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Subjective cognitive complaints are important in PD-MCI criteria: Associations with CSF markers and cognitive decline

Open AccessPublished:November 16, 2022DOI:https://doi.org/10.1016/j.parkreldis.2022.11.013

      Highlights

      • Mild cognitive impairment (PD-MCI) criteria require cognitive complaints (SCC).
      • A majority of studies do not utilize SCC when classifying PD-MCI.
      • Inclusion/exclusion of SCC affects the occurrence of PD-MCI.
      • Inclusion of SCC improves prediction of Alzheimer's pathology from CSF ratios.
      • Failure to utilize the SCC criterion may dilute important associations.

      Abstract

      Introduction

      According to the Movement Disorder Society (MDS), subjective cognitive complaints (SCC) are a diagnostic criterion for PD-mild cognitive impairment (PD-MCI); however, studies often do not incorporate SCC when classifying PD-MCI. This inconsistent use may reflect mixed findings regarding the association between SCC and objective measures of cognitive impairment. Our study aimed to describe the extent that inclusion/exclusion of SCC affects the occurrence of PD-MCI, and if the inclusion of SCC is associated with faster cognitive decline and cerebrospinal fluid markers (CSF) of alpha-synuclein, amyloid beta, total tau, and phophorylated-tau.

      Methods

      Individuals with PD (N = 358) from the PPMI cohort whom completed measures of neuropsychological performance, subjective cognitive complaints, motor severity, and CSF markers were included. Participants were classified as cognitively normal (CN), PD-MCI with subjective cognitive complaints (PD-MCI + SCC) and PD-MCI without subjective cognitive complaints (PD-MCI –SCC).

      Results

      PD-MCI rates were consistently higher (16.5–19.1%) across the 5 years when SCC was not included in the diagnostic criteria as opposed to when SCC was included (4.4–11.0%). PD-MCI + SCC experienced greater cognitive decline and had significantly higher levels of tau/ab and p-tau/ab relative to both the CN and PD-MCI - SCC groups.

      Conclusions

      Inconsistent implementation of an SCC requirement in PD-MCI classifications may have important implications in terms of the occurrence of PD-MCI and its prognostic value. Classifying PD-MCI only using neuropsychological cut-off criterion, without regard to SCC, may lead to higher rates of PD-MCI. Inclusions of SCC in PD-MCI criteria in newly diagnosed PD participants may strengthen the ability to detect individuals at risk for future cognitive decline, though it is possible that this decline is related to Alzheimer's disease changes rather than worse PD pathology.

