Can cell and gene therapies improve cognitive symptoms in Parkinson's disease?

Advanced therapeutic medicinal products (ATMPs), including cell and gene therapies, are in development for Parkinson’s disease (PD). In many cases, the goal is to replace the lost dopamine (DA), which is anticipated to improve motor dysfunctions associated with DA loss. However, it is less clear the extent to which these therapeutic interventions may impact on the wide range of cognitive symptoms that manifest as the disease progresses. Although the accepted perception is that cognitive symptoms are predominately non-DAergic in origin, in this commentary, it is argued that several, specific cognitive processes, such as habit formation, working memory and reward processing, have been reported to be DA-dependent. Furthermore, there is evidence of DAergic medications modulating these behaviours in PD patients. Finally, the potential for cell and gene ATMPs to influence these symptoms is considered. It is concluded that DA replacement through ATMPs is likely to improve certain DA-dependent symptoms, but only sparse clinical data are currently available and the ability to precisely titrate DA transmission is likely to be complex

Influence of beta-amyloid pathology on emotional learning and memory in the APPswe model of Alzheimer's disease

Previous studies have shown that both the amygdala and frontal cortex contribute to emotional and motivational processes in rodents and humans. These regions show extensive amyloid pathology in humans with Alzheimer's disease (AD) and in mouse models of AD. However, the impact of amyloid production on emotional and motivational processes in mouse models of AD has not been systematically examined. The presence of pathology within key regions linked to emotional processes led to the hypothesis that Tg2576 mice, which express a human genetic mutation associated with early onset AD, would show age-related deficits in emotional reactivity and incentive and aversive learning and memory processes. Biochemical and immunohistochemical analysis confirmed the presence of extensive amyloid pathology in cortical, amygdala and medial temporal lobe structures in Tg2576 mice. Behavioural studies established impairments in anxiety, behavioural disinhibition and fear conditioning in Tg2576 mice. In contrast, other experiments showed that appetitive instrumental and Pavlovian conditioning remained goal-directed in aged Tg2576 mice. However, context-outcome associations were insensitive to post-conditioning changes in the value of the outcome in aged but not in young Tg2576 mice. In order to gain insight into how Ap pathology influenced hippocampal-amygdala system activity during emotional learning, the final set of experiments assessed changes in the expression of the immediate early gene product c-Fos following acquisition and retrieval of fear memories. The findings from this thesis indicate that Tg2576 mice display relatively circumscribed changes in emotional reactivity and emotional memory processes that may reflect age-related alterations in amygdalo-hippocampal network interactions

Cognitive training modifies disease symptoms in a mouse model of Huntington's disease

Huntington's disease (HD) is an incurable neurodegenerative disorder which causes a triad of motor, cognitive and psychiatric disturbances. Cognitive disruptions are a core feature of the disease, which significantly affect daily activities and quality of life, therefore cognitive training interventions present an exciting therapeutic intervention possibility for HD. We aimed to determine if specific cognitive training, in an operant task of attention, modifies the subsequent behavioural and neuropathological phenotype of the Hdh(Q111) mouse model of HD. Three testing groups comprising both Hdh(Q111) mice and wildtype controls were used. The first group received cognitive training in an operant task of attention at 4 months of age. The second group received cognitive training in a comparable non-attentional operant task at 4 months of age, and the third group were control animals that did not receive cognitive training. All groups were then tested in an operant task of attention at 12 months of age. Relative to naïve untrained mice, both wildtype and Hdh(Q111) mice that received cognitive training in the operant task of attention demonstrated an increased number of trials initiated, greater accuracy, and fewer ‘time out’ errors. A specific improvement in response time performance was observed in Hdh(Q111) mice, relative to naïve untrained Hdh(Q111) mice. Relative to the group that received comparable training in a non-attentional task, both wildtype and Hdh(Q111) mice that received attentional training demonstrated superior accuracy in the task and made fewer ‘time out’ errors. Despite significant behavioural change, in both wildtype and Hdh(Q111) mice that had received cognitive training, no significant changes in neuropathology were observed between any of the testing groups. These results demonstrate that attentional cognitive training implemented at a young age significantly improves attentional performance, at an older age, in both wildtype and Hdh(Q111) mice. Attentional cognitive training also improved motor performance in Hdh(Q111) mice, thus leading to the conclusion that cognitive training can improve disease symptoms in a mouse model of HD

Rethinking functional outcome measures: the development of an upper limb test to assess basal ganglia dysfunction

The basal ganglia is implicated in a wide range of motor, cognitive and behavioural activities required for normal function. This region is predominantly affected in Huntington’s disease (HD), meaning that functional ability progressively worsens. However, functional outcome measures for HD, particularly those for the upper limb, are limited meaning there is an imperative for well-defined, quantitative measures. Here we describe the development and evaluation of the Moneybox test (MBT). This novel, functional upper limb assessment was developed in accordance with translational neuroscience and physiological principles for people with a broad disease manifestation, such as HD. Participants with HD (n=64) and healthy controls (n=21) performed the MBT, which required subjects to transfer tokens into a container in order of size (Baseline Transfer), value (Complex Transfer) with and without reciting the alphabet (Dual Transfer). Disease specific measures of motor, cognition, behaviour and function were collected. HD patients were grouped into disease stage, from which, discriminative and convergent validity was assessed using Analysis of Variance and Pearson’s correlation respectively. Manifest HD participants were slower than pre-manifest and control participants, and achieved significantly lower MBT total scores. Performance in the Complex Transfer and Dual Transfer tasks were significantly different between pre-manifest and stage 1 HD. All MBT performance variables significantly correlated with routinely used measures of motor, cognition, behaviour and function. The MBT provides a valid, sensitive and affordable functional outcome measure. Unlike current assessments, MBT performance significantly distinguished the subtle differences between the earliest disease stages of HD, which are the populations typically targeted in clinical trials

Defining the unknowns for cell therapies in Parkinson's disease

First-in-human clinical trials have commenced to test the safety and efficacy of cell therapies for people with Parkinson's disease (PD). Proof of concept that this neural repair strategy is efficacious is based on decades of preclinical studies and clinical trials using primary foetal cells, as well as a significant literature exploring more novel stem cell-derived products. Although several measures of efficacy have been explored, including the successful in vitro differentiation of stem cells to dopamine neurons and consistent alleviation of motor dysfunction in rodent models, many unknowns still remain regarding the long-term clinical implications of this treatment strategy. Here, we consider some of these outstanding questions, including our understanding of the interaction between anti-Parkinsonian medication and the neural transplant, the impact of the cell therapy on cognitive or neuropsychiatric symptoms of PD, the role of neuroinflammation in the therapeutic process and the development of graft-induced dyskinesias. We identify questions that are currently pertinent to the field that require further exploration, and pave the way for a more holistic understanding of this neural repair strategy for treatment of PD