Background Disease-modifying treatments are in development for Huntington's disease; crucial to their success is to identify a timepoint in a patient's life when there is a measurable biomarker of early neurodegeneration while clinical function is still intact. We aimed to identify this timepoint in a novel cohort of young adult premanifest Huntington's disease gene carriers (preHD) far from predicted clinical symptom onset. Methods We did the Huntington's disease Young Adult Study (HD-YAS) in the UK. We recruited young adults with preHD and controls matched for age, education, and sex to ensure each group had at least 60 participants with imaging data, accounting for scan fails. Controls either had a family history of Huntington's disease but a negative genetic test, or no known family history of Huntington's disease. All participants underwent detailed neuropsychiatric and cognitive assessments, including tests from the Cambridge Neuropsychological Test Automated Battery and a battery assessing emotion, motivation, impulsivity and social cognition (EMOTICOM). Imaging (done for all participants without contraindications) included volumetric MRI, diffusion imaging, and multiparametric mapping. Biofluid markers of neuronal health were examined using blood and CSF collection. We did a cross-sectional analysis using general leastsquares linear models to assess group differences and associations with age and CAG length, relating to predicted years to clinical onset. Results were corrected for multiple comparisons using the false discovery rate (FDR), with FDR <0•05 deemed a significant result. Findings Data were obtained between Aug 2, 2017, and April 25, 2019. We recruited 64 young adults with preHD and 67 controls. Mean ages of participants were 29•0 years (SD 5•6) and 29•1 years (5•7) in the preHD and control groups, respectively. We noted no significant evidence of cognitive or psychiatric impairment in preHD participants 23•6 years (SD 5•8) from predicted onset (FDR 0•22-0•87 for cognitive measures, 0•31-0•91 for neuropsychiatric measures). The preHD cohort had slightly smaller putamen volumes (FDR=0•03), but this did not appear to be closely related to predicted years to onset (FDR=0•54). There were no group differences in other brain imaging measures (FDR >0•16). CSF neurofilament light protein (NfL), plasma NfL, and CSF YKL-40 were elevated in this far-from-onset preHD cohort compared with controls (FDR<0•0001, =0•01, and =0•03, respectively). CSF NfL elevations were more likely in individuals closer to expected clinical onset (FDR <0•0001). Interpretation We report normal brain function yet a rise in sensitive measures of neurodegeneration in a preHD cohort approximately 24 years from predicted clinical onset. CSF NfL appears to be a more sensitive measure than plasma NfL to monitor disease progression. This preHD cohort is one of the earliest yet studied, and our findings could be used to inform decisions about when to initiate a potential future intervention to delay or prevent further neurodegeneration wh...

Providing formative assessment opportunities has been recognised as a significant benefit to student learning. The outcome of any formative assessment should be one that ultimately helps improve student learning through familiarising students with the levels of learning required, informing them about gaps in their learning and providing feedback to guide the direction of learning. This article provides an example of how formative assessments can be developed into a formative assessment journey where a number of different assessments can be offered to students during the course of a module of teaching, thus utilising a spacededucation approach. As well as incorporating the specific drivers of formative assessment, we demonstrate how approaches deemed to be stimulating, interactive and entertaining with the aim of maximising enthusiasm and engagement can be incorporated. We provide an example of a mixed approach to evaluating elements of the assessment journey that focuses student reaction, appraisal of qualitative and quantitative feedback from student questionnaires, focus group analysis and teacher observations. Whilst it is not possible to determine a quantifiable effect of the assessment journey on student learning, usage data and student feedback shows that formative assessment can achieve high engagement and positive response to different assessments. Those assessments incorporating an active learning element and a quiz-based approach appear to be particularly popular. A spaced-education format encourages a building block approach to learning that is continuous in nature rather than focussed on an intense period of study prior to summative examinations.

Drug induced parkinsonism and tardive dyskinesia are iatrogenic consequences of the use of antidopaminergic drugs. Both entities share risk factors, physiopathological mechanisms and to some degree, therapeutic approaches. Here we review both entities and discuss emerging therapies including the recently approved drug deutetrabenazine and relevant aspects for clinical practice such as new diagnostic techniques. Key points:-Drug induced parkinsonism and tardive dyskinesia are iatrogenic consequences of the use of antidopaminergic drugs.-DIP is considered a direct consequence of the blockage of D2 receptors while TD has a more complex physiopathology, including enhanced sensitivity of dopamine receptors.-Both entities are more frequent in older people due to a progressive loss of dopaminergic neurons with age.-New therapies are available for TD, including deutetrabenazine. Compliance with ethical Standards:Disclosure of potential conflicts of interest: no funding was received for this study.The risks of drug-induced parkinsonism/tardive dyskinesia in the elderly and current methods to overcome it. 1.-IntroductionTardive dyskinesia (TD) and drug-induced parkinsonism (DIP) are iatrogenic disorders caused by dopamine receptor blockers (DRB) [1]. They were recognized early after the introduction of antipsychotics[2] to the clinical practice, leading to the finding that DIP caused by reserpine, a dopamine depleter, was related to dopamine deficiency [3].Elderly patients are more susceptible to these side effects, probably due to an age-related decrease in nigral neurons and dopamine [4]. Since the introduction of newer second generation antipsychotics (SGA) the frequency and intensity of these side effects has improved [5] , [6] , [7] , [8] but there is still room for concern [9], [10].TD and DIP share risk factors, pathological mechanisms and management, and might coexist in one given subject. Latest available evidence has clarified some intriguing features of TD and DIP. Meanwhile, new medications to treat TD are now available, highlighting the importance of a thorough, updated, knowledge of this pathologies.This article offers a comprehensive review of the incidence, clinical features and mechanisms behind DIP and TD. The benefits and risks of previous available drugs and those that have been recently approved by regulatory agencies are discussed. Drug induced Parkinsonism DefinitionDIP occurs when symptoms emerge after exposure to drugs, usually those that either deplete dopamine storages [11] or block dopamine receptors [12]. By definition, symptoms should be reversible, six months after the offending agent has been withdrawn[13] but actually up to 20% of patients develop persistent deficits despite drug discontinuation [14] leading to the hypothesis that these patients might have subclinical Parkinson's Disease (PD) unmasked by neuroleptic exposure (umPD), complicating the differential diagnosis [15], especially between aged patients, who are more prone to both PD and DIP. Epidemiology and risk factorsAfter PD, DI...

