Progressive supranuclear palsy: Advances in diagnosis and management

Progressive supranuclear palsy (PSP) is a complex clinicopathologic disease with no current cure or disease modulating therapies that can only be definitively confirmed at autopsy. Growing understanding of the phenotypic diversity of PSP has led to expanded clinical criteria and new insights into etiopathogenesis that coupled with improved in vivo biomarkers makes increased access to current clinical trials possible. Current standard-of-care treatment of PSP is multidisciplinary, supportive and symptomatic, and several trials of potentially disease modulating agents have already been completed with disappointing results. Current ongoing clinical trials target the abnormal aggregation of tau through a variety of mechanisms including immunotherapy and gene therapy offer a more direct method of treatment. Here we review PSP clinicopathologic correlations, in vivo biomarkers including MRI, PET, and CSF biomarkers. We additionally review current pharmacologic and non-pharmacologic methods of treatment, prior and ongoing clinical trials in PSP. Newly expanded clinical criteria and improved specific biomarkers will aid in identifying patients with PSP earlier and more accurately and expand access to these potentially beneficial clinical trials.     

The Genetics of Spinal Muscular Atrophy: Progress and Challenges

Spinal muscular atrophies (SMAs) are a group of inherited disorders characterized by motor neuron loss in the spinal cord and lower brainstem, muscle weakness, and atrophy. The clinical and genetic phenotypes incorporate a wide spectrum that is differentiated based on age of onset, pattern of muscle involvement, and inheritance pattern. Over the past several years, rapid advances in genetic technology have accelerated the identification of causative genes and provided important advances in understanding the molecular and biological basis of SMA and insights into the selective vulnerability of the motor neuron. Common pathophysiological themes include defects in RNA metabolism and splicing, axonal transport, and motor neuron development and connectivity. Together these have revealed potential novel treatment strategies, and extensive efforts are being undertaken towards expedited therapeutics. While a number of promising therapies for SMA are emerging, defining therapeutic windows and developing sensitive and relevant biomarkers are critical to facilitate potential success in clinical trials. This review incorporates an overview of the clinical manifestations and genetics of SMA, and describes recent advances in the understanding of mechanisms of disease pathogenesis and development of novel treatment strategies.

Electronic supplementary material

The online version of this article (doi:10.1007/s13311-014-0314-x) contains supplementary material, which is available to authorized users.     

A randomized, controlled, clinical trial of activity therapy for apathy in patients with dementia residing in long-term care

BACKGROUND: Apathy is a common symptom in patients with dementia and has adverse consequences for patients and caregivers. Most treatments for apathy, particularly non-pharmacologic interventions, have not been evaluated in controlled trials. OBJECTIVES: This study evaluated the efficacy of a kit-based activity intervention, compared to a time and attention control (one-on-one meetings with an activity therapist) in reducing apathy and improving quality of life in 37 patients with dementia. METHODS: The design was a randomized, controlled, partially masked clinical trial. All outcome measures were administered at baseline and follow-up. The primary outcome measure was the apathy score of the Neuropsychiatric Inventory (NPI). Other outcome measures were the NPI total score, the Alzheimer Disease Related Quality of Life scale(ADQRL), and the Copper Ridge Activity Index (CRAI). RESULTS: There was a significant reduction in NPI apathy scores in both treatment groups. The only significant difference between the two treatment groups was a modest advantage for the control intervention on the CRAI cueing subscale (p = 0.027), but not on the other CRAI subscales. There was also a greater within group improvement in quality of life ratings in the control intervention (p=0.03). CONCLUSIONS: Despite the substantial improvement in apathy scores during the course of the study, there was no clear advantage to the reminiscence-based intervention over the time and attention, one-on-one control intervention. More research is needed to develop specific behavioral interventions for apathy in patients with dementia.     

Biomarkers in psychotropic drug development.