      Keywords

      1Introduction

      Parkinson's Disease (PD) is a neurodegenerative disorder occurring mostly in the older adult population and is characterized by both motor and non-motor symptoms. One common non-motor symptom is cognitive impairment. Some symptoms of cognitive impairment in PD patients include deficits in attention, executive functioning, and memory [
      • Svenningsson P.
      • Westman E.
      • Ballard C.
      • Aarsland D.
      Cognitive impairment in patients with Parkinson's disease: diagnosis, biomarkers, and treatment.
      ]. Development of severe cognitive impairments in the form of Parkinson's disease dementia (PDD) is seen in 83% of PD patients within 20 years of disease duration [
      • Hely M.A.
      • Reid W.G.
      • Adena M.A.
      • Halliday G.M.
      • Morris J.G.
      The Sydney multicenter study of Parkinson's disease: the inevitability of dementia at 20 years.
      ]. The time of onset from the initial PD diagnosis is varied, with a mean of 10.9 years [
      • Hely M.A.
      • Reid W.G.
      • Adena M.A.
      • Halliday G.M.
      • Morris J.G.
      The Sydney multicenter study of Parkinson's disease: the inevitability of dementia at 20 years.
      ]. Once PDD has onset, patients have a median survival rate of 54 months [
      • Hely M.A.
      • Reid W.G.
      • Adena M.A.
      • Halliday G.M.
      • Morris J.G.
      The Sydney multicenter study of Parkinson's disease: the inevitability of dementia at 20 years.
      ].
      Parkinson's Disease Mild Cognitive Impairment (PD-MCI) is defined as cognitive decline that is greater than average for the individual's age, but not severe enough to interfere with independence in daily functioning [
      • Gauthier S.
      • Reisberg B.
      • Zaudig M.
      • Petersen R.C.
      • Ritchie K.
      • Broich K.
      • Belleville S.
      • Brodaty H.
      • Bennett D.
      • Chertkow H.
      • Cummings J.L.
      Mild cognitive impairment.
      ,
      • Litvan I.
      • Aarsland D.
      • Adler C.H.
      • Goldman J.G.
      • Kulisevsky J.
      • Mollenhauer B.
      • Rodriguez‐Oroz M.C.
      • Tröster A.I.
      • Weintraub D.
      MDS Task Force on mild cognitive impairment in Parkinson's disease: critical review of PD‐MCI.
      ]. Among PD cohort studies, 19–55% of PD patients met the diagnostic criteria for PD-MCI [
      • Litvan I.
      • Aarsland D.
      • Adler C.H.
      • Goldman J.G.
      • Kulisevsky J.
      • Mollenhauer B.
      • Rodriguez‐Oroz M.C.
      • Tröster A.I.
      • Weintraub D.
      MDS Task Force on mild cognitive impairment in Parkinson's disease: critical review of PD‐MCI.
      ,
      • Goldman J.G.
      • Litvan I.
      Mild cognitive impairment in Parkinson's disease.
      ]. PD-MCI has become a topic of interest because PD-MCI predicts a shorter time to development of PDD compared to cognitively normal PD patients [
      • Aarsland D.
      • Brønnick K.
      • Fladby T.
      Mild cognitive impairment in Parkinson's disease.
      ]. From a systematic review of 39 articles, approximately 20% of those with PD-MCI converted to PDD within 3 years [
      • Saredakis D.
      • Collins-Praino L.E.
      • Gutteridge D.S.
      • Stephan B.C.
      • Keage H.A.
      Conversion to MCI and dementia in Parkinson's disease: a systematic review and meta-analysis.
      ].
      PD-MCI diagnostic criteria from the Movement Disorder Society (MDS) requires both a subjective cognitive complaint (SCC) and objective cognitive deficits on neuropsychological tests [
      • Litvan I.
      • Goldman J.G.
      • Tröster A.I.
      • Schmand B.A.
      • Weintraub D.
      • Petersen R.C.
      • Mollenhauer B.
      • Adler C.H.
      • Marder K.
      • Williams‐Gray C.H.
      • Aarsland D.
      Diagnostic criteria for mild cognitive impairment in Parkinson's disease: Movement Disorder Society Task Force guidelines.
      ]. SCC are commonly defined as a patient, caregiver/study partner, or clinician observation of declines in cognitive abilities [
      • Litvan I.
      • Goldman J.G.
      • Tröster A.I.
      • Schmand B.A.
      • Weintraub D.
      • Petersen R.C.
      • Mollenhauer B.
      • Adler C.H.
      • Marder K.
      • Williams‐Gray C.H.
      • Aarsland D.
      Diagnostic criteria for mild cognitive impairment in Parkinson's disease: Movement Disorder Society Task Force guidelines.
      ]. Prior to the publication of the MDS PD-MCI criteria, a critical review of eight studies on PD-MCI found that only one study used SCC as a diagnostic criterion for PD-MCI [
      • Litvan I.
      • Aarsland D.
      • Adler C.H.
      • Goldman J.G.
      • Kulisevsky J.
      • Mollenhauer B.
      • Rodriguez‐Oroz M.C.
      • Tröster A.I.
      • Weintraub D.
      MDS Task Force on mild cognitive impairment in Parkinson's disease: critical review of PD‐MCI.
      ,
      • Hoops S.
      • Nazem S.
      • Siderowf A.D.
      • Duda J.E.
      • Xie S.X.
      • Stern M.B.
      • Weintraub D.
      Validity of the MoCA and MMSE in the detection of MCI and dementia in Parkinson disease.
      ]. A more recent review found 207 studies that used the MDS PD-MCI criteria but did not mention or use SCC in their criteria [
      • Kjeldsen P.L.
      • Damholdt M.F.
      Subjective cognitive complaints in patients with Parkinson's disease.
      ]. In contrast, only 112 studies did utilize the SCC criterion; albeit only 26 of the 112 studies operationally defined SCC [
      • Kjeldsen P.L.
      • Damholdt M.F.
      Subjective cognitive complaints in patients with Parkinson's disease.
      ]. Clearly, there is inconsistent utilization of SCC in PD-MCI classifications despite clearly published criteria.
      One potential reason for the inconsistent use of SCC in PD-MCI criteria is that studies demonstrating an association between SCC and cognitive impairment are mixed. One study found no association between SCC and PD-MCI nor cognitive decline over time [
      • AlDakheel A.
      • Gasca-Salas C.
      • Armstrong M.J.
      • Duff-Canning S.
      • Marras C.
      Cognitive complaints in nondemented Parkinson's disease patients and their close contacts do not predict worse cognitive outcome.
      ]. However, other studies have reported an association between SCC and objective measures of cognitive impairment. The Vienna Mild Cognitive Impairment and Cognitive Decline in Parkinson's Disease Study included 248 healthy controls and 104 PD patients [
      • Lehrner J.
      • Moser D.
      • Klug S.
      • Gleiß A.
      • Auff E.
      • Pirker W.
      • Pusswald G.
      Subjective memory complaints, depressive symptoms and cognition in Parkinson's disease patients.
      ]. They found that only 7% of controls reported SCC compared to 16% of PD patients [
      • Lehrner J.
      • Moser D.
      • Klug S.
      • Gleiß A.
      • Auff E.
      • Pirker W.
      • Pusswald G.
      Subjective memory complaints, depressive symptoms and cognition in Parkinson's disease patients.
      ]. This percentage increased to 31% reporting SCC in PD patients who also showed memory deficits on neuropsychological testing. Another study found that the severity of SCC was correlated with objective cognitive performance as measured by the Korean versions of the Mini Mental State Examination and the Montreal Cognitive Assessment (MOCA) [
      • Hong J.Y.
      • Lee Y.
      • Sunwoo M.K.
      • Sohn Y.H.
      • Lee P.H.
      Subjective cognitive complaints and objective cognitive impairment in Parkinson's disease.
      ]. Similarly, Purri et al. found PD patients with SCC displayed worse global cognition than PD patients without SCC, suggesting SCC may be prognostically useful in identifying cognitive impairment [
      • Purri R.
      • Brennan L.
      • Rick J.
      • Xie S.X.
      • Deck B.L.
      • Chahine L.M.
      • Dahodwala N.
      • Chen‐Plotkin A.
      • Duda J.E.
      • Morley J.F.
      • Akhtar R.S.
      Subjective cognitive complaint in Parkinson's disease patients with normal cognition: canary in the coal mine?.
      ].
      Cerebrospinal fluid (CSF) biomarkers such as tau and amyloid beta (ab) are associated with cognitive dysfunction in PD. Higher amounts of CSF total (t-tau) and phosphorylated tau (p-tau) were associated with poorer global cognition performance as measured by the Mini Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) [
      • Compta Y.
      • Martí M.J.
      • Ibarretxe-Bilbao N.
      • Junqué C.
      • Valldeoriola F.
      • Muñoz E.
      • Ezquerra M.
      • Ríos J.
      • Tolosa E.
      Cerebrospinal tau, phosphor-tau, and beta-amyloid and neurological functions in Parkinson's disease.
      ,
      • Bellemo G.
      • Paolini Paoletti F.
      • Chipi E.
      • Petricciuolo M.
      • Simoni S.
      • Tambasco N.
      • Parnetti L.
      Profile in cerebrospinal fluid of Parkinson's disease with/without cognitive impairment and dementia with lewy bodies.
      ]. The Norwegian ParkWest Study found CSF markers of amyloid burden were associated with memory impairment among individuals newly diagnosed with PD [
      • Alves G.
      • Brønnick K.
      • Aarsland D.
      • Blennow K.
      • Zetterberg H.
      • Ballard C.
      • Kurz M.
      • Andreasson U.
      • Tysnes O.
      • Larsen J.
      • Mulugeta E.
      CSF amyloid-β and tau proteins, and cognitive performance, in early and untreated Parkinson's Disease: the Norwegian ParkWest study.
      ]. Post-mortem mortem findings revealed that 75% of individuals with PD-MCI had significant amount of Alzheimer's pathology in the hippocampus and limbic regions (i.e. Braak stage III & IV) [
      • Adler C.H.
      • Caviness J.N.
      • Sabbagh M.N.
      • Shill H.A.
      • Connor D.J.
      • Sue L.
      • Evidente V.G.
      • Driver-Dunckley E.
      • Beach T.G.
      Heterogeneous neuropathological findings in Parkinson's disease with mild cognitive impairment.
      ]. Additionally, cortical amyloid or tau pathology (i.e. Braak stage V & VI) are present in 94% of individuals with PDD [
      • Jellinger K.A.
      • Seppi K.
      • Wenning G.K.
      • Poewe W.
      Impact of coexistent Alzheimer pathology on the natural history of Parkinson's disease.
      ]. These post-mortem findings are consistent with a meta-analysis finding that CSF markers of amyloid beta (pooled standard mean difference [Std.MD] = −0.60, 95% CI = −0.75 to −0.45), total tau (pooled Std.MD = 0.21, 95% CI = 0.06 to 0.35), and phosphorylated tau (pooled Std.MD = 0.36, 95% CI = 0.02 to 0.69)were aberrant among individuals with PDD relative to cognitively intact PD patients [
      • Hu X.
      • Yang Y.
      • Gong D.
      Changes of cerebrospinal fluid Aβ42, t-tau, and p-tau in Parkinson's disease patients with cognitive impairment relative to those with normal cognition: a meta-analysis.
      ]. Findings suggest that cognitive impairment in PD may be multifaceted and at least partially associated with Alzheimer's pathology.
      Although past studies are inconsistent regarding whether or not SCC is associated with objective measures of cognitive impairment, and few studies have examined how the inclusion/exclusion of SCC affects the rate of PD-MCI classification and prognostic utility of PD-MCI. Therefore, we will first describe the extent that inclusion/exclusion of SCC in PD-MCI criteria affects the frequency of PD-MCI. Second, we will investigate whether inclusion/exclusion of SCC in PD-MCI criteria is associated with cognitive decline and CSF markers of amyloid, tau, and alpha synuclein. Specifically, we will compare three groups: 1) individuals with PD-MCI and SCC (PD-MCI + SCC); 2) individuals with PD-MCI without SCC (PD-MCI-SCC); 3) cognitive normal individuals with PD (CN). The rationale for comparing these groups is not because we are suggesting that PD-MCI-SCC should be considered as a future diagnostic group (e.g. SCC should not be an exclusion for PD-MCI). Rather, if SCC is an important criterion for classifying PD-MCI, then we would expect group differences among the PD-MCI groups with and without SCC (e.g. the PD-MCI + SCC groups with have worse outcomes relative to the PD-MCI-SCC group). Conversely, if SCC is not an important criteria for classifying PD-MCI (as is commonly practiced in the literature) then we would not expect group differences between the PD-MCI groups with and without SCC.

