Introduction of an assessment toolkit associated with increased rate of DLB diagnosis.

BACKGROUND: Dementia with Lewy bodies (DLB) and dementia in Parkinson's disease (PDD) are recognised to be under-recognised in clinical practice in the UK, with only one third to a half of expected cases diagnosed. We aimed to assess whether clinical diagnostic rates could be increased by the introduction of a structured assessment toolkit for clinicians. METHODS: We established baseline diagnostic rates for DLB and PDD in four memory clinics and three movement disorder/Parkinson's disease (PD) clinics in two separate geographical regions in the UK. An assessment toolkit specifically developed to assist with the recognition and diagnosis of DLB and PDD was then introduced to the same clinical teams and diagnostic rates for DLB and PDD were reassessed. For assessing DLB diagnosis, a total of 3820 case notes were reviewed before the introduction of the toolkit, and 2061 case notes reviewed after its introduction. For PDD diagnosis, a total of 1797 case notes were reviewed before the introduction of the toolkit and 3405 case notes after it. Mean values and proportions were analysed using Student's t test for independent samples and χ2 test, respectively. RESULTS: DLB was diagnosed in 4.6% of dementia cases prior to the introduction of the toolkit, and 6.2% of dementia cases afterwards, an absolute rise of 1.6%, equal to a 35% increase in the number of DLB cases diagnosed when using the toolkit (χ2 = 4.2, P = 0.041). The number of PD patients diagnosed with PDD was not found overall to be significantly different when using the toolkit: 9.6% of PD cases before and 8.2% of cases after its introduction (χ2 = 1.8, P = 0.18), though the ages of PD patients assessed after the toolkit's introduction were lower (73.9 years vs 80.0 years, t = 19.2, p < 0.001). CONCLUSION: Introduction of the assessment toolkit was associated with a significant increase in the rate of DLB diagnosis, suggesting that a structured means of assessing symptoms and clinical features associated with DLB can assist clinicians in recognising cases. The assessment toolkit did not alter the overall rate of PDD diagnosis, suggesting that alternate means may be required to improve the rate of diagnosis of dementia in Parkinson's disease.

Local excision for T1 rectal tumours: are we getting better?

AIM: The objective was to assess the effect of three different surgical treatments for T1 rectal tumours, radical resection (RR), open local excision (open LE) and laparoscopic local excision (laparoscopic LE), on overall survival (OS). METHODS: Adults from the National Cancer Database (2008-2016) with a diagnosis of T1 rectal cancer were stratified by treatment type (LE vs RR). We assumed that laparoscopic LE equates to transanal minimally invasive surgery (TAMIS) or transanal endoscopic microsurgery. The primary outcome was 5-year OS. Subgroup analyses of the LE group stratified by time period [2008-2010 (before TAMIS) vs 2011-2016 (after TAMIS)] and approach (laparoscopic vs open) were performed. RESULTS: Among 10 053 patients, 6623 (65.88%) underwent LE (74.33% laparoscopic LE vs 25.67% open LE) and 3430 (34.12%) RR. The use of LE increased from 52.69% in 2008 to 69.47% in 2016, whereas RR decreased (P < 0.001). In unadjusted analysis, there was no significant difference in 5-year OS between the LE and RR groups (P = 0.639) and between the two LE time periods (P = 0.509), which was consistent with the adjusted analysis (LE vs RR, hazard ratio 1.05, 95% CI 0.92-1.20, P = 0.468; 2008-2010 LE vs 2011-2016 LE, hazard ratio 1.09, 95% CI 0.92-1.29, P = 0.321). Laparoscopic LE was associated with improved OS in the unadjusted analysis only (P = 0.006), compared to the open LE group (hazard ratio 0.94, 95% CI 0.78-1.12, P = 0.495). CONCLUSIONS: This study supports the use of a LE approach for T1 rectal tumours as a strategy to reduce surgical morbidity without compromising survival.

A comparison of visual hallucinations across disorders.

