50 years or older who did or did not have a first degree relative with PD, groups without and with hyposmia, a common finding in early PD, were identified. Ninety-eight hyposmic and 50 normosmic subjects underwent dopamine transporter (DAT) scanning and neuropsychological evaluation. All 17 patients with DAT abnormalities were hyposmic (and, thus, 17/98 hyposmic patients had DAT abnormalities). Hyposmic subjects with DAT abnormalities (presumably at greatest risk for PD) performed significantly more poorly on tests of processing speed (WAIS-III) and executive functions (Trailmaking, semantic and letter verbal fluency) than hyposmic subjects without DAT abnormalities. In contrast, groups with and without DAT abnormalities did not differ on measures of verbal and visual memory, naming, and visuospatial reasoning and construction.

Mild Cognitive Impairment in PD

Instead of studying cognitive impairment in early PD (near time of diagnosis), other studies have attempted to define the domains of cognition compromised in mild cognitive impairment. Attempts to apply the concept of mild cognitive impairment (MCI) from Alzheimer's disease (AD) research to PD, although complicated by methodological and conceptual challenges (Dubois, Reference Dubois2007; Fernandez, Crucian, Okun, Price, & Bowers, Reference Fernandez, Crucian, Okun, Price and Bowers2005; Tröster, Reference Tröster2008), have borne fruit by highlighting heterogeneity of pre-PDD cognitive impairment. These studies are based on the idea that MCI is not a disease state but a syndrome and have generally followed recent classification schemes of MCI (i.e., amnestic vs. non-amnestic and single domain vs. multiple domain). Studies have shown a prevalence of MCI in PD of approximately 15–62% (Aarsland, Bronnick, Larsen, Tysnes, & Alves, Reference Aarsland, Bronnick, Larsen, Tysnes and Alves2009; Caviness et al., Reference Caviness, Driver-Dunckley, Connor, Sabbagh, Hentz, Noble and Adler2007; Hoops et al., Reference Hoops, Nazem, Siderowf, Duda, Xie, Stern and Weintraub2009; Janvin, Larsen, Aarsland, & Hugdahl, Reference Janvin, Larsen, Aarsland and Hugdahl2006; Mamikonyan et al., Reference Mamikonyan, Moberg, Siderowf, Duda, Have, Hurtig and Weintraub2009; Naismith, Pereira, Shine, & Lewis, Reference Naismith, Pereira, Shine and Lewis2010; Sollinger, Goldstein, Lah, Levey, & Factor, Reference Sollinger, Goldstein, Lah, Levey and Factor2010; Song, Kim, Jeong, Song, & Lee, Reference Song, Kim, Jeong, Song and Lee2008).

The wide prevalence range likely reflects differences in MCI definition and sample characteristics (see Table 1). The highest rates are reported by studies that used either clinician consensus or impairment on a single test to define MCI. The lowest rate was reported when a 2 SD below the mean score cutoff was used. Most common are estimates of approximately 30% and generally, single domain MCI is more common than multiple domain MCI and non-amnestic MCI is more common than amnestic MCI. One study found that amnestic MCI is more common when single and multiple domain estimates are combined (Aarsland et al., Reference Aarsland, Bronnick, Williams-Gray, Weintraub, Marder, Kulisevsky and Emre2010). In a retrospective study of eight patients with autopsy verified Lewy body disease (7 with clinical DLB), five initially had non-amnestic MCI (Molano et al., Reference Molano, Boeve, Ferman, Smith, Parisi, Dickson and Petersen2010). Early detection of non-amnestic MCI is important given preliminary evidence that atomoxetine, a selective norepinephrine reuptake inhibitor (Marsh, Biglan, Gerstenhaber, & Williams, Reference Marsh, Biglan, Gerstenhaber and Williams2009; Weintraub et al., Reference Weintraub, Mavandadi, Mamikonyan, Siderowf, Duda, Hurtig and Stern2010) and cognitive rehabilitation might alleviate executive or cognitive dysfunction in PD (Sammer, Reuter, Hullmann, Kaps, & Vaitl, Reference Sammer, Reuter, Hullmann, Kaps and Vaitl2006; Sinforiani, Banchieri, Zucchella, Pacchetti, & Sandrini, Reference Sinforiani, Banchieri, Zucchella, Pacchetti and Sandrini2004).

