Pauly, Laure

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www.lih.luRETROGRADE PROCEDURAL MEMORY IN PARKINSON’S DISEASE AND REM-SLEEP BEHAVIOR DISORDERINTRODUCTIONOBJECTIVESMETHODSRESULTS - II DISCUSSION & OUTLOOKLaure PAULYTransversal Translational Medicine, Luxembourg Institute of Health (LIH), Strassen, Luxembourg;Faculty of Science, Technology and Medicine; University of Luxembourg; Esch-sur-Alzette; Luxembourg;Translational Neuroscience, Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg;Parkinson Research Clinic, Luxembourg, Centre Hospitalier de Luxembourg (CHL), Luxembourg, Luxembourg;The procedural memory, a long-term and implicit memory, is in charge of theencoding, storage, and retrieval of the unconscious procedures that underlie motoror cognitive skills. Its analysis is particularly relevant in neurodegenerative diseaseslike Parkinson‘s disease (PD), due to the central role of the basal ganglia inprocedural memory. Procedural memory can be separated into an anterograde and aretrograde component1 (Fig 1).It has been established that the anterogradeprocedural memory is affected in PD2.Observations on retrograde proceduralmemory have been done indirectly in form ofcase-reports3 and studies on musical memoryor overlearned language1,4.To our knowledge, validated protocols are missing to evaluate the retrograde part ofthis memory concept. Therefore, we developed the CUPRO, a brief assessment toolthat allows to evaluate the functioning of retrograde procedural memory.Figure 1. Procedural memory The main objectives of our study were to:H1PDH2FOGH3RBDTest the hypothesis (H3) of a deficitof retrograde procedural memoryin people with REM-SleepBehavior Disorder (RBD) (at-riskcohort for PD)Develop the CUPRO evaluationsystem to assess functioning ofretrograde procedural memory5Test the hypothesis (H1) of adeficit of retrograde proceduralmemory in people with PDcompared to control subjects (CS)5Test the hypothesis (H2) of a deficitof retrograde procedural memory inpeople with PD and freezing of gait(FOG)+ Validation of our observations in an independent PD/RBD Cohort.For H2, people with typical PD andFOG (FOG+) were compared withtheir age, gender, education anddisease duration matched controlgroup patients without FOG (FOG-(Table 4).Table 4. Demographic and clinical data for FOG+ and FOG- Variable Descriptive statistics P-Values              FOG+            FOG- FOG+ vs. FOG- N Total             127            127  N GBA+ / GBA-                  15/105+7NA                         12/92+23NA            p = 0.988  Mean SD Mean SD  Gender, M / F             87 / 40            83 / 44 p = 0.689 Age, in years  67.26 9.97 66.85 9.49 p = 0.417 Disease duration,  in years  4.66 3.94 4.60 3.92 p = 0.962 Education,  in years  13.35 3.93 13.10 3.63 p = 0.818 MDS-UPDRS I (/52)  10.81 6.34 7.67 4.94 p < 0.001** MDS-UPDRS II (/52)  11.93 6.50 7.49 5.15 p < 0.001** MDS-UPDRS III (/132)  36.60 12.62 33.05 12.78 p = 0.042* Modified Hoehn and Yahr  2.24 0.54 1.99 0.43 p = 0.001 ** Stage 1 / 1.5 / 2  / 2.5 / 3 / 4 / 5          3/4/78/22/14/5/0              9/14/82/15/7/0/0  LEDD  612.10 419.10 523.90 315.30 p = 0.204   BDI-I (/63)  9.61 7.37 6.21 5.42 p < 0.001** SAS (/42)  14.22 5.21 12.52 5.68 p = 0.005* FAQ (/30) 2.82 4.45 1.35 2.32 p = 0.009* PDQ-39 (/156) 25.94 17.60 15.51 11.89 p < 0.001** IQCode (/5) 3.09 0.47 3.09 0.31 p = 0.217 Languages spoken 2.81 1.07 2.73 1.14 p = 0.672  Variable Descriptive statistics P-Values             FOG+            FOG- FOG+ vs. FOG- N Total            127            127  N GBA+ / GBA-                  15/105+7NA                        12/92+23NA            p = 0.988  Mean SD Mean SD  Gender, M / F           87 / 40           83 / 44 p = 0.689 Age, in years  67.26 9.97 66.85 9.49 p = 0.417 Disease duration,  in years  4.66 3.94 4.60 3.92 p = 0.962 Education,  in years  13.35 3.93 13.10 3.63 p = 0.818 MDS-UPDRS I (/52)  10.81 6.34 7.67 4.94 p < 0.001** MDS-UPDRS II (/52)  11.93 6.50 7.49 5.15 p < 0.001** MDS-UPDRS III (/132)  36.60 12.62 33.05 12.78 p = 0.042* Modified Hoe n and Yahr  2.24 0.54 1.99 0.43 p = 0.001 ** Stage 1 / 1.5 / 2  / 2.5 / 3 / 4 / 5          3/4/78/22/14/5/0              9/14/82/15/7/0/0  LEDD  612.10 419.10 523.90 315.30 p = 0.204   BDI-I (/63)  9.61 7.37 6.21 5.42 p < 0.001** SAS (/42)  14.22 5.21 12.52 5.68 p = 0.005* FAQ (/30) 2.82 4.45 1.35 2.32 p = 0.009* PDQ-39 (/156) 25.94 17.60 15.51 11.89 p < 0.001** IQCode (/5) 3.09 0.47 3.09 0.31 p = 0.217 Languages spoken 2.81 1.07 2.73 1.14 p = 0.672    Descriptive