Research into hallucinations typically regards them as single sensory or unimodal experiences leading to a comparative neglect of co-occurring multi-sensory hallucinations (MSH). People with psychosis who have visual hallucinations (VH) report high rates of hallucinations in other senses (auditory, olfactory, tactile). However, it is not known if this is similar to other groups who report VH. Consequently, this study explored MSH in four different patient groups who all had current VH. Archival data from standardised assessments of visual hallucinations in people with psychosis (n = 22), eye disease (ED) (n = 82), Lewy body Dementia (LBD) (n = 41), and Parkinson's disease (PD) (n = 41) determined the presence of MSH. People with psychosis and visual hallucinations reported significantly higher rates of MSH (auditory, 73%; tactile, 82%; olfactory/gustatory hallucinations, 27%) than the LBD group (auditory, 21%; tactile, 28%; olfactory/gustatory, 6%), ED (auditory, 1%; tactile, 11%; olfactory/gustatory, 0%) and PD patients (auditory, 3%; tactile, 8%; olfactory/gustatory, 3%). Regardless of diagnostic grouping, participants with MSH reported greater conviction that the VH were real, and reported greater distress. People with psychosis with VH report high rates of MSH unlike groups of older adults with VH. These between group differences in MSH prevalence have implications for clinical practice and theory.

The use of viable cryopreserved placental tissue in the management of a chronic rectovaginal fistula.

We present a case of a chronic recurrent rectovaginal fistula that initially arose from complications of haemorrhoid surgery and had failed multiple prior surgical repairs. The fistula was successfully managed using viable cryopreserved placental tissue.

Cognitive impairment in Parkinson's disease: impact on quality of life of carers.

BACKGROUND: The quality of life (QoL) of informal caregivers of people with Parkinson's disease (PD) (PwP) can be affected by the caring role. Because of cognitive symptoms and diminished activities of daily living, in addition to the management of motor symptoms, carers of PwP and cognitive impairment may experience increased levels of burden and poorer QoL compared with carers of PwP without cognitive impairment. This study aimed to investigate the impact of cognitive impairment in PD upon QoL of carers. METHODS: Approximately 36 months after diagnosis, 66 dyadic couples of PwP and carers completed assessments. PwP completed a schedule of neuropsychological assessments and QoL measures; carers of PwP completed demographic questionnaires and assessments of QoL. Factor scores of attention, memory/executive function and global cognition, as derived by principal component analysis, were used to evaluate cognitive domains. RESULTS: Hierarchical regression analysis found lower Montreal Cognitive Assessment was a significant independent predictor of poorer carer QoL, in addition to number of hours spent caregiving, carer depression and PD motor severity. Attentional deficits accounted for the largest proportion of variance of carer QoL. Carers of PwP and dementia (n = 9) had significantly poorer QoL scores compared with PwP and mild cognitive impairment (n = 18) or normal cognition (n = 39) carers (p < 0.01). CONCLUSIONS: Attentional deficits were the strongest predictor of carer QoL compared with other cognitive predictors. Carers for those with PD dementia reported the poorest QoL. Interventions such as respite or cognitive behavioural therapy to improve mood and self-efficacy in carers may improve carer QoL. © 2016 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons, Ltd.

Endovascular treatment of an arterioportal fistula following pancreaticoduodenectomy.

We present a rare case of an arterioportal fistula that formed between the superior mesenteric artery and portal vein 30 days following a pancreaticoduodenectomy, which was successfully managed with endovascular procedures.

Barley malt wort fermentation by exopolysaccharide-forming Weissella cibaria MG1 for the production of a novel beverage.

AIMS: The growing interest of governments and industry in developing healthy and natural alternative foods and beverages that will fulfil the consumer drive towards a healthy lifestyle and clean-label, natural diet has led to an increase in traditional lactic acid bacteria fermentation research. In particular, this research aims to address the organoleptic modulation of beverages using in situ-produced bacterial polysaccharides. METHODS AND RESULTS: Weissella cibaria MG1 is capable of producing exopolysaccharides (dextran) and oligosaccharides (glucooligosaccharides) during sucrose-supplemented barley-malt-derived wort fermentation. Up to 36·4 g l(-1) of dextran was produced in an optimized system, which improved the rheological profile of the resulting fermentate. Additionally, small amounts of organic acids were formed, and ethanol remained below 0·5% (v/v), the threshold volume for a potential health claim designation. CONCLUSIONS: The results suggest that the cereal fermentate produced by W. cibaria MG1 could be potentially used for the production of a range of novel, nutritious and functional beverages. SIGNIFICANCE AND IMPACT OF THE STUDY: Using conventional raw materials and traditional processes, novel LAB-fermented beverages can be produced representing an innovative mechanism towards fulfilling the aim to decrease government and personal costs as well as potentially ameliorating consumer lifestyle regarding dietary-related disease.