Table 1 Studies of mild cognitive impairment (MCI) subtypes and prevalence in Parkinson's disease (PD) (studies using only cognitive screening instruments or not explicitly defining MCI criteria were excluded)

CERAD = Consortium to Establish a registry for Alzheimer's Disease; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; MCI = mild cognitive impairment; MMSE = Mini Mental State Exam; NA = not available; PDD = Parkinson's disease dementia.

Progression of Early and Mild Cognitive Impairment in PD

Studies of the progression of cognitive impairment in PD without dementia have generally found modest to small declines over relatively short re-test intervals. A meta-analysis of 25 longitudinal studies of 901 patients (average disease duration approximately 8 years; mean follow-up 29 months) observed the largest declines (albeit of small effect sizes, not exceeding d = .40) among eight domains in overall level of cognition, visuoconstruction, and memory (Muslimovic, Schmand, Speelman, & De Haan, Reference Muslimovic, Schmand, Speelman and De Haan2007), and these declines were generally associated with advancing age and lower education. Similarly, when examining change among individual patients rather than groups, patients re-evaluated after approximately 18 months tended to rarely (<10%) show gains or declines exceeding reliable change indices corrected for practice effect in fluency, naming, memory, visuoperceptual, and executive function tests (Tröster, Woods, & Morgan, Reference Tröster, Woods and Morgan2007).

What is less well studied is how cognitive deficits progress in newly or recently diagnosed patients. One study compared neuropsychological performance in newly diagnosed patients and patients with established PD (average disease duration 6.5 years) over approximately 3 years (Muslimovic, Post, Speelman, De Haan, & Schmand, Reference Muslimovic, Post, Speelman, De Haan and Schmand2009). The newly diagnosed patients demonstrated declines especially in attention and psychomotor speed (Trailmaking A and B) and impairments on Trailmaking Part B were noted in 21% at 3-year follow-up compared to 11% at baseline. The established patients too showed declines in attention and psychomotor speed, but also on constructional tasks. The newly diagnosed patients showed a greater decrease than healthy controls on 20 of 27 measures, and 48% evidenced changes in a multivariate measure exceeding the 5th percentile in controls (a similar analysis showed that 50% of established PD showed declines). Of the newly diagnosed patients, 8.5% were demented at follow-up, either by neuropsychological test criteria or neurologist diagnosis. This dementia incidence is similar to that (10%) observed among recently diagnosed patients after 3.5-year follow-up in the Cambridge cohort (Williams-Gray, Foltynie, Brayne, Robbins, & Barker, Reference Williams-Gray, Foltynie, Brayne, Robbins and Barker2007).