The authors review the use of biomarkers in the development of novel psychotropic agents. They briefly review clinical drug development, emphasizing the importance of incorporating biomarkers. For the development of psychotropic agents, biomarkers are particularly useful for assessing central nervous system exposure and effects and for serving as surrogate measures for safety and efficacy. Collectively, biomarkers allow for more accurate estimation of doses for clinical trials as drug development progresses. For drugs that target the pathophysiology of Alzheimer disease, several promising biomarkers are becoming available that may allow improved signal detection in clinical trials. Procedures for developing new drugs are evolving rapidly. Technical advances in the field are making it possible to shift from empirically-based methods to mechanistically-driven schemes. Biomarkers enhance the quality and safety of clinical drug development and reduce its cost and duration.     

Treating Posttraumatic Stress Disorder in Diverse Settings: Recent Advances and Challenges for the Future

Racial and ethnic minorities are at high risk for developing posttraumatic stress disorder (PTSD) after experiencing a traumatic event and are less likely to receive evidence-based treatment for their symptoms. There is a growing body of literature showing that culturally appropriate interventions result in greater uptake, symptom reduction, and sustained treatment gains. This article review explores new findings in the cultural understanding of PTSD among racial and ethnic minorities. We first review recent advances in the understanding of PTSD symptomotology. Next, we provide overview of trials demonstrating efficacy and effectiveness of cognitive processing therapy (CPT), prolonged exposure (PE), and trauma-focused cognitive-behavioral therapy (TF-CBT) in diverse communities. Then, we discuss specific implementation strategies common across intervention trials used to increase feasibility, acceptability, adoption, and sustainability. Last, we discuss areas for future research and dissemination efforts.     

Frontotemporal lobar degeneration: recent progress in antemortem diagnosis

Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disorder characterized by changes in behaviour and language dysfunction. Two broad pathological subdivisions of FTLD are recognized in a recent classification scheme based on biochemical features: tau-positive pathology due to the accumulation of various forms of the microtubule-associated protein tau, such as FTLD with Pick bodies and corticobasal degeneration; and tau-negative pathology such as frontotemporal lobar degeneration with ubiquitin/TDP-43-immunoreactive inclusions. Etiologically based treatments aim to target the mechanisms underlying the accumulation of these abnormal proteins in these conditions. It is essential for us to develop biomarkers that support the accurate diagnosis of the specific diseases causing FTLD. These biomarkers also can be useful in assessing efficacy during treatment trials. This review summarizes the epidemiologic, clinical, neuropsychological, imaging and cerebrospinal fluid (CSF) biomarker features that can help identify these pathologically defined conditions during life.     

Surrogate endpoints in Parkinson’s disease research

Biomarkers are important tools in understanding the underlying mechanisms of causation, progression, and treatment effects in Parkinson’s disease (PD). In addition, these biomarkers may be utilized as surrogate endpoints that, when used appropriately, can lead to important advances in therapeutics in a timely and cost-effective manner. This paper outlines the definition, role, validity process, and risks associated with surrogate endpoints. The use of biomarkers in recent PD clinical trials is discussed and potential shortcomings and unanswered questions related to interpreting these outcomes are reviewed. Finally, the significant challenges that lie ahead for validating and interpreting surrogate endpoints in PD are addressed.     

Magnetic resonance imaging as an approach towards identifying neuropathological biomarkers for Huntington's disease

Magnetic Resonance Imaging (MRI), functional MRI (fMRI) and Diffusion Tensor Imaging (DTI) have been central to characterisation of abnormalities in brain structure and function in both clinical and preclinical Huntington's disease (HD). One current challenge in clinical HD research is the identification of sensitive and reliable biomarkers to detect progressive neurodegeneration and neural dysfunction, which could be used to assess the effect of therapeutic intervention on brain structure and function in a HD clinical trial. To this end, both established and novel neuroimaging approaches could potentially provide sensitive, reliable and non-invasive tools to assess long-term and dynamic effects of treatment on specific brain regions, including their microstructure and connectivity. This review examines contributions from structural MRI, fMRI and DTI studies to our current understanding of preclinical and clinical HD, and critically appraises MRI methods potentially suitable for both scientific characterisation and for use as biomarkers in HD clinical trials. A combined neuroimaging approach incorporating structural MRI, fMRI and DTI is yet to be realised in HD clinical trials, however if proven to be sensitive and reliable, these methods could potentially serve as biomarkers for use in future clinical drug trials in HD.     