      2Methods

      2.1Study design & participants

      This study utilized data taken from the Parkinson's Markers Initiative (PPMI) database (http://www.ppmi-info.org/data). The PPMI is an international longitudinal observational study conducted at multiple sites and designed to identify various biomarkers in PD. The data was downloaded from the PPMI database in February 2019. At enrollment, participants were newly diagnosed and followed for up to 5 years (baseline and 5 annual follow-ups); however, data on SCC was not routinely collected until the 1st annual follow-up; therefore this secondary analysis only utilizes data from the first through fifth annual follow up. From the 487 individuals with PD enrolled, 127 participants were excluded for missing SCC data and two participants were excluded due to the presence of PDD (based on 1.5 SD below the mean on two neuropsychological tests and reported functional impairment) at the first available assessment. This resulted in a total of 358 participants. Additionally, All participants provided informed consent and approval from the Institutional Review Board (IRB) was obtained at each site.

      2.2Cognitive measures

      Participants completed a series of neurocognitive tests at each annual visit. These tests included Hopkins Verbal Learning Test (HVLT-II; trials 1–3 and delayed free recall) assessing verbal learning and verbal delayed recall, Letter-Number Sequencing (LNS) assessing attention/working memory, Judgment of Line Orientation (JOLO) measuring visuospatial function, Animal Fluency measuring verbal fluency, and Symbol Digit Modalities Test (SDMT) assessing processing speed. The Montreal Cognitive Assessment (MOCA) assessed global cognitive functioning.

