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Safety and Preliminary Efficacy of Intranasal Insulin for Cognitive Impairment in Parkinson Disease and Multiple System Atrophy

Vera Novak Peter Novak

Published: April 10, 2019. Version: 1.0

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Novak, V., & Novak, P. (2019). Safety and Preliminary Efficacy of Intranasal Insulin for Cognitive Impairment in Parkinson Disease and Multiple System Atrophy (version 1.0). PhysioNet.

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Goldberger, A., Amaral, L., Glass, L., Hausdorff, J., Ivanov, P. C., Mark, R., ... & Stanley, H. E. (2000). PhysioBank, PhysioToolkit, and PhysioNet: Components of a new research resource for complex physiologic signals. Circulation [Online]. 101 (23), pp. e215–e220.


This dataset was collected as part of a study that aimed to determine the effects of intranasal insulin (INI) on cognition and motor performance in PD. The study was a proof of concept, randomized, double-blinded, placebo-controlled trial evaluating the effects of 40 international units (IU) of insulin or saline once daily for four weeks on cognitive and functional performance. Of 16 subjects enrolled, eight in the INI group and six in the placebo group completed verbal fluency (FAS), Unified Parkinson Disease Scale (UPDRS), and modified Hoehn and Yahr scale (HY, PD severity) at baseline and post-treatment and were included in the analyses.


Parkinson disease (PD) is associated with a decline in cognitive performance and about 26% of patients diagnosed with PD develop mild cognitive impairment (MCI), more commonly the non-amnestic type [1–2]. The MCI incidence increases with age, disease severity and duration. MCI increases the risk for dementia and disability in PD patients [1, 2, 3] as well as the care-giver’s burden [4]. Insulin plays a key role in glucose metabolism in the brain where it exerts important neuromodulatory, neurotrophic, and neuroprotective effects [5]. Intranasal insulin (INI) administration acutely increased resting-state functional connectivity between hippocampal and DMN regions in patients with type 2 diabetes without affecting serum glucose [6]. INI improved verbal and visuospatial memory in older diabetic and healthy adults, likely via regional vasodilatation in the anterior cerebral circulation [7]. The rationale is that central insulin resistance and consequently impaired insulin signaling in the brain may be the common pathways for cognitive decline with aging, diabetes and Alzheimer’s disease.  In the brain, insulin has vasodilatory and neurotrophic effects, and therefore INI potential benefits are mediated by other mechanisms than by improving peripheral glycemic control.  The effects of INI administration on cognitive performance in patients with PD are yet to be elucidated. We evaluated the cognitive and functional effects of the daily administration of 40 international units (IU) of INI in adults with PD over a four week period as compared to placebo administration. This dataset was collected as part of an accompanying study, in which we hypothesized that INI would improve verbal cognition and motor disability in non-demented PD participants after the four weeks of treatment when compared to placebo [8].


Participants in the study completed a screening visit, a baseline assessment, two follow-up visits, and an end-of treatment assessment over a four week treatment period [8]. All participants completed detailed medical histories, neurologic physical exams and laboratory investigations (basic metabolic panel and pregnancy test in women of childbearing age). Functional assessments included neuropsychological testing, disease severity scales (to evaluate motor function and disease progression) and a walking test. Functional assessments at baseline and post-treatment were conducted while participants took their usual medications. The last INI/placebo dose administration was on the day of post treatment assessment.

The Montreal Cognitive Assessment (MoCA) test was used to assess symptoms of cognitive impairment [9]. The verbal fluency FAS test was used to assess phonemic fluency and verbal memory [10]. For FAS, participants were asked to name words starting with letters F, A and S over a one-minute interval. The Beck Depression Inventory (BDI) is a 21-item scale that was used to evaluate depressive symptoms [11]. The clinical and motor assessments included the modified Hoehn and Yahr Scale (HY) to evaluate the severity of PD and treatment response [12] and the Unified Parkinson Disease Rating Scale (UPDRS, version modified by the Movement Disorders Society) to clinically assess PD effects on motor, cognitive, and other functions [13]. UPDRS, a widely-used outcome measure in clinical trials, is a sensitive indicator of motor progression and has satisfactory interrater reliability [14, 15]. Motor score was calculated as proposed by Van Rooden et al. [16]. Bradykinesia score was calculated from the UPDRS item 23 + 24 + 25 +26 + 31 bilaterally. Motor asymmetry was estimated using lateralized UPDRS scores (item 20–26) (UPDRS I-III) as suggested by Jankovic et al. [13]. The UPDRS sub-scores summarize: UPDRS-I intellectual, mood and motivation impairment; UPDRS-II eating, activities of daily living, walking and balance; UPDRS-III speech, tremor; Bradykinesia finger tapping, postural stability, and body bradykinesia and dyskinesia.

All participants completed a standard four meter walking test [17] at their preferred walking speed to assess normal walking speed, number of steps and average stride length. The time used to complete a four meter walk was recorded. Average stride length was calculated by dividing the walked distance by the recorded number of steps.

Data Description


This file contains the data summary table which includes the pre- and post-intervention study variables and their values for every subject:

  • Group (Insulin-Placebo)
  • Demographics
  • Disease (PD, MSA)
  • Laboratory
  • Vital Signs
  • Walking Test
  • Montreal Cognitive Assessment (MoCA)
  • Becker Depression Inventory (BDI)
  • Verbal Fluency (FAS)


This file contains the data summary table which includes the pre- and post-intervention UPDRS values for every subject. The columns updrsN_base and updrsN_tre1 refer to pre- and post-treatment respectively.


This file lists all the variables of the study (variable description and units) and actual values from two participants as examples.