Improving the prediction of response to therapy in autism

Autism is a heterogeneous disorder involving complex mechanisms and systems occurring at diverse times. Because an individual child with autism may have only a subset of all possible abnormalities at a specific time, it may be challenging to identify beneficial effects of an intervention in double-blind, randomized, controlled trials, which compare the mean responses to treatments. Beneficial effects in a small subset of children may be obscured by the lack of effect in the majority. We review the evidence for several potential model systems of biochemical abnormalities that may contribute to the etiology of autism, we describe potential biomarkers or treatment targets for each of these abnormalities, and we provide illustrative treatment trials using this methodology. Potential model systems include immune over and under reactivity, inflammation, oxidative stress, free fatty acid metabolism, mitochondrial dysfunction, and excitotoxicity. Including potential biomarkers and targeted treatments in clinical trials for autism provides a potential method for limiting the heterogeneity of enrolled subjects, which may improve the power of studies to identify beneficial effects of treatments while also improving the understanding of the disease.     

Trait and state biomarkers for psychiatric disorders: Importance of infrastructure to bridge the gap between basic and clinical research and industry

To further improve clinical activities in psychiatry by early diagnosis and early intervention with novel mechanism‐guided treatments, there is a great need for biomarkers that reflect ‘trait’ and ‘state’ in major mental disorders. Stable trait biomarkers would allow early diagnosis, prognosis, and hopefully early intervention in these disorders, while dynamic state markers that reflect symptomatic changes would help to develop treatments that target these molecular mechanisms. However, in the search for such biomarkers, and eventually translating them to the clinic and industry, challenges currently exist at multiple levels, from basic scientific understanding, patient sample collection, and sample and data management, to bridging the gap between basic and clinical research and industry. To address these challenges, we propose an infrastructure that emphasizes: (i) a research and educational framework to facilitate translation between basic neuroscience, clinical research, and industry; (ii) patient recruitment and collection of disease‐relevant samples to study trait and state biomarkers; and (iii) a comprehensive database to integrate patient and sample information with biological and clinical data. We believe that such an approach would bolster: research into the biological mechanisms of psychiatric disorders; and collaboration among the laboratory, clinic, and industry to translate these findings into successful treatments.     

Biological markers of amyloid β-related mechanisms in Alzheimer's disease

Recent research progress has given detailed knowledge on the molecular pathogenesis of Alzheimer's disease (AD), which has been translated into an intense, ongoing development of disease-modifying treatments. Most new drug candidates are targeted on inhibiting amyloid β (Aβ) production and aggregation. In drug development, it is important to co-develop biomarkers for Aβ-related mechanisms to enable early diagnosis and patient stratification in clinical trials, and to serve as tools to identify and monitor the biochemical effect of the drug directly in patients. Biomarkers are also requested by regulatory authorities to serve as safety measurements. Molecular aberrations in the AD brain are reflected in the cerebrospinal fluid (CSF). Core CSF biomarkers include Aβ isoforms (Aβ40/Aβ42), soluble APP isoforms, Aβ oligomers and β-site APP-cleaving enzyme 1 (BACE1). This article reviews recent research advances on core candidate CSF and plasma Aβ-related biomarkers, and gives a conceptual review on how to implement biomarkers in clinical trials in AD.     

Disordered Decision Making: A Cognitive Framework for Apathy and Impulsivity in Huntington's Disease

A caregiver's all-too-familiar narrative - “He doesn't think through what he does, but mostly he does nothing.” Apathy and impulsivity, debilitating and poorly understood, commonly co-occur in Huntington's disease (HD). HD is a neurodegenerative disease with manifestations bridging clinical neurology and psychiatry. In addition to movement and cognitive symptoms, neurobehavioral disturbances, particularly apathy and impulsivity, are prevalent features of HD, occurring early in the disease course, often worsening with disease progression, and substantially reducing quality of life. Treatments remain limited, in part because of limited mechanistic understanding of these behavioral disturbances. However, emerging work within the field of decision-making neuroscience and beyond points to common neurobiological mechanisms underpinning these seemingly disparate problems. These insights bridge the gap between underlying disease pathology and clinical phenotype, offering new treatment strategies, novel behavioral and physiological biomarkers of HD, and deeper understanding of human behavior. In this review, we apply the neurobiological framework of cost-benefit decision making to the problems of apathy and impulsivity in HD. Through this decision-making lens, we develop a mechanistic model that elucidates the occurrence of these behavioral disturbances and points to potential treatment strategies and crucial research priorities. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.     