      2.3SCC criteria

      Participants and/or study partners were asked a simple yes or no question indicating whether they have observed a decline in cognitive functioning in the participant. MCI participants were categorized as having a cognitive complaint if either the participant, study partner, or both individuals endorsed decline.

      3.4 PD-MCI criteria

      Participants were classified into the following grou2.4ps: cognitively normal (CN), PD-MCI with subjective cognitive complaints (PD-MCI + SCC) or PD-MCI without subjective cognitive complaints (PD-MCI –SCC) at each time point. PD-MCI criteria was consistent with MDS Level 1 (abbreviated assessment) [
      • Litvan I.
      • Goldman J.G.
      • Tröster A.I.
      • Schmand B.A.
      • Weintraub D.
      • Petersen R.C.
      • Mollenhauer B.
      • Adler C.H.
      • Marder K.
      • Williams‐Gray C.H.
      • Aarsland D.
      Diagnostic criteria for mild cognitive impairment in Parkinson's disease: Movement Disorder Society Task Force guidelines.
      ]. Individuals were classified as PD-MCI + SCC if two or more neuropsychological scores fell greater than 1.5 SD below the normative mean score and the participant and/or study partner endorsed that the participant had experienced cognitive decline. Conversely, participants were classified as PD-MCI –SCC if two or more neuropsychological scores fell greater than 1.5 SD below the mean score but both the participant and the study partner subjectively denied the presence of cognitive decline. The MOCA was not used for classifying PD-MCI because it was used as a separate outcome/measure of cognitive functioning.

      2.5Motor severity

      The clinician rated MDS Unified Parkinson's Disease Rating Scale-part III motor scale (UPDRS-III) was used to assess the severity of motor symptoms with higher scores representing more severity.

      2.6CSF markers

      For details on collection, shipment, storage and standard operating procedures at each site, see the biologics manual ppmi.info.org. Briefly, a lumbar puncture was performed to collect 15–20 mL of CSF from participants during 1st, 2nd and 3rd annual follow-ups. Samples were analyzed using an enzyme-linked immunosorbent assay (ELISA) to detect tau (total tau), phosphorylated tau (p-tau), amyloid beta (ab), and alpha-synuclein (asyn). The Elecsys electrochemiluminescence immunoasssays on cobas e 601 platform were used. Tau and ab markers were examined as ratios: tau/ab, p-tau/ab and p-tau/tau. Ratios were log transformed to reduce problematic skewness and kurtosis. Asyn was not transformed (skewness and kurtosis values were less than 2). The tau/ab and p-tau/ab ratios are markers of Alzheimer's disease pathologies, while Asyn was included as a marker of PD/Lewy body pathology.

      2.7Statistical analyses

      Aim 1 examined the occurrence of PD-MCI as a function of inclusion/exclusion of SCC in the PD-MCI classification criteria. The frequency of each group (CN, PD-MCI + SCC, PD-MCI –SCC) was examined over the 5 years of the study.
      Aim 2 examined if inclusion of SCC in PD-MCI criteria was associated with cognitive performance and CSF markers. First, multilevel modeling (MLM) was used to examine group differences (CN, PD-MCI –SCC, and PD-MCI + SCC) in trajectories of global cognition (MOCA). MOCA scores were entered as the dependent variable and group was entered as an independent variable. Additional independent variables included age at baseline, motor severity, gender, education, occasion (1st, 2nd, 3rd, 4th, and 5th annual follow-up visits) and a group × occasion interaction term. Random intercept and slope effects were modeled for all time-varying parameters (e.g. motor severity, occasion, group × occasion interaction).
      Similar analyses were repeated with CSF biomarkers entered as the dependent variable. Separate analyses were conducted for each marker ratio: tau/ab, p-tau/ab, and p-tau/tau, and asyn. Independent variables included: group (CN, PD-MCI –SCC, and PD-MCI + SCC), occasion, age, motor severity, gender, and education. Statistical significance was evaluated at the alpha = 0.05 level.

      3Results

      Participants included 358 individuals diagnosed with PD. Baseline sample information can be found in Table 1. Sample size at each occasion is available in Supplemental Table 1. Regarding the source of SCC, the patient was the sole source of data for 88.1% of cases, a study partner for 0.4% of cases, and both the patient and a study partner for 11.4% of cases. In the final year (year 5) 13 individuals met criteria for PDD based on criteria of 1.5 SD below the mean on two cognitive tests and reported functional impairment. Of these 13 individuals, at the first available assessment 3 were CN, 2 were PD-MCI –SCC and 8 were PD-MCI + SCC.
      Table 1Demographic and clinical information at the first available assessment.
      CN (n = 299)PD-MCI –SCC (n = 26)PD-MCI + SCC (n = 33)pContrast
      MSDMSDMSD
      Age61.110.061.38.765.58.40.047CN < MCI + SCC
      % Male65.6%73.1%63.6%0.710
      % White93.3%92.3%81.8%0.076
      Education15.72.815.02.415.003.70.292
      MDS-UPDRS III26.410.831.414.830.813.40.047CN < MCI-SCC,

      CN < MCI + SCC
      Hoehn & Yahr Stage1.70.51.80.51.90.50.364
      LEDD3052122962393381990.881
      MOCA26.92.524.03.422.04.7<0.001CN > MCI-SCC > MCI + SCC
      Immediate Verbal

      Recall
      24.85.018.83.916.84.1<0.001CN > MCI-SCC > MCI + SCC
      Delayed Verbal