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ObjectivesCognitive flexibility, which is key for adaptive decision-making, engages prefrontal cortex (PFC)-striatal circuitry and is impaired in both manifest and premanifest Huntington’s disease (pre-HD). The aim of this study was to examine cognitive flexibility in a far from onset pre-HD cohort to determine whether an early impairment exists and if so, whether fronto-striatal circuits were associated with this deficit.MethodsIn the present study, we examined performance of 51 pre-HD participants (mean age=29.22 (SD=5.71) years) from the HD Young Adult Study cohort and 53 controls matched for age, sex and IQ, on the Cambridge Neuropsychological Test Automated Battery (CANTAB) Intra-Extra Dimensional Set-Shift (IED) task. This cohort is unique as it is the furthest from disease onset comprehensively studied to date (mean years=23.89 (SD=5.96) years). The IED task measures visual discrimination learning, cognitive flexibility and specifically attentional set-shifting. We used resting-state functional MRI to examine whether the functional connectivity between specific fronto-striatal circuits was dysfunctional in pre-HD, compared with controls, and whether these circuits were associated with performance on the critical extradimensional shift stage.ResultsOur results demonstrated that the CANTAB IED task detects a mild early impairment in cognitive flexibility in a pre-HD group far from onset. Attentional set-shifting was significantly related to functional connectivity between the ventrolateral PFC and ventral striatum in healthy controls and to functional connectivity between the dorsolateral PFC and caudate in pre-HD participants.ConclusionWe postulate that this incipient impairment of cognitive flexibility may be associated with intrinsically abnormal functional connectivity of fronto-striatal circuitry in pre-HD.

The optimal way to manage diabetic foot osteomyelitis remains uncertain, with debate in the literature as to whether it should be managed conservatively (ie, nonsurgically) or surgically. We aimed to identify clinical variables that influence outcomes of nonsurgical management in diabetic foot osteomyelitis. We conducted a retrospective study of consecutive patients with diabetes presenting to a tertiary center between 2007 and 2011 with foot osteomyelitis initially treated with nonsurgical management. Remission was defined as wound healing with no clinical or radiological signs of osteomyelitis at the initial or contiguous sites 12 months after clinical and/or radiological resolution. Nine demographic and clinical variables including osteomyelitis site and presence of foot pulses were analyzed. We identified 100 cases, of which 85 fulfilled the criteria for analysis. After a 12-month follow-up period, 54 (63.5%) had achieved remission with nonsurgical management alone with a median (interquartile range) duration of antibiotic treatment of 10.8 (10.1) weeks. Of these, 14 (26%) were admitted for intravenous antibiotics. The absence of pedal pulses in the affected foot (n = 34) was associated with a significantly longer duration of antibiotic therapy to achieve remission, 8.7 (7.1) versus 15.9 (13.3) weeks (P = .003). Osteomyelitis affecting the metatarsal was more likely to be amputated than other sites of the foot (P = .016). In line with previous data, we have shown that almost two thirds of patients presenting with osteomyelitis healed without undergoing surgical bone resection.

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Objectives: To investigate the timeframe prior to symptom onset when cortico-basal ganglia white matter (WM) loss begins in premanifest Huntington's disease (preHD), and which striatal and thalamic sub-region WM tracts are most vulnerable. Methods: We performed fixel-based analysis, which allows resolution of crossing WM fibres at the voxel level, on diffusion tractography derived WM tracts of striatal and thalamic sub-regions in two independent cohorts; TrackON-HD, which included 72 preHD (approx. 11 years before disease onset) and 85 controls imaged at three time points over two years; and the HD young adult study (HD-YAS), which included 54 preHD (approx. 25 years before disease onset) and 53 controls, imaged at one time point. Group differences in fibre density and cross section (FDC) were investigated. Results: We found no significant group differences in cortico-basal ganglia sub-region FDC in preHD gene carriers 25 years before onset. In gene carriers 11 years before onset, there were reductions in striatal (limbic and caudal motor) and thalamic (premotor, motor and sensory) FDC at baseline, with no significant change over 2 years. Caudal motor-striatal, pre-motor-thalamic, and primary motor-thalamic FDC at baseline, showed significant correlations with the Unified Huntington's disease rating scale (UHDRS) total motor score (TMS). Limbic cortico-striatal FDC and apathy were also significantly correlated. Conclusions: Our findings suggest that the initiation of disease modifying therapies 25 years before onset could protect these important brain networks from undergoing neurodegeneration and highlight selectively vulnerable sub-regions of the striatum and thalamus that may be important targets for future therapies.