Milestones in Huntington disease

There have been extraordinary advances in our knowledge of the underlying gene, the protein it encodes, various models of disease, and potential targets for effective therapies for Huntington disease. Huntington disease research has increased exponentially in the past 25 years, and we now understand many of the molecular mechanisms underlying the disease. Still, more work needs to be done before we have a full understanding of the pathophysiology of the disease. Clinical research on biomarkers and clinical trials on potential neuroprotective agents are underway. Here we review our progress in these areas over the last 25 years and speculate on what the next 25 years may hold. © 2011 Movement Disorder Society     

Early intervention in bipolar disorder,part I: clinical and imaging findings

The concept of prevention is not new to psychiatry and has long been recognized in general medicine. Recent evidence has highlighted that early pharmacological and psychosocial treatment dramatically ameliorates poor prognosis and outcome for individuals with psychotic disorders, reducing conversion rates to full‐blown illness and decreasing symptom severity. Nevertheless, despite the many recent advances in our thinking about early intervention, the need for early intervention in bipolar disorder (BPD) is an area that has been relatively neglected. This review attempts to synthesize what is currently known about early intervention in BPD. We discuss methodological issues pertaining to this topic, review clinical studies that focus on high‐risk subjects as well as first‐episode patients and review findings from brain imaging studies in the offspring of individuals with BPD as well as in first‐episode patients. A companion paper discusses the cellular and molecular mechanisms of action of agents with neurotrophic and neuroplastic properties, with a particular emphasis on lithium and valproate.     

Behavioral and language variants of frontotemporal dementia: A review of key symptoms

While recent advances in the development of neuroimaging and molecular biomarkers for studying neurodegenerative conditions have revolutionized the field, dementia remains a clinical diagnosis. No component of the diagnostic process is more crucial than obtaining a good history. Getting to know the first manifestations of the disease, tracking their evolution and functional impact, combined with a targeted neurological examination, further guides differential diagnosis. This paper summarizes the key symptoms of the behavioral and language variants of frontotemporal dementia. The behavioral variant of frontotemporal dementia (bvFTD) is characterized by severe changes in behavior and personality such as disinhibition, apathy, loss of empathy, or stereotypic behavior, leading to a loss of social competence. Executive functions are impaired, while memory and visuospatial skills are relatively better preserved. By contrast, the language variants or primary progressive aphasias (PPAs) are marked by prominent language disturbances that can be subclassified into a non-fluent/agrammatic variant (naPPA), a semantic variant (svPPA), and a logopenic variant (lvPPA). Although combined characterization of clinical, imaging, biological and genetic biomarkers is essential to establish a detailed diagnosis of such heterogeneous conditions, the author emphasizes the importance of accurate recognition of key symptoms that can lead to better identification of underlying neuropathology and appropriate treatment approaches.     

Harnessing Cerebrospinal Fluid Biomarkers in Clinical Trials for Treating Alzheimer's and Parkinson's Diseases: Potential and Challenges

No disease-modifying therapies (DMT) for neurodegenerative diseases (NDs) have been established, particularly for Alzheimer''s disease (AD) and Parkinson''s disease (PD). It is unclear why candidate drugs that successfully demonstrate therapeutic effects in animal models fail to show disease-modifying effects in clinical trials. To overcome this hurdle, patients with homogeneous pathologies should be detected as early as possible. The early detection of AD patients using sufficiently tested biomarkers could demonstrate the potential usefulness of combining biomarkers with clinical measures as a diagnostic tool. Cerebrospinal fluid (CSF) biomarkers for NDs are being incorporated in clinical trials designed with the aim of detecting patients earlier, evaluating target engagement, collecting homogeneous patients, facilitating prevention trials, and testing the potential of surrogate markers relative to clinical measures. In this review we summarize the latest information on CSF biomarkers in NDs, particularly AD and PD, and their use in clinical trials. The large number of issues related to CSF biomarker measurements and applications has resulted in relatively few clinical trials on CSF biomarkers being conducted. However, the available CSF biomarker data obtained in clinical trials support the advantages of incorporating CSF biomarkers in clinical trials, even though the data have mostly been obtained in AD trials. We describe the current issues with and ongoing efforts for the use of CSF biomarkers in clinical trials and the plans to harness CSF biomarkers for the development of DMT and clinical routines. This effort requires nationwide, global, and multidisciplinary efforts in academia, industry, and regulatory agencies to facilitate a new era.     