statistics  P-Values  Variable FOG+ (n = 127) FOG- (n = 127) N FOG+ /FOG- FOG+ vs. FOG-   Mean SD Mean SD   CUPRO Evaluation System IS1 (/3) 1.88 1.10 2.23 1.07 127/127 p =  0.009* IS2 (/3) 2.24 1.12 2.32 1.01 127/127 p = 0.719         General Cognition MOCA total score (/30) 25.91 2.67 26.69 2.39 127/127 p = 0.022* Psychomotor speed / Executive functions TMT-A (sec) 54.72 33.55 47.73 22.59 123/122 p = 0.057 TMT-B (sec) 141.20 80.63 112.20 58.63 123/122 p = 0.006* Delta TMT (sec) 86.46 70.65 64.51 46.75 123/122 P = 0.007* Table 5. Neuropsychological assessmentsBesides lower global cognition and executive functions, FOG+ performed worse inretrograde procedural memory compared to matched control patients (Table 5).Global cognition was evaluated with the MoCA7. Given that a wide range of cognitive& neural processing capabilities are required for cube copying, additional testing fordiscriminant validity by investigating associations of cube copying performance withseveral related constructs was done with a subgroup of participants for whichrelevant tests were available (34≤N≤73) (Table 3).YES NOINTERMEDIATE SCORE 1 - IS1 The subject starts with one of the squares / surfaces / with the 3 axes 1 01 0The subject fills in the connection lines correctly 1 0INTERMEDIATE SCORE 1 IS1                                             /3INTERMEDIATE SCORE 2 – IS2The drawing is 3D, the proportions are correct 1 0The orientation of the drawing is correct (mirror image) 1 0The final result is correct 1 0INTERMEDIATE SCORE 2 IS2                                             /3TOTAL SCORE                                                                                                                  /6The subject drew the inside sides The subject drew a second square (superposition)The subject drew a second face The subject drew the 3 axes and continued by drawing any other surfaceABCDRetrograde procedural memory Visuo-constructive abilitiesFigure 2. Representation of the extended evaluation system for the Cube Copying Test, the CUPRO evaluation system. The first intermediate score (IS1) evaluates the copying  procedure, the second intermediate score (IS2) the visuo-constructive functions. (A-D) Representation of the four copying procedures.Based on the Necker’s Cube6, we established an extendedevaluation system, the CUPRO. It assesses both the:• copying procedure, representing retrograde procedural memory• final result, representing visuo-constructive functions (Fig. 2).The Cube Copying Testmeets the conditionsof assessing retrogradeprocedural memory èby copying the cube, a(i) previously learnedprocedure is (ii)unconsciously applied.Despite the importance of procedural memory in our daily life activities and thenumerous studies that have investigated this topic, there are still manydiscrepancies, mainly due to the varying definitions of the memory concept and tothe nature of the used tasks8. Until now, assessments primarily evaluated themotor, perceptual and cognitive procedural learning, with tasks such as the pursuitrotor task9, serial reaction time task10, and arithmetic alphabet test11. Only fewstudies focused on the suggested long-term retention of new skills 12,13,14.The CUPRO evaluation system has a number of strengths: it is simple to administerand as the Cube Copying test is widely used in clinical and research settings it isRetrograde Procedural Memory in Parkinson’s diseaseThe integrity of retrograde procedural memory is crucial for a person’s ability toconduct routine activities of daily living. This study established a new tool to assessfunctioning of retrograde procedural memory and showed deficits in retrogradeprocedural memory in people with PD compared with control subjects.Furthermore, we were able to observe declined procedural memory in PD withFOG. These insights may lead to hypotheses on FOG aetiology and the developmentof treatment options.The CUPRO evaluation system will not only fill the gap of techniques for reliablyassessing functioning of retrograde procedural memory in clinical settings but mayalso help to identify valuable perspectives for future research.CONCLUSIONProcedural memoryRetrogradeprocedural memoryAnterograde procedural memoryAbility to execute skillsacquired in earlier life stages Ability to learn new skillsRESULTS - I  Descriptive statistics P-Values Variable PD (n = 201) CS (n = 201) PD vs. CS  Mean SD Mean SD  Gender, M / F 111 / 90 109 / 92 p = 0.920 Handedness , R / L / A 170 / 14 / 7 +10 na 180 / 6 / 10 +5 na p = 0.139 Age, in years  64.84 