Abbreviations Used

  • MoCA = the Montreal Cognitive Assessment
  • HY = Hoehn and Yahr Scale
  • BDI = Beck Depression Inventory
  • F,A,S = phonemic fluency and verbal memory
  • UPDRS= Unified Parkinson Disease Scale I-III
  • SBP= systolic blood pressure
  • DBP= diastolic blood pressure.

Usage Notes

Pre- and post-intervention variables and values are described in summary tables (PD-Table 1 and Pd-Table2), and a data dictionary, all provided in CSV format.


This study was funded in part by The Langer Family Charitable Foundation, Chirag Foundation Investment Trust, Baker’s MSA fund, Mr. Yash R. Puri (awarded to Dr. Peter Novak), and by the Department of Neurology at the University of Massachusetts. Research (manuscript preparation) reported in this publication was in part supported by the National Institute Of Diabetes And Digestive And Kidney Diseases of the National Institutes of Health under Award Number R01DK103902 (awarded to Dr. Vera Novak) that is unrelated to this study. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health (

Conflicts of Interest

The authors declare no conflicts of interest.


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  2. Janvin CC, Larsen JP, Aarsland D, Hugdahl K. Subtypes of mild cognitive impairment in Parkinson’s disease: progression to dementia. Mov Disord Off J Mov Disord Soc. 2006;21: 1343–1349. doi:10.1002/mds.20974
  3. Aarsland D, Bronnick K, Williams-Gray C, Weintraub D, Marder K, Kulisevsky J, et al. Mild cognitive impairment in Parkinson disease: a multicenter pooled analysis. Neurology. 2010;75: 1062–1069. doi:10.1212/WNL.0b013e3181f39d0e.
  4. Coelho M, Marti MJ, Sampaio C, Ferreira JJ, Valldeoriola F, Rosa MM, et al. Dementia and severity of parkinsonism determines the handicap of patients in late-stage Parkinson’s disease: the Barcelona-Lisbon cohort. Eur J Neurol. 2015;22: 305–312. doi:10.1111/ene.12567.
  5. Shemesh E, Rudich A, Harman-Boehm I, Cukierman-Yaffe T. Effect of intranasal insulin on cognitive function: a systematic review. J Clin Endocrinol Metab. 2012;97: 366–376. doi:10.1210/jc.2011-1802.
  6. Zhang H, Hao Y, Manor B, Novak P, Milberg W, Zhang J, et al. Intranasal insulin enhanced resting-state functional connectivity of hippocampal regions in type 2 diabetes. Diabetes. 2015;64: 1025–1034. doi:10.2337/db14-1000.
  7. Novak V, Milberg W, Hao Y, Munshi M, Novak P, Galica A, et al. Enhancement of vasoreactivity and cognition by intranasal insulin in type 2 diabetes. Diabetes Care. 2014;37: 751–759. doi:10.2337/dc13-1672.
  8. Novak P, Pimentel Maldonado DA, Novak V. Safety and preliminary efficacy of intranasal insulin for cognitive impairment in Parkinson disease and multiple system atrophy: A double-blinded placebo-controlled pilot study. PLoS One. 2019;14(4):e0214364. Published 2019 Apr 25.
  9. Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53: 695–699. doi:10.1111/j.1532-5415.2005.53221.x
  10. Yeudall LT, Reddon JR, Gill DM, Stefanyk WO. Normative data for the Halstead-Reitan neuropsychological tests stratified by age and sex. J Clin Psychol. 1987;43: 346–367.
  11. Whisman MA, Judd CM, Whiteford NT, Gelhorn HL. Measurement invariance of the Beck Depression Inventory-Second Edition (BDI-II) across gender, race, and ethnicity in college students. Assessment. 2013;20: 419–428. doi:10.1177/1073191112460273
  12. Goetz CG, Poewe W, Rascol O, Sampaio C, Stebbins GT, Counsell C, et al. Movement Disorder Society Task Force report on the Hoehn and Yahr staging scale: status and recommendations. Mov Disord Off J Mov Disord Soc. 2004;19: 1020–1028. doi:10.1002/mds.20213
  13. Jankovic J, McDermott M, Carter J, Gauthier S, Goetz C, Golbe L, et al. Variable expression of Parkinson’s disease: a base-line analysis of the DATATOP cohort. The Parkinson Study Group. Neurology. 1990;40: 1529–1534.
  14. Martínez-Martín P, Gil-Nagel A, Gracia LM, Gómez JB, Martínez-Sarriés J, Bermejo F. Unified Parkinson’s Disease Rating Scale characteristics and structure. The Cooperative Multicentric Group. Mov Disord Off J Mov Disord Soc. 1994;9: 76–83. doi:10.1002/mds.870090112
  15. Richards M, Marder K, Cote L, Mayeux R. Interrater reliability of the Unified Parkinson’s Disease Rating Scale motor examination. Mov Disord Off J Mov Disord Soc. 1994;9: 89–91. doi:10.1002/mds.870090114
  16. Van Rooden SM, Visser M, Verbaan D, Marinus J, van Hilten JJ. Motor patterns in Parkinson’s disease: a data-driven approach. Mov Disord Off J Mov Disord Soc. 2009;24: 1042–1047. doi:10.1002/mds.22512
  17. Maggio M, Ceda GP, Ticinesi A, De Vita F, Gelmini G, Costantino C, et al. Instrumental and Non-Instrumental Evaluation of 4-Meter Walking Speed in Older Individuals. PloS One. 2016;11: e0153583. doi:10.1371/journal.pone.0153583


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Data_Dictionary.csv (download) 1.1 KB 2019-04-10
LICENSE.txt (download) 19.9 KB 2019-04-10
PD-Table1.csv (download) 3.0 KB 2019-04-10
PD-Table2.csv (download) 818 B 2019-04-10
SHA256SUMS.txt (download) 3.4 KB 2019-04-10