Ascertainment bias in dementias: a secondary to tertiary centre analysis in Central Italy and conceptual review.

BACKGROUND AND AIMS: Ascertainment bias (AB) indicates a bias of an evaluation centre in estimating the prevalence/incidence of a disease due to the specific expertise of the centre. The aim of our study was to evaluate classification of different types of dementia in new cases appearing in secondary and tertiary centres, in order to evidence possible occurrence of AB in the various (secondary to tertiary) dementia centres. METHODS: To assess the mechanism of AB, the rates of new cases of the different forms of dementia reported by different centres were compared. The centres involved in the study were 11 hospital-based centres including a tertiary centre, located in the University Department of Clinical Neurology. The tertiary centre is endowed with state-of-the-art diagnostic facilities and its scientific production is prominently focused on dementia with Lewy bodies (DLB) thus suggesting the possible occurrence of a bias. Four main categories of dementia were identified: Alzheimer's disease (AD), DLB, fronto-temporal dementia (FTD), vascular dementia (VaD), with other forms in a category apart. The classification rate of new cases of dementia in the tertiary centre was compared with rates reported by secondary centres and rates of recoding were calculated during a follow-up of 2 years. RESULTS: The study classified 2,042 newly diagnosed cases of dementia in a population of 1,370,000 inhabitants of which 315,000 were older than 65. AD was categorized in 48-52 % of cases, DLB in 25-28 %, FTD in 2-4 % and VaD in 17-28 %. During the 2-year follow-up the diagnosis was re-classified in 40 patients (3 %). The rate of recoding was 5 % in the tertiary centre, 2-8 % in referrals from secondary to tertiary centre, 2-10 % in recodings performed in secondary centres and addressed to tertiary centre. Recoding or percentages of new cases of AD or DLB were not different in the comparison between secondary or between secondary and tertiary centres. FTD and VaD were instead significantly recoded. CONCLUSION: The results of the study suggest that in a homogeneous area, AB is not interfering with diagnosis of AD or DLB.

Visual hallucinations in PD and Lewy body dementias: old and new hypotheses.

Visual Hallucinations (VH) are a common non-motor symptom of Parkinson's Disease (PD) and the Lewy body dementias (LBD) of Parkinson's disease with dementia (PDD) and Dementia with Lewy Bodies (DLB). The origin of VH in PD and LBD is debated: earlier studies considered a number of different possible mechanisms underlying VH including visual disorders, Rapid Eye Movement (REM) Sleep Intrusions, dysfunctions of top down or bottom up visual pathways, and neurotransmitter imbalance. More recently newer hypotheses introduce, among the possible mechanisms of VH, the role of attention networks (ventral and dorsal) and of the Default Mode Network (DMN) a network that is inhibited during attentional tasks and becomes active during rest and self referential imagery. Persistent DMN activity during active tasks with dysfunctional imbalance of dorsal and ventral attentional networks represents a new hypothesis on the mechanism of VH. We review the different methods used to classify VH and discuss reports supporting or challenging the different hypothetical mechanisms of VH.

A novel, multidisciplinary clinic for complex visual problems in older people.

BACKGROUND: Visual symptoms in older people can be complex and inadequately explained by eye pathology alone. Psychological and neurodegenerative processes may manifest as complex visual symptoms, and thus some patients may be poorly served by a purely ophthalmic approach. We have developed a novel multidisciplinary clinic with input from neurology, ophthalmology, and psychiatric specialists. Here, we describe the patient population, disease prevalence, and potential impact of this new clinic. METHODS: A retrospective audit of paper and electronic records from June 2010 to February 2012 and selected case reports. RESULTS: Between June 2010 and February 2012 48 patients attended the clinic. Notes were available for 47 (98%). Mean age was 76.2 (range 48-92). The main presenting complaints were hallucinations, followed by nonspecific visual deficit, double vision, blurred vision, and visuospatial deficit. Cognitive impairment was noted in 68% (32/47) of patients, of which 16/32 (50%) were new diagnoses. We were able to give a diagnosis to 98% (46/47) of patients; of these, 74% (35/46) were new diagnoses. A total of 6% (3/47) were felt to have presentations attributable to eye pathology alone, whereas 89% (42/47) were felt to have a neuropsychiatric component. Management included referral to other clinics for continuing care in 43% (20/47) and initiation of therapy in 36% (17/47). The three case reports demonstrate cases, where our multidisciplinary approach aided diagnosis and management of patients with complex visual symptoms. CONCLUSION: A combined clinic with neurological, ophthalmic, and psychiatric input is an effective way to diagnose and manage complex visual problems in older people.