      Recall
      8.82.76.42.34.52.8<0.001CN > MCI-SCC > MCI + SCC
      Working Memory10.82.58.72.96.92.8<0.001CN > MCI-SCC > MCI + SCC
      Animal Fluency21.95.515.94.215.65.0<0.001CN > MCI-SCC,

      CN > MCI + SCC
      Processing Speed42.59.030.79.323.111.7<0.001CN > MCI-SCC > MCI + SCC
      Line Orientation13.21.811.43.110.43.4<0.001CN > MCI-SCC,

      CN > MCI + SCC
      CN = cognitively normal, MCI- SCC = mild cognitive impairment without subjective cognitive complaints, MCI + SCC = mild cognitive impairment with subjective cognitive complaints, MDS-UPDRS III = Movement Disorder Society Unified Parkinson's Disease Rating Scale- Part III; LEDD = levodopa equivalent daily dose MOCA = Montreal Cognitive Assessment.

      3.1Aim 1. SCC criteria and PD-MCI frequency

      The frequencies of PD-MCI status over the 5 years of the study were examined among the three groups (CN, PD-MCI, PD + MCI; Fig. 1). When SCC was included in diagnostic criteria, rates of PD-MCI ranged from 4.4% to 11%. When SCC was not required as diagnostic criteria (i.e. combining both the PD-MCI-SCC and PD-MCI + SCC groups) the rates of PD-MCI ranged from 16.5% to 19.1%.
      Fig. 1
      Fig. 1Relative Frequency of PD-MCI With and Without a SCC Criterion. CN = cognitively normal, PD-MCI = mild cognitive impairment, PD-MCI + SCC = mild cognitive impairment with subjective cognitive complaints.

      3.2Aim 2. SCC criteria, cognitive decline and CSF markers

      Multilevel modeling examined if inclusion of SCC, relative to exclusion of SCC, in PD-MCI criteria was associated with performance on a separate measure of global cognition (MOCA; Table 2). Analyses revealed a significant group × time interaction (Fig. 2). Specifically, the PD-MCI + SCC group experienced greater decline in global cognition relative to the other two groups. The CN and PD-MCI –SCC groups did not significantly differ. Worse performance on global cognition was also associated with older age, male gender, fewer years of education and more severe motor symptoms.
      Table 2Subjective cognitive complaint and cognitive outcome.
      ParameterStandardized Estimate95% CIp-value
      CN vs. PD-MCI + SCC X Time−0.18−0.31 to −0.040.009
      PD-MCI-SCC vs. PD-MCI + SCC X Time−0.14−0.24 to −0.020.018
      CN vs. PD-MCI + SCC−0.88−1.0 to −0.70< 0.001
      PD-MCI-SCC vs. PD-MCI + SCC.−0.41−0.55 to −0.26< 0.001
      Male Sex/Gender0.080.01 to 0.150.036
      Age at Baseline−0.34−0.42 to −0.26< 0.001
      MDS-UPDRS III−0.13−0.19 to −0.06< 0.001
      Education0.150.07 to 0.22< 0.001
      Occasion0.070.04 to 0.11< 0.001
      Between-Person Pseudo R20.602
      Within-Person Pseudo R20.279
      Dependent Variable = Montreal Cognitive Assessment. CN = cognitively normal, MCI-SCC = mild cognitive impairment without subjective cognitive complaints, MCI + SCC = mild cognitive impairment with subjective cognitive complaints; MDS-UPDRS III = Movement Disorder Society Unified Parkinson's Disease Rating Scale- Part III.
      Fig. 2
      Fig. 2Group Differences in Cognition. Cognition is depicted as the standardized predicted value. CN = cognitively normal, MCI- SCC = mild cognitive impairment without subjective cognitive complaints, MCI + SCC = mild cognitive impairment with subjective cognitive complaints.
      Multilevel modeling also examined if inclusion of SCC, relative to exclusion of SCC, in PD-MCI criteria was associated with Alzhiemer's disease and PD CSF markers. Analyses revealed the PD-MCI + SCC group had significantly higher levels of tau/ab and p-tau/ab relative to both the CN and PD-MCI –SCC group (Fig. 3; Table 3). There were no significant group differences in p-tau/tau and asyn (Supplemental Table 2).
      Fig. 3
      Fig. 3Group Differences in CSF Markers. CSF markers were log transformed and the predicted values are depicted. AB = amyloid beta; CN = cognitively normal, MCI- SCC = mild cognitive impairment without subjective cognitive complaints, MCI + SCC = mild cognitive impairment with subjective cognitive complaints.
      Table 3Subjective cognitive complaint and CSF markers.
      Parametertau/ABp-tau/AB
      Estimate95% CIp-valueEstimate95% CIp-value
      CN vs. PD-MCI + SCC−0.31−0.55 to −0.050.007−0.26−0.47 to −0.050.015
      PD-MCI-SCC vs PD-MCI + SCC−0.30−0.52 to −0.080.018−0.26−0.51 to −0.020.035
      Male Sex/Gender−0.05−0.25 to 0.150.633−0.04−0.23 to 0.160.713
      Age0.250.15 to 0.35<0.0010.250.15 to 0.35<0.001
      MDS-UPDRS III−0.04−0.12 to 0.030.249−0.05−0.12 to 0.020.198
      Occasion0.06−0.01 to 0.130.0690.03−0.04 to 0.100.353
      Education0.09−0.02 to 0.190.0980.110.01 to 0.210.037
      Between- Person Pseudo R20.1710.130
      Within-Person Pseudo R20.0760.191
      CI = confidence interval; AB = amyloid beta; CN = cognitively normal, MCI-SCC = mild cognitive impairment without subjective cognitive complaints, MCI + SCC = mild cognitive impairment with subjective cognitive complaints; MDS-UPDRS III = Movement Disorder Society Unified Parkinson's Disease Rating Scale- Part III.

