Goal management training and psychoeducation / mindfulness for treatment of executive dysfunction in Parkinson's disease: A feasibility pilot trial.

INTRODUCTION: As there is currently no pharmacological treatment for Parkinson's Disease Mild Cognitive Impairment (PD-MCI) with executive dysfunctions, specific cognitive interventions must be investigated. Most previous studies have tested bottom-up cognitive training programs but have not shown very good results. OBJECTIVES: The aim of this study was to test ease of implementation, differential safety and preliminary efficacy of two top-down (strategy-learning) home-based, individualized, cognitive interventions: Goal Management Training (GMT), adapted for PD-MCI (Adapted-GMT), and a psychoeducation program combined with mindfulness exercises (PSYCH-Mind). METHODS: This was a single-blind block-randomized between-group comparative study. Twelve PD-MCI with mild executive dysfunctions were divided in four blocks and randomly assigned to any of the two interventions. The participants were included if they had PD-MCI diagnosis (no dementia), with stabilized medication. Both groups (Adapted-GMT and PSYCH-mind) received five intervention sessions each lasting 60-90 minutes for five weeks. Measures were collected at baseline, mid-point, one-week, four-week and 12-week follow-ups. Executive functions were assessed with the Dysexecutive questionnaire (DEX) and the Zoo Map Test (ZMT). Quality of life (QoL) and psychiatric symptoms were also evaluated. Repeated measures ANCOVAs (mixed linear analysis) were applied to all outcomes. RESULTS: There was one drop out, and both interventions were feasible and acceptable. Despite the small sample size limiting statistical power, patients of both groups significantly improved executive functions per the DEX-patient (Time: F(4,36) = 2.96, p = 0.033, CI95%: 10.75-15.23) and DEX-caregiver scores (Time: F(4,36) = 6.02, p = 0.017, CI95%: 9.63-17.23). Both groups significantly made fewer errors between measurement times on the ZMT (Time: F(3,36) = 16.66, p = 0.001, CI95%: 1.07-2.93). However, QoL significantly increased only in PSYCH-Mind patients at four-week follow-up (interaction Time*Group: F(4,36) = 5.31, p = 0.002, CI95%: 15.33-25.61). CONCLUSION: Both interventions were easily implemented and proved to be safe. Because both interventions are arguably cost-effective, these pilot findings, although promising, need to be replicated in large samples. CLINICALTRIALS.GOV IDENTIFIER: NCT04636541.

Altered Theory of Mind in Parkinson's Disease and Impact on Caregivers: A Pilot Study.

Mild cognitive impairment (MCI) in Parkinson's disease (PD) includes deficits in theory of mind (ToM). However, associations between ToM and caregiver burden and distress are still unclear. The objective of this pilot study was to preliminarily explore the relation between ToM and caregiver burden and distress in a sample of PD-MCI patients. Twelve PD-MCI patients were evaluated on a ToM task (Faux Pas), whereas their caregivers were assessed on caregiver burden (Zarit Burden Interview-12 items) and distress (Neuropsychiatric Inventory-Distress). Cognitive ToM was significantly associated with caregiver distress, but caregiver burden was associated with the severity of patient psychiatric symptoms.

The impact of cognitive interventions on cognitive symptoms in idiopathic Parkinson's disease: a systematic review.

This systematic review addressed efficacy of cognitive stimulation (CS), cognitive training (CT), and cognitive rehabilitation (CR) to improve cognitive functions in Parkinson's disease (PD) with (PD-MCI) and without mild cognitive impairment (PD-H). Five databases were searched. Twelve CT, four CS, and a combination of CT with CR were found. PD-H benefited from CT or CS compared to active or passive controls in 42.1% of cognitive tests, and in 33.3% of psychological and functional measures. PD-MCI alone, compared with controls, only improved in 6.9% of cognitive measures after CT. PD-H and PD-MCI, alone or together, somehow improved information processing speed, attention, working memory, executive functions, and visual episodic memory. PD-MCI improved better than PD-H in global cognition and planning abilities. The outcomes suggest some efficacy of cognitive interventions in PD. However, small samples, lack of information regarding standardization of interventions, and poor methodological quality limit results validity and prevent firm conclusions.