Valosin-containing protein (VCP) mutations in sporadic amyotrophic lateral sclerosis.

We recently reported that mutations in the valosin-containing protein (VCP) gene are a cause of 1%-2% of familial amyotrophic lateral sclerosis (ALS) cases, but their role in the pathogenesis of sporadic ALS is unclear. We undertook mutational screening of VCP in 701 sporadic ALS cases. Three pathogenic variants (p.Arg159Cys, p.Asn387Thr, and p.R662C) were found in three U.S. cases, each of whom presented with progressive upper and lower motor neuron signs consistent with definite ALS by El Escorial diagnostic criteria. Our data indicate that VCP mutations may underlie apparently sporadic ALS but account for <1% of this form of disease.

Impaired dopaminergic neurotransmission and microtubule-associated protein tau alterations in human LRRK2 transgenic mice.

Mutations in the Leucine Rich Repeat Kinase 2 (LRRK2) gene, first described in 2004 have now emerged as the most important genetic finding in both autosomal dominant and sporadic Parkinson's disease (PD). While a formidable research effort has ensued since the initial gene discovery, little is known of either the normal or the pathological role of LRRK2. We have created lines of mice that express human wild-type (hWT) or G2019S Lrrk2 via bacterial artificial chromosome (BAC) transgenesis. In vivo analysis of the dopaminergic system revealed abnormal dopamine neurotransmission in both hWT and G2019S transgenic mice evidenced by a decrease in extra-cellular dopamine levels, which was detected without pharmacological manipulation. Immunopathological analysis revealed changes in localization and increased phosphorylation of microtubule binding protein tau in G2019S mice. Quantitative biochemical analysis confirmed the presence of differential phospho-tau species in G2019S mice but surprisingly, upon dephosphorylation the tau isoform banding pattern in G2019S mice remained altered. This suggests that other post-translational modifications of tau occur in G2019S mice. We hypothesize that Lrrk2 may impact on tau processing which subsequently leads to increased phosphorylation. Our models will be useful for further understanding of the mechanistic actions of LRRK2 and future therapeutic screening.

National guidelines for psychological care in diabetes: how mindful have we been?

AIMS: To assess the availability and types of psychological services for people with diabetes in the UK, compliance with national guidelines and skills of the diabetes team in, and attitudes towards, psychological aspects of diabetes management. METHODS: Postal questionnaires to team leads (doctor and nurse) of all UK diabetes centres (n = 464) followed by semi-structured telephone interviews of expert providers of psychological services identified by team leads. RESULTS: Two hundred and sixty-seven centres (58%) returned postal questionnaires; 66 (25%) identified a named expert provider of psychological services, of whom 53 (80%) were interviewed by telephone. Less than one-third (n = 84) of responding centres had access to specialist psychological services and availability varied across the four UK nations (P = 0.02). Over two-thirds (n = 182) of centres had not implemented the majority of national guidelines and only 2.6% met all guidelines. Psychological input into teams was associated with improved training in psychological issues for team members (P < 0.001), perception of better skills in managing more complex psychological issues (P < or = 0.01) and increased likelihood of having psychological care pathways (P < or = 0.05). Most (81%) expert providers interviewed by telephone were under-resourced to meet the psychological needs of their population. CONCLUSIONS: Expert psychological support is not available to the majority of diabetes centres and significant geographical variation indicates inequity of service provision. Only a minority of centres meet national guidelines. Skills and services within diabetes teams vary widely and are positively influenced by the presence of expert providers of psychological care. Lack of resources are a barrier to service provision.