      4Discussion

      The 2012 Movement Disorder Society (MDS) published criteria for PD-MCI had minimal discussion on the SCC criterion [
      • Litvan I.
      • Goldman J.G.
      • Tröster A.I.
      • Schmand B.A.
      • Weintraub D.
      • Petersen R.C.
      • Mollenhauer B.
      • Adler C.H.
      • Marder K.
      • Williams‐Gray C.H.
      • Aarsland D.
      Diagnostic criteria for mild cognitive impairment in Parkinson's disease: Movement Disorder Society Task Force guidelines.
      ]. The rationale provided was that a report of SCC from the patient, informant, or clinician would increase the likelihood of capturing a change in cognitive functioning. Due to the lack of a strong rationale, and inconsistent findings for the associations between SCC and cognitive impairment, it is not surprising that the majority of studies on PD-MCI do not utilize the SCC criterion proposed by the MDS taskforce.
      Findings from this paper suggest that inclusion/exclusion of SCC may have important implications for PD-MCI criteria among relatively newly diagnosed PD patients. Specifically, the percentage of patients classified as PD-MCI was larger when SCC was not a diagnostic requirement (16.5%–19.1%) compared to when it was a requirement (4.4%–11.0%). Researchers generally do not utilize SCC in PD-MCI criteria and typically report the rates of PD-MCI to be ranging from 18.9 to 55% [
      • Purri R.
      • Brennan L.
      • Rick J.
      • Xie S.X.
      • Deck B.L.
      • Chahine L.M.
      • Dahodwala N.
      • Chen‐Plotkin A.
      • Duda J.E.
      • Morley J.F.
      • Akhtar R.S.
      Subjective cognitive complaint in Parkinson's disease patients with normal cognition: canary in the coal mine?.
      ,
      • Compta Y.
      • Martí M.J.
      • Ibarretxe-Bilbao N.
      • Junqué C.
      • Valldeoriola F.
      • Muñoz E.
      • Ezquerra M.
      • Ríos J.
      • Tolosa E.
      Cerebrospinal tau, phosphor-tau, and beta-amyloid and neurological functions in Parkinson's disease.
      ]. Past studies incorporating SCC in PD-MCI criteria report PD-MCI to be present in 21–24% of participants [
      • Kjeldsen P.L.
      • Damholdt M.F.
      Subjective cognitive complaints in patients with Parkinson's disease.
      ,
      • Caviness J.N.
      • Driver‐Dunckley E.
      • Connor D.J.
      • Sabbagh M.N.
      • Hentz J.G.
      • Noble B.
      • Evidente V.G.H.
      • Shill H.A.
      • Adler C.H.
      Defining mild cognitive impairment in Parkinson's disease, Movement disorders.
      ,
      • Lawson R.A.
      • Williams-Gray C.H.
      • Camacho M.
      • Duncan G.W.
      • Khoo T.K.
      • Breen D.P.
      • Barker R.A.
      • Rochester L.
      • Burn D.J.
      • Yarnall A.J.
      ICICLE-PD study group, Which neuropsychological tests? Predicting cognitive decline and dementia in Parkinson's disease in the ICICLE-PD cohort.
      ]. Consistent with our results, the presence of PD-MCI in past studies is considerably higher when SCC is excluded from criteria. This raises the possibility of inflated rates when SCC is not a requirement for PD-MCI classification, or potentially an underestimate when SCC is utilized in PD-MCI classifications.
      A review article of PD-MCI suggests that varied prevalence in the literature may be a result of differing methods of criteria, including a SCC requirement [
      • Cammisuli D.M.
      • Cammisuli S.M.
      • Fusi J.
      • Franzoni F.
      • Pruneti C.
      Parkinson's disease–mild cognitive impairment (PD-MCI): a useful summary of update knowledge.
      ]. Another review by Kjeldsen and Damholdt suggests the lack of a SCC requirement has to do with inconsistency in scale of measurement, though standardized measures of SCC do exist [
      • Kjeldsen P.L.
      • Damholdt M.F.
      Subjective cognitive complaints in patients with Parkinson's disease.
      ]. Furthermore, evidence suggests standardized measures have reasonable reproducibility, and certain measures may have the added benefit of assessing complaints across cognitive domains as opposed to a single construct [
      • Dupouy J.
      • Ory‐Magne F.
      • Mekies C.
      • Rousseau V.
      • Puel M.
      • Rerat K.
      • Pariente J.
      • Brefel‐Courbon C.
      • Andrieu P.
      • Angibaud G.
      PARKMIP group
      Cognitive complaint in early Parkinson's disease: a pilot study.
      ]. Continued work to establish a widely-recognized standard approach for assessing SCC may lead to improved uniformity in the rates of PD-MCI reported in the literature.
      Results from the current study demonstrate that the rate of cognitive decline was fastest among the PD-MCI + SCC group, relative to CN and PD-MCI –SCC groups.. This suggests that failure to utilize the SCC criterion in PD-MCI classifications (i.e. combining the PD-MCI + SCC and the PD-MCI –SCC groups) may dilute or weaken group differences between PD-MCI and CN on important outcomes. The importance is highlighted by the fact that a majority of studies do not require SCC when classifying PD-MCI [
      • Litvan I.
      • Aarsland D.
      • Adler C.H.
      • Goldman J.G.
      • Kulisevsky J.
      • Mollenhauer B.
      • Rodriguez‐Oroz M.C.
      • Tröster A.I.
      • Weintraub D.
      MDS Task Force on mild cognitive impairment in Parkinson's disease: critical review of PD‐MCI.
      ,
      • Goldman J.G.
      • Litvan I.
      Mild cognitive impairment in Parkinson's disease.
      ,
      • Kjeldsen P.L.
      • Damholdt M.F.
      Subjective cognitive complaints in patients with Parkinson's disease.
      ,
      • Caviness J.N.
      • Driver‐Dunckley E.
      • Connor D.J.
      • Sabbagh M.N.
      • Hentz J.G.
      • Noble B.
      • Evidente V.G.H.
      • Shill H.A.
      • Adler C.H.
      Defining mild cognitive impairment in Parkinson's disease, Movement disorders.
      ].
      The inconsistent use of SCC in PD-MCI criteria likely reflects contradicting results on whether SCC is a valid marker of objective cognitive impairment. Some studies have reported associations between SCC and objective measures of cognitive functioning [
      • Lehrner J.
      • Moser D.
      • Klug S.
      • Gleiß A.
      • Auff E.
      • Pirker W.
      • Pusswald G.
      Subjective memory complaints, depressive symptoms and cognition in Parkinson's disease patients.
      ,
      • Purri R.
      • Brennan L.
      • Rick J.
      • Xie S.X.
      • Deck B.L.
      • Chahine L.M.
      • Dahodwala N.
      • Chen‐Plotkin A.
      • Duda J.E.
      • Morley J.F.
      • Akhtar R.S.
      Subjective cognitive complaint in Parkinson's disease patients with normal cognition: canary in the coal mine?.
      ]. However, this has not been consistent in the literature [
      • AlDakheel A.
      • Gasca-Salas C.
      • Armstrong M.J.
      • Duff-Canning S.
      • Marras C.
      Cognitive complaints in nondemented Parkinson's disease patients and their close contacts do not predict worse cognitive outcome.
      ]. One study examined the relationship between SCC and measures of psychological and cognitive impairment [
      • Slavin M.J.
      • Brodaty H.
      • Kochan N.A.
      • Crawford J.D.
      • Trollor J.N.
      • Draper B.
      • Sachdev P.S.
      Prevalence and predictors of “subjective cognitive complaints” in the sydney memory and ageing study.