Neurocognitive Predictors of Dementia

The majority of prospective and retrospective studies demonstrate the importance of frontal/executive dysfunction in the prediction of dementia in PD. Predictive tasks include: Lurian tasks (Piccirilli, D'Alessandro, Finali, Piccinin, & Agostini, Reference Piccirilli, D'Alessandro, Finali, Piccinin and Agostini1989), Raven Matrices (Reid et al., Reference Reid, Hely, Morris, Broe, Adena, Sullivan and Williamson1996), perseverative errors on the Wisconsin Card Sorting Test (Woods & Tröster, Reference Woods and Tröster2003), letter verbal fluency (Mahieux et al., Reference Mahieux, Fenelon, Flahault, Manifacier, Michelet and Boller1998), identification of similarities and differences on the Dementia Rating Scale (Jacobs et al., Reference Jacobs, Marder, Cote, Sano, Stern and Mayeux1995), and the Stroop interference task (Janvin, Aarsland, & Larsen, Reference Janvin, Aarsland and Larsen2005; Mahieux et al., Reference Mahieux, Fenelon, Flahault, Manifacier, Michelet and Boller1998). Tests on which performance is thought to be primarily mediated by more posterior brain regions, however, also may have predictive value and include tests of memory (Jacobs et al., Reference Jacobs, Marder, Cote, Sano, Stern and Mayeux1995; Reid et al., Reference Reid, Hely, Morris, Broe, Adena, Sullivan and Williamson1996; Woods & Tröster, Reference Woods and Tröster2003), semantic verbal fluency (Jacobs et al., Reference Jacobs, Marder, Cote, Sano, Stern and Mayeux1995; Williams-Gray et al., Reference Williams-Gray, Foltynie, Brayne, Robbins and Barker2007), and visual attention, perception, and/or construction (Mahieux et al., Reference Mahieux, Fenelon, Flahault, Manifacier, Michelet and Boller1998; Williams-Gray et al., Reference Williams-Gray, Foltynie, Brayne, Robbins and Barker2007). Only one study examined MCI in the prediction of dementia, and in that study, single domain non-amnestic MCI and multiple domain MCI were associated with dementia after 4-year follow-up (Janvin et al., Reference Janvin, Larsen, Aarsland and Hugdahl2006). Specifically, 59 patients (85%) completed 4-year follow-up, including 29 (76%) of those with MCI at baseline and 30 (88%) of those cognitively intact at baseline. By follow-up 62% of those with baseline MCI had dementia, whereas only 20% of those intact at baseline had developed dementia 4 years later. Significantly higher proportions of those with single domain, non-amnestic MCI (69%) or multiple domain MCI (63%) than those with single domain amnestic MCI (40%) developed dementia.

In the CamPaIGN cohort, decline in cognition (MMSE score) by 3.5 year follow-up was associated with “below average performance” on executive function tests (ToL), semantic fluency, visuoconstructional skill (pentagon copy) and spatial recognition memory (SRM) at baseline, though most strongly associated with poor fluency and pentagon copy independent of age (Williams-Gray et al., Reference Williams-Gray, Foltynie, Brayne, Robbins and Barker2007). The latter were also predictors of dementia at 5-year follow-up (Williams-Gray et al., Reference Williams-Gray, Evans, Goris, Foltynie, Ban, Robbins and Barker2009).

Neuropathologic Correlates of Cognitive Impairment and Progression in PD

The prospective Sydney Multicenter Study of PD (Halliday & McCann, Reference Halliday and McCann2010) identified three cognitive phenotypes of patients: (1) a group with early, prominent dementia and akinetic-rigid PD (corresponding clinically to DLB); (2) a group of older (greater than 70 years) PD patients developing dementia in 3–10 years (corresponding clinically to PDD) who have widespread alpha-synuclein pathology; and (3) a younger PD group (disease onset before 70 years) who may remain cognitively intact for some time (dementia occurs late in the disease, after 10 to 15 years) and who have a cell-loss dominant pathology with lesser alpha-synuclein deposition. Congruently, another study reported that PD patients developing dementia late in the disease (after approximately 10 years) had less cortical alpha-synuclein pathology (and fewer plaques) but greater cholinergic abnormalities than those developing dementia early on, whose pathology resembled that of DLB (Ballard et al., Reference Ballard, Ziabreva, Perry, Larsen, O'Brien, McKeith and Aarsland2006). How these differences in progression to dementia are related to various cognitive phenotypes in early PD and PD-MCI remains unknown.