Poor attentional function predicts cognitive decline in patients with non-demented Parkinson's disease independent of motor phenotype.

BACKGROUND: Postural instability gait difficulty (PIGD) motor phenotype in Parkinson's disease (PD) is associated with a faster rate of cognitive decline than in tremor dominant cases and may be a risk factor for incident dementia. People with PD display attentional deficits; however, it is not clear whether attentional deficits in patients with non-demented PD are associated with (i) PIGD phenotype and/or (ii) subsequent cognitive decline. AIMS: (i) To examine rates of cognitive decline (Mini-Mental State Examination (MMSE) and Cambridge Cognitive Examination (CAMCOG)) over 3 years in subjects with non-demented PD aged over 65 years, (ii) using Cognitive Drug Research computerised assessment test battery, determine the rate of change in power of attention (PoA) scores over time (sum of mean choice reaction time, simple reaction time and digit vigilance reaction time scores), (iii) determine whether the PIGD phenotype is associated with changes in PoA and (iv) establish whether baseline PoA is associated with subsequent cognitive decline. RESULTS: 14 subjects (38%) were classified as PIGD motor phenotype at baseline. Cognitive decline was greater in PIGD compared with non-PIGD subjects (p < or = 0.02). PIGD phenotype was not associated with baseline PoA score although it was associated with subsequent worsening in PoA (mean PoA increase/year: non-PIGD subjects 11.4 ms; PIGD subjects 244.0 ms; p = 0.01). Higher baseline PoA scores were associated with greater cognitive decline (MMSE, p = 0.03; CAMCOG, p = 0.05) independent of PIGD status. CONCLUSION: PIGD phenotype and attention deficits are independently associated with a greater rate of cognitive decline in patients with non-demented PD. We propose that subtle attentional deficits in patients with non-demented PD predict subsequent cognitive impairment.

A comparative analysis of leucine-rich repeat kinase 2 (Lrrk2) expression in mouse brain and Lewy body disease.

Pathogenic substitutions in leucine-rich repeat kinase 2 (LRRK2, Lrrk2) have been genetically linked to familial, late-onset Parkinsonism. End-stage disease is predominantly associated with nigral neuronal loss and Lewy body pathology, but patients may have gliosis, tau or ubiquitin inclusions (pleomorphic pathology). The anatomical distribution of Lrrk2 protein may provide insight into its function in health and neurodegeneration, thus we performed a comparative study with 'in-house' and commercially available Lrrk2 antibodies using brain tissue from wild type and human Lrrk2 transgenic bacterial artificial chromosome (BAC) mice, and from diffuse Lewy body disease (DLBD) patients. Lrrk2 protein was ubiquitously expressed and relatively abundant in most brain regions, including the substantia nigra, thalamus and striatum. Lrrk2 was not a major component of Lewy body or neuritic pathology associated with Parkinson's disease. However, selective loss of dopaminergic neurons in Lrrk2-associated Parkinsonism argues the protein may have regional-specific interactions. Lrrk2 immunohistochemical staining was present in the subventricular zone, a region containing stem cells that give rise to both neurons and glia. A role for Lrrk2 in neurogenesis might provide further insight into the aberrant role of mutant protein in age-associated neurodegeneration with pleomorphic pathology.

Evidence of activity-dependent withdrawal of corticospinal projections during human development.

OBJECTIVE: To characterize the development of ipsilateral corticospinal projections from birth and compare to 1) development of contralateral projections in the same subjects and 2) ipsilateral corticospinal projections in subjects with unilateral lesions of the corticospinal system acquired perinatally or in adulthood. METHOD: Transcranial magnetic stimulation excited the motor cortex, and responses were recorded bilaterally in pectoralis major, biceps brachii, and the first dorsal interosseus muscles. Subjects studied included 9 neonates recruited at birth, studied longitudinally for 2 years; 85 healthy subjects aged from birth to adulthood; 10 subjects with hemiplegic cerebral palsy; and 8 with hemiplegia after stroke. RESULTS: In neonates, ipsilateral responses had significantly shorter onsets than contralateral responses but similar thresholds and amplitudes. Thresholds within both pathways increased in the first 3 months. Differential development was present from 3 months so that by 18 months ipsilateral responses were significantly smaller and had significantly higher thresholds and longer onset latencies than contralateral responses. A similar pattern of smaller and later ipsilateral responses was observed after transcranial magnetic stimulation of the intact cortex in subjects with stroke. In contrast, subjects with hemiplegic cerebral palsy had ipsilateral responses with onsets, thresholds and amplitudes similar to those of contralateral responses. Significant branching of contralateral corticospinal axons from the intact motor cortex was excluded by cross-correlation analysis. CONCLUSIONS: These data, together with previously published anatomic and radiologic studies, are consistent with activity-dependent corticospinal axonal withdrawal during development and maintenance of increased corticomotoneuronal projections from the intact hemisphere after unilateral perinatal lesions.