Tuberous Sclerosis: A New Frontier in Targeted Treatment of Autism

Tuberous sclerosis complex (TSC) is a genetic disorder with a high prevalence of autism spectrum disorder (ASD). Tremendous progress in understanding the pathogenesis of TSC has been made in recent years, along with initial trials of medical treatment aimed specifically at the underlying mechanism of the disorder. At the cellular level, loss of TSC1 or TSC2 results in upregulation of the mechanistic target of rapamycin (mTOR) pathway. At the circuitry level, TSC and mTOR play crucial roles in axonal, dendritic, and synaptic development and function. In this review, we discuss the molecular mechanism underlying TSC, and how this disease results in aberrant neural connectivity at multiple levels in the central nervous system, leading to ASD symptoms. We then review recent advances in mechanism-based treatments of TSC, and the promise that these treatments provide for future mechanism-based treatment of ASD. Because of these recent advances, TSC represents an ideal model for how to make progress in understanding and treating the mechanisms that underlie ASD in general.

Electronic supplementary material

The online version of this article (doi:10.1007/s13311-015-0359-5) contains supplementary material, which is available to authorized users.Key Words: mTOR, translation, white matter, cerebellum     

Apathy after acquired brain impairment: A systematic review of non-pharmacological interventions

Apathy commonly occurs after acquired brain impairment. It is characterised by impaired initiative, diminished activity, and lack of concern; formally delineated as a decrease in cognitive, behavioural and emotional components of goal-directed activity. The impact is widespread, hampering rehabilitation and outcome. This systematic review identifies and assesses the efficacy of non-pharmacological treatments for apathy following four types of acquired brain impairment (traumatic brain injury, dementia, cerebrovascular accident, encephalitis). Nine databases were searched. Studies were reviewed according to the following criteria: age over 16 years, acquired brain impairment, non-pharmacological intervention for apathy, and data reported on treatment efficacy. The methodological quality of the studies was assessed. Searches yielded 1754 articles, with 28 meeting criteria. Methodological quality ranged greatly. The majority of trials involved the dementia population. Cognitive interventions were the most frequent mode of treatment. For those with severe impairments, the strongest evidence suggested music therapy and for milder impairment, the strongest evidence was for cognitive rehabilitation. This review reveals a need for more high quality, methodologically rigorous treatment studies for apathy, particularly within the milder ranges of impairment. Initially, however, a uniform operational definition needs to be utilised in all research studies to minimise variability. Additionally, employing a standardised outcome measure specific to apathy would greatly enhance comparison among treatments.     

Evoked potentials generated by deep brain stimulation for Parkinson's disease

Background and objectivesThe goal of this review is to describe the general features, mechanisms, technical recording factors, and clinical applications of brain evoked potentials (EPs) generated by deep brain stimulation (DBS) for Parkinson's disease (PD).ResultsEvoked potentials in response to DBS pulses occur on the timescale of milliseconds and are found both locally at the site of stimulation and remotely in the cortex. DBS evoked potentials arise from a complex integration of antidromic and orthodromic conduction pathway responses, and provide information valuable for understanding the mechanisms and circuits involved in symptom treatment. Furthermore, these signals may provide biomarkers for improving DBS outcomes and function. For example, evoked potentials may have utility as control signals for DBS programming or adaptive DBS. Despite their promise there are still critical gaps in our understanding of the mechanisms by which evoked potentials arise and how these signals may be measured and applied in the clinical setting. Technical challenges of recording a highly transient signal at sufficient resolution without the interference of stimulation artifact present a barrier to understanding better DBS-induced EPs.ConclusionsWe describe the current scientific landscape of evoked potentials to facilitate and stimulate further investigation.