By the time of clinical PD diagnosis (usually at Braak stage III or IV, when Lewy bodies and neurites extend to midbrain, including the substantia nigra, basal forebrain, transentorhinal cortex and the hippocampal CA2 cell field) (Braak et al., Reference Braak, Tredici, Rüb, de Vos, Jansen Steur and Braak2003) cognitive impairments may be detectable in some patients even on cognitive screening instruments (Braak, Rub, Jansen Steur, Del Tredici, & de Vos, Reference Braak, Rub, Jansen Steur, Del Tredici and de Vos2005). Once MCI is apparent, pathology is likely heterogeneous. An autopsy series of eight persons with PD-MCI (heterogeneous in cognitive domains affected), found highly variable pathology (Adler et al., Reference Adler, Caviness, Sabbagh, Shill, Connor, Sue and Beach2010): five of the eight cases had limbic and/or neocortical Lewy bodies, while three had only brainstem Lewy bodies. Only three cases had no neuritic plaques. Two cases (both with amnestic MCI) met neuropathologic criteria for AD. Concomitant cerebrovascular pathology was observed in three cases.

Amyloid-beta pathology biomarkers associated with AD and amnestic MCI [especially reductions in cerebrospinal fluid (CSF) Aβ-42] may be evident in PD (Alves et al., Reference Alves, Bronnick, Aarsland, Blennow, Zetterberg, Ballard and Mulugeta2010) and PD-MCI (Montine et al., Reference Montine, Shi, Quinn, Peskind, Craft, Ginghina and Zhang2010), and associated with more rapid cognitive decline (Siderowf et al., Reference Siderowf, Xie, Hurtig, Weintraub, Duda, Chen-Plotkin and Clark2010), processing speed and semantic verbal fluency (Leverenz et al., Reference Leverenz, Stennis Watson, Shofer, Zabetian, Zhang and Montine2010), and memory deficits in early, untreated patients (Alves et al., Reference Alves, Bronnick, Aarsland, Blennow, Zetterberg, Ballard and Mulugeta2010). Unfortunately amyloid imaging (PIB binding) has generally not been informative in PD (see below). CSF markers of Tau in early PD appear unremarkable and unrelated to cognitive status (Alves et al., Reference Alves, Bronnick, Aarsland, Blennow, Zetterberg, Ballard and Mulugeta2010).

Neuroimaging Correlates of Cognitive Impairment in PD

Cholinergic abnormalities have been implicated in the neurobehavioral changes in PDD (Mattila et al., Reference Mattila, Roytta, Lonnberg, Marjamaki, Helenius and Rinne2001) and PD-MCI (Choi et al., Reference Choi, Jung, Lee, Lee, Sohn and Lee2011) and functional imaging studies are beginning to yield corroborating evidence in this regard. Cortical acetylcholinesterase (AChE) activity has been imaged in vivo using [11C] methyl-4-piperidinyl propionate (PMP) or [11C] methyl-4-piperidyl acetate (MP4A). Decreased PMP activity has been associated with depression (Bohnen et al., Reference Bohnen, Kaufer, Hendrickson, Constantine, Mathis and Moore2007) and working memory and executive deficits in PD and PDD (Bohnen et al., Reference Bohnen, Kaufer, Hendrickson, Ivanco, Lopresti, Constantine and Dekosky2006). Cross-sectional studies of small samples agree that MP4A binding reductions, especially in posterior brain regions, occur in PD without dementia and are less pronounced than in PDD (Klein et al., Reference Klein, Eggers, Kalbe, Weisenbach, Hohmann, Vollmar and Hilker2010; Shimada et al., Reference Shimada, Hirano, Shinotoh, Aotsuka, Sato, Tanaka and Irie2009). These findings’ importance in elucidating a biologic basis of specific cognitive impairments in early PD or PD-MCI, and their progression to PDD, is difficult to define given the very small sample sizes. Furthermore, the PD patients without dementia in one study already had marked cognitive impairments, having scored ≥2 SD below normative means on list learning and verbal fluency tasks (Klein et al., Reference Klein, Eggers, Kalbe, Weisenbach, Hohmann, Vollmar and Hilker2010) and in the other study no cholinergic abnormality differences were found between early (≤3 years) and advanced (>3 years) disease duration) PD groups (Shimada et al., Reference Shimada, Hirano, Shinotoh, Aotsuka, Sato, Tanaka and Irie2009).