      ]. They found that SCC provided by participants correlated more with depression, anxiety and neuroticism than objective cognitive performance. Although SCC may be associated with psychiatric complications, the conclusion ‘SCC holds minimal value’ may be an overgeneralization. Researchers likely have two concerns regarding the SCC criterion in PD-MCI: 1) patients may exaggerate/hyperfocus on benign cognitive complaints; 2) patients may lack insight/awareness or concern about the severity of the cognitive impairment. Although these concerns may be reasonable in some patients, the other MDS PD-MCI criteria may reduce these concerns. Most obviously, PD-MCI criteria requires objective evidence of cognitive impairment in the form of neuropsychological testing. Although individuals with PD-MCI may still have a subjective complaint that is out of proportion to the objective deficits, by definition all complaints from individuals with PD-MCI will have at least some validity. Second, the fact that the MDS PD-MCI criteria allows the cognitive complaint to come from either the patient, informant or clinician may reduce concerns of lack of insight from a single source.
      The rationale for requiring SCC in PD-MCI criteria is that it may increase the likelihood of capturing a change in cognitive functioning, in contrast to longstanding cognitive weaknesses that may be relatively common and non-pathological. A review of neuropsychological testing in healthy normative adults revealed that impaired scores are common when participants are presented with a battery of multiple tests [
      • Binder L.M.
      • Iverson G.L.
      • Brooks B.L.
      To err is human:“Abnormal” neuropsychological scores and variability are common in healthy adults.
      ]. Approximately 72–75% of healthy individuals score 1 SD below the mean at least two tests when more than 20 scores are administered [
      • Heaton R.K.
      Revised comprehensive norms for an expanded Halstead-Reitan Battery: demographically adjusted neuropsychological norms for African American and Caucasian adults, professional manual.
      ,
      • Schretlen D.J.
      • Testa S.M.
      • Winicki J.M.
      • Pearlson G.D.
      • Gordon B.
      Frequency and bases of abnormal performance by healthy adults on neuropsychological testing.
      ]. Although this number drops if fewer tests are administered (35% of healthy individuals have ≥2 scores in the impaired range when 10 tests are administered) it suggests non-pathological low scores are quite common in the normative population. Indeed, results from the current study found individuals with objective impairments but without SCC (i.e. the PD-MCI –SCC group) in general did not experience declines over the five annual assessments. Inclusion of SCC in addition to objective neuropsychological testing may be an efficient means to increase confidence that PD-MCI is reflective of pathological declines in cognitive functioning rather than long standing and non-pathological weaknesses.
      While SCC may contribute greater prognostic certainty for predicting early cognitive decline, the PD-MCI + SCC group displayed significantly higher levels of biomarkers indicative of Alzheimer's disease pathology compared to the CN and PD-MCI –SCC groups, but not alpha-synuclein. These findings suggest that individuals classified as PD-MCI + SCC may be experiencing comorbid Alzheimer's disease pathology, which could be related to their faster cognitive declines. Another cohort study of individuals newly diagnosed with PD found tau (MAPT H1/H1) genotype and a “posterior cognitive profile” were associated with PDD within the first 5 and 10 years of diagnosis [
      • Williams-Gray C.H.
      • Mason S.L.
      • Evans J.R.
      • Foltynie T.
      • Brayne C.
      • Robbins T.W.
      • Barker R.A.
      The CamPaIGN study of Parkinson's disease: 10-year outlook in an incident population-based cohort.
      ]. Indeed, pathological studies have confirmed that comorbid AD is present in approximately 20%–33% of PD cases and that amyloid pathology is associated with a more rapid cognitive decline [
      • Smith C.
      • Malek N.
      • Grosset K.
      • Cullen B.
      • Gentleman S.
      • Grosset D.G.
      Neuropathology of dementia in patients with Parkinson's disease: a systematic review of autopsy studies.
      ]. In the AD literature, SCC is a common requirement in amnestic mild cognitive impairment (a-MCI) diagnostic criteria set by [
      • Petersen R.C.
      Mild cognitive impairment as a diagnostic entity.
      ]. However, studies examining the association between SCC and amyloid burden have been inconsistent among individuals with MCI/AD [
      • Pavisic I.M.
      • Lu K.
      • Keuss S.E.
      • James S.N.
      • Lane C.A.
      • Parker T.D.
      • Keshavan A.
      • Buchanan S.M.
      • Murray-Smith H.
      • Cash D.M.
      • Coath W.
      Subjective cognitive complaints at age 70: associations with amyloid and mental health.
      ,
      • Verfaillie S.C.
      • Timmers T.
      • Slot R.E.
      • Van Der Weijden C.W.
      • Wesselman L.M.
      • Prins N.D.
      • Sikkes S.A.
      • Yaqub M.
      • Dols A.
      • Lammertsma A.A.
      • Scheltens P.
      Amyloid-β load is related to worries, but not to severity of cognitive complaints in individuals with subjective cognitive decline: the SCIENCe project.
      ]. The inclusion of SCC in PD-MCI, particularly in relatively newly diagnosed PD, may be detecting individuals experiencing comorbid PD and AD pathology who are at increased risk for more rapid cognitive decline.
      There are limitations worth noting within this study. The sample consisted of relatively newly diagnosed PD patients, who may display lower rates of PD-MCI compared to patients who have had a longer diagnosis. The frequency of PD-MCI has been shown to increase with age, disease duration, and severity [
      • Saredakis D.
      • Collins-Praino L.E.
      • Gutteridge D.S.
      • Stephan B.C.
      • Keage H.A.
      Conversion to MCI and dementia in Parkinson's disease: a systematic review and meta-analysis.
      ]. Additionally, the cognitive battery was relatively limited and PD-MCI classification was based on only 6 cognitive scores across 5 tests. Although the battery assesses aspects of cognition that are commonly subsumed under the domain of executive functioning (e.g. verbal fluency, working memory), other common aspects of executive functioning were not assessed (e.g. inhibition, set-shifting, novel problem solving). Indeed the sample characteristics (newly onset PD patients) and limited number of neuropsychological tests may at least partially explain why the reported rates of PD-MCI are relatively lower than other past studies. The current study used a single-item yes or no question to determine presence of SCC. While no standardized measure/method is widely accepted, it is possible that standardized and more psychometrically sound measures of SCC may provide meaningful information above and beyond a single item. Given the possibility that apathy may also play a role in endorsement of SCC, future studies may wish to examine whether self- or study partner-report differentially impacts the prognostic value of SCC. Additionally, SCC was determined from the report of the patient and/or study partner only. MDS PD-MCI criteria state that clinicians can also be a possible source of SCC. PD-MCI classification was based on neuropsychological cut-offs; variations in approaches (i.e. actuarial approaches, consensus clinician diagnosis procedures) could lead to variations in PD-MCI rates across studies.
      Overall, inconsistent implementation of an SCC requirement in PD-MCI classifications may have important implications in terms of the occurrence of PD-MCI and its prognostic value. This study provides initial evidence to support the inclusion of SCC in PD-MCI diagnostic criteria. Failure to incorporate SCC may lead to inflated rates of PD-MCI. Additionally, incorporation of SCC in PD-MCI criteria may improve detection of future cognitive decline. Continued research in the area of SCC in PD is needed, though the current work highlights the potential value of utilizing SCC in PD-MCI criteria if the goal is specificity to determine individuals a risk for future decline regardless of etiology.

