Therapeutic Development Paths for Cognitive Impairment in Parkinson's Disease: Report of a Regulatory Roundtable

Eberling, Jamie L.; Vincent, Lona; Goldman, Jennifer G.; Weintraub, Daniel; Kulisevsky, Jaime; Marras, Connie; Stebbins, Glenn T.; Kieburtz, Karl

doi:10.3233/jpd-140385

Cited by 17 publications

(16 citation statements)

References 26 publications

(24 reference statements)

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“…8–10,19,20 The explicit intent of a PD-MCI diagnosis is to identify patients who are at risk of PDD, and this can only be determined by longitudinal follow-up of patients. Dementia is an outcome facing most PD patients as the disease unfolds and multiple brain networks become increasingly disrupted.…”

Section: Discussionmentioning

confidence: 99%

Different PD-MCI criteria and risk of dementia in Parkinson’s disease: 4-year longitudinal study

Wood

Myall

Livingston

et al. 2016

npj Parkinson's Disease

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The Movement Disorder Society Task Force (MDS-TF) has proposed diagnostic criteria for mild cognitive impairment in Parkinson’s disease (PD-MCI). We hypothesized that the risk of dementia (PDD) varies across the different cutoff schemes allowed. A longitudinal study followed 121 non-demented PD patients for up to 4.5 years. In Part One, unique groups of patients were identified as PD-MCI at baseline using the MDS-TF requirement of two impaired cognitive test scores, with both scores classified as impaired at either (i) 2 s.d., (ii) 1.5 s.d. or (iii) 1 s.d. below normative data; relative risk (RR) of PDD was assessed at each criterion. In Part Two, the whole sample was reassessed and (i) RR of PDD determined when two impairments at 1.5 s.d. existed within a single cognitive domain, followed by (ii) RR of PDD in the unique group whose two impairments at 1.5 s.d. did not exist within a single domain (i.e., only across two domains). Twenty-one percent of patients converted to PDD. Part One showed that the 1.5 s.d. criterion at baseline is optimal to maximize progression to PDD over 4 years. Part Two, however, showed that the 1.5 s.d. cutoff produced a high RR of PDD only when two impairments were identified within a single cognitive domain (7.2, 95% confidence interval (CI)=3.4–16.6, P<0.0001; 51% converted). The RR when the 1.5 s.d. impairments occurred only across two different domains, was nonsignificant (1.7, CI=0.5–7.4, P=0.13; 11% converted) and similar to using a 1 s.d. criterion (1.9, CI=0.3–4.3, P=0.13; 8% converted). If the intent of a PD-MCI diagnosis is to detect increased risk of PDD in the next 4 years, optimal criteria should identify at least two impairments at 1.5 s.d. within a single cognitive domain.

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Section: Discussionmentioning

confidence: 99%

Different PD-MCI criteria and risk of dementia in Parkinson’s disease: 4-year longitudinal study

Wood

Myall

Livingston

et al. 2016

npj Parkinson's Disease

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“…A methodological challenge in all randomized controlled trials involving cognitive outcome measures is identifying tests with suitable psychometric properties for detecting change. 43 As detailed in the 2015 review by Goldman and Weintraub, 44 most published clinical trials of cognitive interventions in PD use screening measures like the MMSE. Although scores on screening measures are readily interpretable to clinicians and researchers, such tools are not designed to measure functioning within specific cognitive domains.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A Randomized Clinical Trial of Atomoxetine for Mild Cognitive Impairment in Parkinson's Disease