SPECT has also implicated posterior (parietal and occipital) resting state metabolic abnormalities in PD with amnestic MCI (Nobili et al., Reference Nobili, Abbruzzese, Morbelli, Marchese, Girtler, Dessi and Rodriguez2009), and multiple (but not single) domain MCI was related to prefrontal and parietal glucose hypometabolism in comparison to PD without cognitive impairment (Huang et al., Reference Huang, Mattis, Perrine, Brown, Dhawan and Eidelberg2008). Similarly, CDR-defined PD-MCI has been associated with posterior, especially parieto-temporal glucose hypometabolism in comparison to PD without cognitive impairment (Hosokai et al., Reference Hosokai, Nishio, Hirayama, Takeda, Ishioka, Sawada and Mori2009).

Dopaminergic augmentation has no profound impact on cognition in PD, but very specific aspects of cognition may be impacted transiently, especially during the early stages of the disease (Owen, Iddon, Hodges, Summers, & Robbins, Reference Owen, Iddon, Hodges, Summers and Robbins1997; Owen et al., Reference Owen, Sahakian, Hodges, Summers, Polkey and Robbins1995) and correlated with functional imaging (Cools, Stefanova, Barker, Robbins, & Owen, Reference Cools, Stefanova, Barker, Robbins and Owen2002). Caudate dopaminergic abnormalities have been related especially to executive dysfunction in newly diagnosed PD patients (Nobili et al., Reference Nobili, Campus, Arnaldi, De Carli, Cabassi, Brugnolo and Rodriguez2010).

Measurement of amyloid load by [11C] PIB PET imaging has revealed that only a minority of PDD patients (16–33%) has increased PIB uptake (Edison et al., Reference Edison, Rowe, Rinne, Ng, Ahmed, Kemppainen and Brooks2008; Maetzler et al., Reference Maetzler, Liepelt, Reimold, Reischl, Solbach, Becker and Berg2009). These and other studies (Foster et al., Reference Foster, Campbell, Burack, Hartlein, Flores, Cairns and Perlmutter2010; Gomperts et al., Reference Gomperts, Rentz, Moran, Becker, Locascio, Klunk and Johnson2008; Jokinen et al., Reference Jokinen, Scheinin, Aalto, Nagren, Savisto, Parkkola and Rinne2010) have failed to reveal PIB binding abnormalities in PD patients without dementia, though parietal PIB uptake has been associated with visuospatial test performance (Gomperts et al., Reference Gomperts, Rentz, Moran, Becker, Locascio, Klunk and Johnson2008). The contradiction with CSF biomarker findings might reflect that patients in the CSF biomarker studies were probably more heterogeneous in severity of cognitive impairment than in the imaging studies.

Cognition in Early PD and Genetics

Studies examining the role of genetic risk factors for AD in PDD (e.g., apolipoprotein E4) have yielded inconclusive findings (Huang, Chen, Kaufer, Troster, & Poole, Reference Huang, Chen, Kaufer, Troster and Poole2006) and the association of the H1/H1 haplotype of the microtubule associated protein (MAP) gene encoding for tau protein (a component of neurofibrillary tangles) with PDD (Goris et al., Reference Goris, Williams-Gray, Clark, Foltynie, Lewis, Brown and Sawcer2007; Williams-Gray et al., Reference Williams-Gray, Evans, Goris, Foltynie, Ban, Robbins and Barker2009), awaits independent replication.

