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The ability to repair or promote regeneration within the adult human brain has been envisioned for decades. Until recently, such efforts mainly involved delivery of growth factors and cell transplants designed to rescue or replace a specific population of neurons, and the results have largely been disappointing. New approaches using stem-cell-derived cell products and direct cell reprogramming have opened up the possibility of reconstructing neural circuits and achieving better repair. In this Review we briefly summarize the history of neural repair and then discuss these new therapeutic approaches, especially with respect to chronic neurodegenerative disorders.

Key Points Dopaminergic drugs were established as an effective treatment for Parkinson disease (PD) in the 1960s, and are still the mainstay of therapy for this condition Experiments that heralded the modern era of neural grafting for PD began in the 1970s in Sweden Despite limited preclinical data, adrenal medullary transplantation was adopted by many groups during the 1980s, with largely disappointing results Human fetal ventral mesencephalic (fVM) allografts have been shown to survive and function for over 20 years in some patients The protocol for neural transplantation in patients with PD remains to be optimized Human fVM grafts are currently being revisited, and stem cell-based dopamine replacement therapies are close to clinical trials Following the success of pharmacological dopamine replacement in patients with Parkinson disease (PD), cell-based dopamine replacement strategies seemed the next logical step. In this Review, the authors outline the history of this therapeutic approach to PD, emphasizing the importance of obtaining robust preclinical data before proceeding to clinical trials. In addition, they discuss the challenges of bringing the new generation of stem cell-derived dopamine cells to the clinic. Parkinson disease (PD) is characterized by loss of the A9 nigral neurons that provide dopaminergic innervation to the striatum. This discovery led to the successful instigation of dopaminergic drug treatments in the 1960s, although these drugs were soon recognized to lose some of their efficacy and generate their own adverse effects over time. Despite the fact that PD is now known to have extensive non-nigral pathology with a wide range of clinical features, dopaminergic drug therapies are still the mainstay of therapy, and work well for many years. Given the success of pharmacological dopamine replacement, pursuit of cell-based dopamine replacement strategies seemed to be the next logical step, and studies were initiated over 30 years ago to explore the possibility of dopaminergic cell transplantation. In this Review, we outline the history of this therapeutic approach to PD and highlight the lessons that we have learned en route . We discuss how the best clinical outcomes have been obtained with fetal ventral mesencephalic allografts, while acknowledging inconsistencies in the results owing to problems in trial design, patient selection, tissue preparation, and immunotherapy used post-grafting. We conclude by discussing the challenges of bringing the new generation of stem cell-derived dopamine cells to the clinic.

Clinical use of allografts of fetal ventral mesencephalic tissue as a treatment to replace dopaminergic neurons in patients with Parkinson's disease was first done more than 20 years ago. Since then, many patients have received transplants, with variable results. During this time, our knowledge of Parkinson's disease has changed and the nature and extent of problems associated with the disorder have been better defined. Our understanding on how best to implement this cell-replacement strategy for patients has grown, but gaining this insight has entailed critical reappraisal of data from transplant trials that have already been undertaken.

Parkinson's disease (PD) is a common neurodegenerative disease typified by a movement disorder consisting of bradykinesia, rest tremor, rigidity, and postural instability. Treatment options for PD are limited, with most of the current approaches based on restoration of dopaminergic tone in the striatum. However, these do not alter disease course and do not treat the non-dopamine-dependent features of PD such as freezing of gait, cognitive impairment, and other non-motor features of the disorder, which often have the greatest impact on quality of life. As understanding of PD pathogenesis grows, novel therapeutic avenues are emerging. These include treatments that aim to control the symptoms of PD without the problematic side effects seen with currently available treatments and those that are aimed towards slowing pathology, reducing neuronal loss, and attenuating disease course. In this latter regard, there has been much interest in drug repurposing (the use of established drugs for a new indication), with many drugs being reported to affect PD-relevant intracellular processes. This approach offers an expedited route to the clinic, given that pharmacokinetic and safety data are potentially already available. In terms of better symptomatic therapies that are also regenerative, gene therapies and cell-based treatments are beginning to enter clinical trials, and developments in other neurosurgical strategies such as more nuanced deep brain stimulation approaches mean that the landscape of PD treatment is likely to evolve considerably over the coming years. In this review, we provide an overview of the novel therapeutic approaches that are close to, or are already in, clinical trials.

Cognitive impairment in patients with Parkinson's disease is gaining increased clinical significance owing to the relative success of therapeutic approaches to the motor symptoms of this disorder. Early investigations contributed to the concept of subcortical dementia associated with bradyphrenia and cognitive rigidity. For cognition in parkinsonian disorders, this notion developed into the concept of mild cognitive impairment and fronto-executive dysfunction in particular, driven mainly by dopaminergic dysmodulation and manifesting as deficits in flexibility, planning, working memory, and reinforcement learning. However, patients with Parkinson's disease could also develop a syndrome of dementia that might depend on non-dopaminergic, cholinergic cortical dysfunction. Recent findings, supplemented by advances in neuroimaging and genetic research, reveal substantial heterogeneity in the range of cognitive deficits in patients with Parkinson's disease. Remediation and management prospects for these cognitive deficits are based on neuropharmacological and cognitive rehabilitation approaches.