Hinson

Delambo

Elm

et al. 2016

Movement Disord Clin Pract

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Background Mild cognitive impairment in Parkinson's disease (PD‐MCI) is associated with diminished norepinephrine from the locus coeruleus to the prefrontal cortex. Atomoxetine is a specific norepinephrine reuptake inhibitor that has been approved by the US Food and Drug Administration to treat attention deficit hyperactivity disorder in adults. The authors hypothesized that atomoxetine would improve attention and executive functioning in patients with PD‐MCI. Methods Thirty participants who met Movement Disorder Society Task Force Level I criteria for PD‐MCI were enrolled in a randomized controlled trial of atomoxetine. Cognitive evaluations were performed at baseline and after 10 weeks of treatment or placebo. A safety visit was performed at Week 12. A global statistical test was used to examine treatment effects on standardized tests of attention, working memory, processing speed, and set shifting (primary outcome measure). Secondary outcomes included cognitive measures hypothesized to be insensitive to atomoxetine, the Conners Adult Attention Deficit Hyperactivity Disorder Rating Scale, and safety measures. Results Fifteen participants were randomized to each arm. Groups were similar on medical and demographic variables and baseline cognition. Three serious adverse events occurred; 2 on atomoxetine (syncope, isolated episode of atrial fibrillation) and 1 on placebo (atrial fibrillation). The global statistical test of primary outcome measures did not reveal a significant difference between groups. However, significant improvements were observed for atomoxetine but not placebo on subjective measures of attention and impulsivity (Conners Adult Attention Deficit Hyperactivity Disorder Rating Scale). Conclusions Atomoxetine treatment produced subjective, but not objective, improvements in PD‐MCI. Failure to detect objective differences may be due to insensitivity of cognitive tests or severity of cognitive deficits in the study participants.

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“…We will need a clear regulatory pathway for pharmacological and non-pharmacological interventions for PD cognitive impairment, including the PD-MCI stage, and for not only symptomatic, but also disease-modifying agents that prevent or slow cognitive decline. 122 As these therapies come to fruition, we will need to have appropriate insurance coverage for them. Lastly, we will need better support and education regarding cognitive changes for people with PD and their care partners, early on in the disease as well as throughout their disease course.…”

Section: Current/future Researchmentioning

confidence: 99%

Cognitive impairment in Parkinson’s disease: a report from a multidisciplinary symposium on unmet needs and future directions to maintain cognitive health

Goldman

Vernaleo

Camicioli

et al. 2018

npj Parkinson's Disease

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137

111

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People with Parkinson’s disease (PD) and their care partners frequently report cognitive decline as one of their greatest concerns. Mild cognitive impairment affects approximately 20–50% of people with PD, and longitudinal studies reveal dementia in up to 80% of PD. Through the Parkinson’s Disease Foundation Community Choice Research Award Program, the PD community identified maintaining cognitive function as one of their major unmet needs. In response, a working group of experts across multiple disciplines was organized to evaluate the unmet needs, current challenges, and future opportunities related to cognitive impairment in PD. Specific conference goals included defining the current state in the field and gaps regarding cognitive issues in PD from patient, care partner, and healthcare professional viewpoints; discussing non-pharmacological interventions to help maintain cognitive function; forming recommendations for what people with PD can do at all disease stages to maintain cognitive health; and proposing ideas for how healthcare professionals can approach cognitive changes in PD. This paper summarizes the discussions of the conference, first by addressing what is currently known about cognitive dysfunction in PD and discussing several non-pharmacological interventions that are often suggested to people with PD. Second, based on the conference discussions, we provide considerations for people with PD for maintaining cognitive health and for healthcare professionals and care partners when working with people with PD experiencing cognitive impairment. Furthermore, we highlight key issues and knowledge gaps that need to be addressed in order to advance research in cognition in PD and improve clinical care.

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Therapeutic Development Paths for Cognitive Impairment in Parkinson's Disease: Report of a Regulatory Roundtable

Cited by 17 publications

References 26 publications

Different PD-MCI criteria and risk of dementia in Parkinson’s disease: 4-year longitudinal study

Different PD-MCI criteria and risk of dementia in Parkinson’s disease: 4-year longitudinal study

A Randomized Clinical Trial of Atomoxetine for Mild Cognitive Impairment in Parkinson's Disease

Cognitive impairment in Parkinson’s disease: a report from a multidisciplinary symposium on unmet needs and future directions to maintain cognitive health

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