Studies of neurobehavioral correlates of genetic polymorphisms implicated in other disorders, for example, brain derived neurotrophic factor (BDNF) (Foltynie et al., Reference Foltynie, Lewis, Goldberg, Blackwell, Kolachana, Weinberger and Barker2005), cathechol-O-methyl-transferase (COMT) (Foltynie et al., Reference Foltynie, Goldberg, Lewis, Blackwell, Kolachana, Weinberger and Barker2004; Williams-Gray et al., Reference Williams-Gray, Evans, Goris, Foltynie, Ban, Robbins and Barker2009; Williams-Gray, Hampshire, Barker, & Owen, Reference Williams-Gray, Hampshire, Barker and Owen2008) have not been replicated (Hoogland et al., Reference Hoogland, de Bie, Williams-Gray, Muslimovic, Schmand and Post2010) or yielded inconsistent results. Studies of polymorphisms and mutations associated with familial PD, namely in leucine-rich repeat kinase 2 (LRRK2) (Healy et al., Reference Healy, Falchi, O'Sullivan, Bonifati, Durr, Bressman and Wood2008) and parkin (PARK2) (Lohmann et al., Reference Lohmann, Thobois, Lesage, Broussolle, du Montcel, Ribeiro and Brice2009), and in glucoceribrosidase (GBA) (Alcalay et al., Reference Alcalay, Mejia-Santana, Tang, Rakitin, Rosado, Ross and Caccappolo2010) which has been associated with DLB, have yielded negative findings. Future studies using a variety of sensitive neuropsychological measures in large samples are much needed.

Mild Cognitive Impairment: Preliminary Research Criteria

Given the variety of definitions of MCI to date, and the importance of this construct in detecting (and potentially treating) pre-PDD, uniform criteria are needed. The criteria proposed here are preliminary and offered for empirical evaluation. A two tier approach to “MCI” definition in PD is suggested. The first category is a general PD-MCI category in which cognitive impairment is evident in PD without dementia, but an etiologic attribution is not required. That is, the impairment may be related to PD or possibly attributed to other conditions such as depression or co-existing vascular impairment, or be of a qualitative pattern that suggests the possibility of another condition (e.g., early AD or DLB). The term “possible MCI” is not chosen here as such a term might convey uncertainty about the presence rather than etiology of MCI. The possibility of moving into and out of this category is illustrated in Figure 1, with possible change in diagnostic classification over time perhaps related to measurement error, etiology of MCI, co-morbidities such as REM sleep behavior disorder (Gagnon et al., Reference Gagnon, Vendette, Postuma, Desjardins, Massicotte-Marquez, Panisset and Montplaisir2009), and treatment effects. In the second category, MCI is confidently attributed to PD. Consequently this clinical entity is referred to as PCI or Parkinson Cognitive Impairment, rather than by the more ambiguous “probable” PD-MCI. The label PCI makes clear the need to distinguish general MCI (often associated with AD and theoretically present in, but independent of PD) from PCI. The diagnostic criteria for the two categories are presented in Tables 2 and 3.

Table 2 Criteria for Parkinson's disease with mild cognitive impairment (PD-MCI)

Table 3 Criteria for Parkinson cognitive impairment (PCI)