Secretory bulk flow of soluble proteins is efficient and COPII dependent.

COPII-coated vesicles, first identified in yeast and later characterized in mammalian cells, mediate protein export from the endoplasmic reticulum (ER) to the Golgi apparatus within the secretory pathway. In these organisms, the mechanism of vesicle formation is well understood, but the process of soluble cargo sorting has yet to be resolved. In plants, functional complements of the COPII-dependent protein traffic machinery were identified almost a decade ago, but the selectivity of the ER export process has been subject to considerable debate. To study the selectivity of COPII-dependent protein traffic in plants, we have developed an in vivo assay in which COPII vesicle transport is disrupted at two distinct steps in the pathway. First, overexpression of the Sar1p-specific guanosine nucleotide exchange factor Sec12p was shown to result in the titration of the GTPase Sar1p, which is essential for COPII-coated vesicle formation. A second method to disrupt COPII transport at a later step in the pathway was based on coexpression of a dominant negative mutant of Sar1p (H74L), which is thought to interfere with the uncoating and subsequent membrane fusion of the vesicles because of the lack of GTPase activity. A quantitative assay to measure ER export under these conditions was achieved using the natural secretory protein barley alpha-amylase and a modified version carrying an ER retention motif. Most importantly, the manipulation of COPII transport in vivo using either of the two approaches allowed us to demonstrate that export of the ER resident protein calreticulin or the bulk flow marker phosphinothricin acetyl transferase is COPII dependent and occurs at a much higher rate than estimated previously. We also show that the instability of these proteins in post-ER compartments prevents the detection of the true rate of bulk flow using a standard secretion assay. The differences between the data on COPII transport obtained from these in vivo experiments and in vitro experiments conducted previously using yeast components are discussed.

Transcription of intermediate filament genes is enhanced in focal cortical dysplasia.

Focal cortical dysplasia (FCD) is characterized by disorganized cerebral cortical cytoarchitecture. Increased expression of several intermediate filament (IF) proteins such as neurofilament, vimentin, alpha-internexin, and nestin observed in dysplastic "balloon" neurons (DN) may contribute to disrupted cortical lamination. We hypothesized that increased IF protein expression results from enhanced IF gene transcription within dysplastic neurons. We used a novel strategy to evaluate IF mRNA expression in three FCD specimens from medically intractable epilepsy patients. Poly(A) mRNA was amplified (aRNA) from single microdissected DN, morphologically normal neurons at the margin of the FCD resection, morphologically normal neurons in non-FCD cortex from epilepsy patients, and normal control neurons. Radiolabeled aRNA from single neurons was used to probe cDNA arrays containing the low (NFL), medium (NFM) and high (NFH) molecular weight neurofilament isoform, alpha-internexin, desmin, vimentin, peripherin (PRPH), nestin, and glial fibrillary acidic protein (GFAP) cDNAs. Hybridization intensity of aRNA-cDNA hybrids was used to quantify relative IF abundance. Increased expression of nestin, alpha-internexin, PRPH, vimentin, NFL, NFM, and NFH mRNAs was found in DN when compared with the three control neuronal subtypes. Desmin and GFAP mRNAs were not detected in any cell types. Expression of PRPH mRNA and protein in select DN was confirmed by reverse transcription-polymerase chain reaction and immunohistochemistry. We conclude that aberrant expression of IF proteins in FCD likely results from enhanced transcription of IF genes in dysplastic neurons and propose that future analysis of transcriptional elements that regulate IF expression be evaluated in FCD.