Background Prognosis in Parkinson's disease (PD) remains poorly understood due to a lack of unbiased data on the natural history of treated PD. The CamPaIGN study has been the first to prospectively track disease evolution from diagnosis in an unselected population-representative incident cohort. We now report the 10-year follow-up data, focusing on three key irreversible milestones: postural instability (Hoehn and Yahr 3), dementia and death. Methods The cohort was collected between December 2000 and 2002. Those meeting diagnostic criteria (n=142) were followed-up until 1 January 2012. Clinical, neuropsychological and genetic testing were performed. Progression to key milestones was evaluated using Kaplan–Meier and Cox regression survival analyses. Results At 10 years, 55% had died, 68% had postural instability and 46% dementia. 23% had a good outcome at 10 years (surviving free of dementia/postural instability). Death rate was comparable with the UK population (standardised mortality ratio 1.29 (0.97–1.61)). Death certificates indicated PD was a substantial contributor in only 20%, with pneumonia being the commonest cause of death. Age, non-tremor-dominant motor phenotype and comorbidity predicted earlier postural instability. Baseline predictors of dementia were age, motor impairment, ‘posterior-cortical’ cognitive deficits and MAPT genotype. Conclusions (1) outlook in PD is heterogeneous, with most dying or developing dementia or postural instability by 10 years from diagnosis, but a quarter still doing well, with preserved mobility and intact cognition; (2) death is not directly related to PD in the majority; (3) baseline clinical and genetic variables are predictive of outcome and may be helpful in selecting patients for clinical trials.

Research into the heterogeneous nature of cognitive impairment documented in patients with Parkinson’s disease (PD) has focused on disentangling deficits that vary between individuals, evolve and respond differentially to pharmacological treatments, and relate differentially to PD dementia (PDD). We summarise studies conducted in our laboratory over the last 2 decades, outlining the incremental development of our hypotheses, the starting point for which is our early work on executive deficits mirroring fronto-striatal dysfunction. We present subsequent findings linking these deficits to a model of dopaminergic function that conforms to an inverted curvilinear function. We review studies that investigated the range of dopamine-independent attentional and visuospatial memory deficits seen in PD, demonstrating that abnormalities in these domains more accurately predict PDD. We conclude with an exposition of the dual syndrome hypothesis, which distinguishes between dopaminergically mediated fronto-striatal executive impairments and a dementia syndrome with distinctive prodromal visuospatial deficits in which cholinergic treatments offer some clinical benefits.

Huntington’s disease (HD) is an inherited neurodegenerative disease characterised by neuropsychiatric symptoms, a movement disorder (most commonly choreiform) and progressive cognitive impairment. The diagnosis is usually confirmed through identification of an increased CAG repeat length in the huntingtin gene in a patient with clinical features of the condition. Though diagnosis is usually straightforward, unusual presentations can occur, and it can be difficult to know when someone has transitioned from being an asymptomatic carrier into the disease state. This has become increasingly important recently, with several putative disease-modifying therapies entering trials. A growing number of conditions can mimic HD, including rare genetic causes, which must be considered in the event of a negative HD genetic test. Patients are best managed in specialist multidisciplinary clinics, including when considering genetic testing. Current treatments are symptomatic, and largely directed at the chorea and neurobehavioural problems, although supporting trial evidence for these is often limited.

Parkinson's disease (PD) is the second most common neurodegenerative disease, manifesting as a characteristic movement disorder with a number of additional non-motor features. The pathological hallmark of PD is the presence of intra-neuronal aggregates of α-synuclein (Lewy bodies). The movement disorder of PD occurs largely due to loss of dopaminergic neurons of the substantia nigra, resulting in striatal dopamine depletion. There are currently no proven disease modifying treatments for PD, with management options consisting mainly of dopaminergic drugs, and in a limited number of patients, deep brain stimulation. Long-term use of established dopaminergic therapies for PD results in significant adverse effects, and there is therefore a requirement to develop better means of restoring striatal dopamine, as well as treatments that are able to slow progression of the disease. A number of exciting treatments have yielded promising results in pre-clinical and early clinical trials, and it now seems likely that the landscape for the management of PD will change dramatically in the short to medium term future. Here, we discuss the promising regenerative cell-based and gene therapies, designed to treat the dopaminergic aspects of PD whilst limiting adverse effects, as well as novel approaches to reducing α-synuclein pathology.

Visual hallucinations are common in older people and are especially associated with ophthalmological and neurological disorders, including dementia and Parkinson’s disease. Uncertainties remain whether there is a single underlying mechanism for visual hallucinations or they have different disease-dependent causes. However, irrespective of mechanism, visual hallucinations are difficult to treat. The National Institute for Health Research (NIHR) funded a research programme to investigate visual hallucinations in the key and high burden areas of eye disease, dementia and Parkinson’s disease, culminating in a workshop to develop a unified framework for their clinical management. Here we summarise the evidence base, current practice and consensus guidelines that emerged from the workshop.Irrespective of clinical condition, case ascertainment strategies are required to overcome reporting stigma. Once hallucinations are identified, physical, cognitive and ophthalmological health should be reviewed, with education and self-help techniques provided. Not all hallucinations require intervention but for those that are clinically significant, current evidence supports pharmacological modification of cholinergic, GABAergic, serotonergic or dopaminergic systems, or reduction of cortical excitability. A broad treatment perspective is needed, including carer support. Despite their frequency and clinical significance, there is a paucity of randomised, placebo-controlled clinical trial evidence where the primary outcome is an improvement in visual hallucinations. Key areas for future research include the development of valid and reliable assessment tools for use in mechanistic studies and clinical trials, transdiagnostic studies of shared and distinct mechanisms and when and how to treat visual hallucinations.