The criteria attempt to be congruent with the DSM-V draft criteria for Mild Neurocognitive Disorder (Jeste et al., Reference Jeste, Blacker, Blazer, Ganguli, Grant, Paulsen and Sachdev2010) and current PDD criteria (Emre et al., Reference Emre, Aarsland, Brown, Burn, Duyckaerts, Mizuno and Dubois2007). It is beyond the scope of a brief review to provide a detailed rationale for each aspect of the research criteria, and (as is the case for any set of research diagnostic criteria) clinical judgment will be required in arriving at a diagnosis. Subjective complaint of cognitive problems is required. Mild impairments in cognition do not appear to preclude valid self-report of disability (Brown, MacCarthy, Jahanshahi, & Marsden, Reference Brown, MacCarthy, Jahanshahi and Marsden1989), although PD patients might be biased to reporting memory problems as their first cognitive complaint (Noe et al., Reference Noe, Marder, Bell, Jacobs, Manly and Stern2004). An absence of significant compromise in instrumental activities of daily living (iADL) should be queried over a broad range of iADLs because MCI in different domains may impact different aspects of iADL (Bangen et al., Reference Bangen, Jak, Schiehser, Delano-Wood, Tuminello, Han and Bondi2010). Impairments or declines on multiple neuropsychological or cognitive tests are recommended because this enhances diagnostic reliability, especially in non-amnestic MCI (Jak et al., Reference Jak, Bondi, Delano-Wood, Wierenga, Corey-Bloom, Salmon and Delis2009). Furthermore, if the base rate of having at least one impaired score (−2 SD) in two different cognitive domains is approximately 5% in healthy elderly (Palmer, Boone, Lesser, & Wohl, Reference Palmer, Boone, Lesser and Wohl1998), one assumes that this approach is adequately conservative in PD, where a neurologic diagnosis already exists and the a priori probability of cognitive impairment is probably greater. A rigid use of a cutoff of ≥1.5 SD below means might be eschewed for that same reason. Consistent with DSM draft criteria, perhaps more relaxed criteria (1–2 SD below means) can be used. The possibility of defining PD-MCI on the basis of declines from premorbid levels of cognitive function [or when prior testing is available, preferably using reliable change index scores (Tröster et al., Reference Tröster, Woods and Morgan2007)] is consistent with DSM-V draft criteria and perhaps alleviates the problem of not detecting MCI in high functioning persons ≥0.5 SD above the mean who would need to show declines in excess of 2 SD to meet definitions based on a 1.5 SD cutoff. Table 4 provides a list of preferred tests for establishing PD-MCI or PCI, though this list is intended to be neither prescriptive nor exhaustive and will no doubt change as new or existing tests receive greater validation for use in PD.

Table 4 Recommended tests for use in PD-MCI and PCI research

Summary

Cognitive impairment is heterogeneous and present in approximately 30% of persons at time of PD diagnosis and subtle declines may be evident in at-risk populations. Attention and executive deficits, likely related to dopaminergic abnormalities, are among the most common cognitive changes in early PD and they typically progress slowly over time. Progression to dementia is highly variable and at least three possible phenotypes have been identified, with those showing earlier and more rapid dementia development neuropathologically resembling DLB, and those developing dementia late (more than 10 years after diagnosis) having more cell loss, less alpha-synuclein deposition, and greater cholinergic abnormalities. Point prevalence of MCI is approximately 25–30%, though MCI identification is challenging in the absence of diagnostic criteria. Whether subtypes of MCI have prognostic significance remains unclear, as is the neurobiological basis of the various subtypes. Pathology of MCI is heterogeneous. While AD pathology exists in a minority of PD patients, and CSF biomarkers of amyloid abnormalities may herald cognitive decline, these markers may not reflect cerebral plaque formation given that brain imaging has not linked amyloid deposition to cognitive deficits. Similarly, the finding of increased dementia risk conferred by the H1/H1 haplotype of the MAP gene encoding for tau remains to be replicated. Recent imaging implicates especially posterior resting and glucose metabolic and cholinergic deficits in dementia and amnestic and multiple-domain MCI in PD, but the predictive utilities of these measures is unknown. Similarly, although impairment on neuropsychological tests sensitive to posterior cerebral dysfunction might increase risk of cognitive decline and dementia, it is unclear if superimposition of “posterior” upon “anterior” or executive deficits is an artifact of the very definition of dementia (involving impairment of multiple cognitive domains) or a bias in studying patients developing more pronounced cognitive impairments relatively soon after PD diagnosis. Better understanding of the evolution of PDD will benefit from use of consistent MCI criteria and preliminary research criteria were provided in this study. Early identification of cognitive changes, especially those amenable to treatment, may reduce morbidity and enhance quality of life.