      Acknowledgements/study funding

      Jacob Jones was supported by NIH SC3 NS124906 .
      Kelsey Thomas was supported by the U.S. Department of Veterans Affairs Clinical Sciences Research and Development Service (Career Development Award-2 1IK2CX001865 ) and the NIH ( R03 AG070435 ).
      Data used in the preparation of this article were obtained from the Parkinson's Progression Markers Initiative (PPMI) database (www.ppmi-info.org/data). For up-to-date information on the study, visit www.ppmi-info.org.
      PPMI – a public-private partnership – is funded by the Michael J. Fox Foundation for Parkinson's Research funding partners 4D Pharma, Abbvie, Acurex Therapeutics, Allergan, Amathus Therapeutics, ASAP, Avid Radiopharmaceuticals, Bial Biotech, Biogen, BioLegend, Bristol-Myers Squibb, Calico, Celgene, Dacapo Brain Science, Denali, The Edmond J. Safra Foundation, GE Healthcare, Genentech, GlaxoSmithKline, Golub Capital, Handl Therapeutics, Insitro, Janssen Neuroscience, Lilly, Lundbeck, Merck, Meso Scale Discovery, Neurocrine Biosciences, Pfizer, Piramal, Prevail, Roche, Sanofi Genzyme, Servier, Takeda, Teva, UCB, Verily, and Voyager Therapeutics.

      Appendix A. Supplementary data

      The following are the Supplementary data to this article:

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