Goal management training ® home-based approach for mild cognitive impairment in Parkinson's disease: a multiple baseline case report.

Approximately 30% of patients with Parkinson's disease experience mild cognitive impairment (PD-MCI), often affecting executive functions. Our objective was to assess tolerability, safety and preliminarily efficacy of Goal Management Training® (GMT) for PD-MCI. GMT was administered at home, for five weeks. Dysexecutive Questionnaire (DEX), Parkinson Disease Questionnaire (PDQ-39), Zoo Map Test and Dementia Rating Scale-II were administered before, one and four weeks after Adapted-GMT. Reliable Change Index (RCI) was calculated. One participant completed GMT with caregiver. Executive complaints decreased (DEX RCIs between -2.10 and -1.68), PDQ-39 was maintained (RCI = -0.18). Adapted-GMT seems safe for PD-MCI, but efficacy remains doubtful.

Altered cerebral insulin response in transgenic mice expressing the epsilon-4 allele of the human apolipoprotein E gene.

Apolipoprotein E epsilon-4 (APOEε4 or APOE4), an allelic variation of the APOE gene, not only increases the risk of developing the late-onset form of Alzheimer's disease (AD), but also influences the outcome of treatment. Indeed, data from clinical studies show that the beneficial effect of insulin on cognition is blunted in APOE4 carriers. To investigate how APOE impacts insulin response, we assessed the effects of an acute insulin injection in APOE3- and APOE4-targeted replacement mice that respectively express the human APOE3 or APOE4 isoform instead of the endogenous murine ApoE protein. We evaluated cognition, insulin signaling and proteins implicated in Aß transport and tau phosphorylation in the cortex and brain capillaries. We found that a single acute insulin injection increased Akt pSer473 in APOE4 compared to APOE3 mice (+113% versus +78.5%), indicating that APOE4 carriage potentiates activation of insulin upstream signaling pathway in the brain. Insulin also led to decreased concentrations of the receptor for advanced glycation endproducts (RAGE) in brain capillaries in both groups of mice. Moreover, higher phosphorylation of tau at Ser202, one of the key markers of AD neuropathology, was observed in insulin-injected APOE4 mice (+44%), consistent with findings in human APOE4 carriers (+400% compared to non-carriers). Therefore, our data suggest that APOE4 carriage leads to an increased insulin-induced activation of cerebral Akt pathway, associated with higher AD-like tau neuropathology. Our results provide evidence of altered insulin signaling in APOE4 carriers as well as a possible mechanism to explain the absence of cognitive benefit from insulin therapy in these individuals.

Partial neurorescue effects of DHA following a 6-OHDA lesion of the mouse dopaminergic system.

Pre-clinical data collected in mouse models of Parkinson's disease (PD) support the neuroprotective potential of omega-3 polyunsaturated fatty acids (n-3 PUFA)-enriched diet on the dopaminergic (DAergic) system. In this study, we investigated the effects of an n-3 PUFA-rich diet using a neurorescue/neurorestorative paradigm. C57BL/6 adult mice were submitted to a striatal stereotaxic injection of the neurotoxin 6-hydroxydopamine (6-OHDA) to induce striatal DAergic denervation and subsequent nigral DAergic cell loss. Three weeks post-lesion, mice received either a docosahexaenoic acid (DHA)-enriched or a control diet for a period of 6 weeks. HPLC analyses revealed a 111% post-lesion increase in striatal dopamine levels in the DHA-fed animals compared to controls (ctrl, P<0.05), although no improvement in the motor behavior was observed. DHA treatment led to a 89% rise in tyrosine-hydroxylase (TH)-immunoreactive terminals within the striatum (P<0.05) in lesioned animals. Despite the fact that DHA did not change the number of TH+ neurons in the substantia nigra pars compacta (SNpc), morphological analyses revealed an increased in perimeters (+7%) and areas (+21%) of DAergic cell bodies in treated animals. Collectively, our results suggest that DHA induces a partial neurorescue/neurorestoration of the DAergic system and support further studies to investigate the potential of a diet-based intervention, or at least the combination of such approach, to current treatments in PD.