10.20 64.71 10.18 p = 0.943 Education,  in years  13.60 3.80 14.25 3.96 p = 0.128 MOCA total score (/30)  26.58 2.68 26.97 2.29 p = 0.246 MDS-UPDRS-III (/132)  32.80 13.40 4.59 5.10 p < 0.001 *,** Hoehn and Yahr  2.06 0.53 0.00 0.00 p < 0.001 *,** Stage 1 / 1.5 / 2  / 2.5 / 3 / 4 / 5 19 / 13 / 119 / 29 / 18 / 2 / 1+1 na    BDI-I (/63)  8.32 6.36 4.95 4.72 p < 0.001*,** SAS (/42)  13.63 5.49 9.84 4.75 p < 0.001 *,** Languages spoken 2.81 1.10 3.56 0.78 p < 0.001 *,** Disease duration,  in years  5.37 4.39 - - -  LEDD  596.35 391.30 - - - Table 1. Demographic and clinical data for PD and CS memory in PD compared to the CS (Table 2).Higher MoCA scores and education correlatedsignificantly with higher scores for retrogradeprocedural memory. No significant correlationfor disease duration, MDS-UPDRS-III score,LEDD and depressive symptoms were found.Table 2. CUPRO Cube scoring system   Descriptive statistics P-Values  Variable PD (n = 201) CS (n = 201) PD vs. CS Extended evaluation system of the Cube Copying Test  Mean SD Mean SD  IS1 (/3)  2.05 1.13 2.43 0.90 p =  0.008 *,** IS2 (/3)  2.26 1.10 2.59 0.84 p = 0.013 *,**    N Spearman – Correlation coefficient R p Visuo-constructive abilities Qualitative Scoring MMSE Pentagone Test 54 - 0.103 + 0.058 + 0.102 + 0.169 - 0.381 p = 0.462 Visuo-spatial abilities Judgment of Ligne Orientation Benton 56 p = 0.249 Executive functions Frontal Assessment Battery 73 p = 0.392 Visuo-constructive abilities Rey-Osterrieth Complex Figure - Copy 34 p = 0.338 Planning functions Rey-Osterrieth Complex Figure - Type 34 p = 0.831 Table 3. Discriminant validity - correlations for the IS1 and possible interfering factorsFor H1, people with typical PD were compared with age and gender matched controls(CS) (Table 1). We observed significantly worse functioning of retrograde proceduralNeither visuo-constructive, visuo-spatial,planning nor executive functions significantlyinterfered with the score representingretrograde procedural memory (Table 3).already incorporated in standard assessments, i.e. MoCA.Therefore, it can be easily integrated in protocols. It addsvaluable information to an already well-establishedscreening tool without increasing the burden for patients.However, we can not verify if all participants learned thedrawing of geometric forms . The non-conscious acquiringof skills makes it difficult to gain insights into if and howthe strategy of cube drawing has been learned.Our findings suggest that impaired retrograde proceduralmemory could be detectable in a prodromal, non-motor stage of the disease. Giventhat diagnosing PD means identifying an already advanced disorder with progressedneurodegeneration, it is essential to advance in the identification of early marker inorder to aim the early diagnosis of PD. Therefore, in an upcoming study weinvestigate this memory concept in a PD-risk cohort, with people with REM sleepBehavior Disorder (RBD) (H3). Additionally, future research will validate the CUPROevaluation system in an independent Parkinson’s disease cohort.Abbreviations SD: Standard Deviation; PD: People with Parkinson’s disease; CS: Control subjects; FOG+: Freezers ;FOG-: non-Freezers; M: Male; F: Female; R: Right-handed; L: Left-handed; A: Ambidextrous; na = not available; n= sample size; MDS-UPDRS: Movement Disorder Society - Unified Parkinson’s Disease Rating Scale; BDI: BeckDepression Inventory; SAS: Starkstein Apathy Scale; PDQ-39: Parkinson’s disease questionnaire 39-item MoCA:Montreal Cognitive Assessment; LEDD: Levodopa Equivalent Daily Dose; IS: Intermediate Score. * Significant atthe 5% level (2-tailed). ** Significant at the Bonferroni-adjusted 5% level (2-tailed).References: 1Crystal et al. (1989); 2Muslimović et al. (2007); 3Matthews et al. 2015; 4Bridges et al. (2013), 5Paulyet al. (2022), 6Necker (1832); 7Nasreddine (2005); 8Seidler et al. (2007); 9Heindel et al. (1989), 10Clark et al.(2019); 11Thomas et al. (1996); 12Crystal et al. (1989), 13Cohen et al. (2007), 14Mochizuki-Kawai et l. (2004).For more information about my PhD projectLinkedIn Profile5Pauly L, Pauly C, Hansen M, Schröder VE, Rauschenberger A, Leist AK - Retrograde Procedural Memory in Parkinson’s Disease: A Cross-Sectional, Case-Control Study. J Parkinsons Dis; 2022 

Retrograde procedural memory in Parkinson's Disease and in REM-Sleep Behavior Disorder

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Retrograde procedural memory in Parkinson's Disease and in REM-Sleep Behavior Disorder

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