Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series.

Next-generation genetic sequencing (NGS) technologies facilitate the screening of multiple genes linked to neurodegenerative dementia, but there are few reports about their use in clinical practice. Which patients would most profit from testing, and information on the likelihood of discovery of a causal variant in a clinical syndrome, are conspicuously absent from the literature, mostly for a lack of large-scale studies. We applied a validated NGS dementia panel to 3241 patients with dementia and healthy aged controls; 13,152 variants were classified by likelihood of pathogenicity. We identified 354 deleterious variants (DV, 12.6% of patients); 39 were novel DVs. Age at clinical onset, clinical syndrome and family history each strongly predict the likelihood of finding a DV, but healthcare setting and gender did not. DVs were frequently found in genes not usually associated with the clinical syndrome. Patients recruited from primary referral centres were compared with those seen at higher-level research centres and a national clinical neurogenetic laboratory; rates of discovery were comparable, making selection bias unlikely and the results generalisable to clinical practice. We estimated penetrance of DVs using large-scale online genomic population databases and found 71 with evidence of reduced penetrance. Two DVs in the same patient were found more frequently than expected. These data should provide a basis for more informed counselling and clinical decision making.

Biomarkers in dementia: clinical utility and new directions.

Imaging, cerebrospinal fluid (CSF) and blood-based biomarkers have the potential to improve the accuracy by which specific causes of dementia can be diagnosed in vivo, provide insights into the underlying pathophysiology, and may be used as inclusion criteria and outcome measures for clinical trials. While a number of imaging and CSF biomarkers are currently used for each of these purposes, this is an evolving field, with numerous potential biomarkers in varying stages of research and development. We review the currently available biomarkers for the three most common forms of neurodegenerative dementia, and give an overview of research techniques that may in due course make their way into the clinic.

Tetrathiomolybdate-associated copper depletion decreases circulating endothelial progenitor cells in women with breast cancer at high risk of relapse.

BACKGROUND: Bone marrow-derived endothelial progenitor cells (EPCs) are critical for metastatic progression. This study explores the effect of tetrathiomolybdate (TM), an anti-angiogenic copper chelator, on EPCs in patients at high risk for breast cancer recurrence. PATIENTS AND METHODS: This phase 2 study enrolled breast cancer patients with stage 3 and stage 4 without evidence of disease (NED), and stage 2 if triple-negative. TM 100 mg orally was administered to maintain ceruloplasmin <17 mg/dl for 2 years or until relapse. The primary end point was change in EPCs. RESULTS: Forty patients (28 stage 2/3, 12 stage 4 NED) were enrolled. Seventy-five percent patients achieved the copper depletion target by 1 month. Ninety-one percent of triple-negative patients copper-depleted compared with 41% luminal subtypes. In copper-depleted patients only, there was a significant reduction in EPCs/ml by 27 (P = 0.04). Six patients relapsed while on study, of which only one patient had EPCs maintained below baseline. The 10-month relapse-free survival was 85.0% (95% CI 74.6%-96.8%). Only grade 3/4 toxicity was hematologic: neutropenia (3.1% of cycles), febrile neutropenia (0.2%), and anemia (0.2%). CONCLUSIONS: TM is safe and appears to maintain EPCs below baseline in copper-depleted patients. TM may promote tumor dormancy and ultimately prevent relapse.

Presymptomatic studies in genetic frontotemporal dementia.

Approximately 20% of patients with the neurodegenerative disorder frontotemporal dementia (FTD) have an autosomal dominant pattern of inheritance. Genetic FTD is caused by mutations in three genes in most cases (progranulin, microtubule-associated protein tau and chromosome 9 open reading frame 72) although a number of other genes are rare causes. Studies of other neurodegenerative diseases have shown imaging and biomarker evidence of disease onset many years prior to the development of symptoms. Similar studies in genetic FTD are now revealing evidence of a series of presymptomatic changes, initially in plasma biomarkers followed by MR imaging abnormalities of functional and structural connectivity and then grey matter atrophy. Lastly, neuropsychometric tests become abnormal in proximity to the onset of symptoms. Such studies have been relatively small until now but research centres with an expertise in genetic FTD are now forming consortia such as the Genetic Frontotemporal Dementia Initiative (GenFI) to create larger cohorts that can form the basis of future clinical trials.

Results from a randomised controlled pilot study of the Better Conversations with Primary Progressive Aphasia (BCPPA) communication partner training program for people with PPA and their communication partners.

BACKGROUND: There has been a growing focus on functional communication interventions for primary progressive aphasia (PPA). These interventions aim to support individuals to participate in life situations. One such intervention, communication partner training (CPT) aims to change conversation behaviours in both the person with PPA and their communication partner (CP). CPT has a growing evidence base in stroke aphasia; however, these programmes are not designed to meet the needs of people with progressive communication difficulties. To address this, the authors developed a CPT program entitled Better Conversations with PPA (BCPPA) and undertook a pilot trial to establish for a future full trial; predicted recruitment rates, acceptability, an assessment of treatment fidelity and an appropriate primary outcome measure. METHODOLOGY: This was a single-blind, randomised controlled pilot study comparing BCPPA to no treatment, delivered across 11 National Health Service Trusts in the UK. A random sample of eight recordings of local collaborators delivering the intervention were analysed to examine fidelity. Participants completed feedback forms reporting on acceptability. Pre- and post-intervention measures targeted conversation behaviours, communication goals and quality of life. RESULTS: Eighteen people with PPA and their CPs (9 randomised to BCPPA, 9 randomised to no treatment) completed the study. Participants in the intervention group rated BCPPA positively. Treatment fidelity was 87.2%. Twenty-nine of 30 intervention goals were achieved or over-achieved and 16 of 30 coded conversation behaviours demonstrated change in the intended direction. The Aphasia Impact Questionnaire was identified as the preferred outcome measure. CONCLUSION: The first randomised controlled UK pilot study of a CPT program for people with PPA and their families demonstrates BCPPA is a promising intervention. The intervention was acceptable, treatment fidelity high and an appropriate measure identified. Results of this study indicate a future RCT of BCPPA is feasible. TRIAL REGISTRATION: Registered 28/02/2018 ISRCTN10148247 .

EFNS-ENS Guidelines on the diagnosis and management of disorders associated with dementia.

BACKGROUND AND OBJECTIVES: The last version of the EFNS dementia guidelines is from 2007. In 2010, the revised guidelines for Alzheimer's disease (AD) were published. The current guidelines involve the revision of the dementia syndromes outside of AD, notably vascular cognitive impairment, frontotemporal lobar degeneration, dementia with Lewy bodies, corticobasal syndrome, progressive supranuclear palsy, Parkinson's disease dementia, Huntington's disease, prion diseases, normal-pressure hydrocephalus, limbic encephalitis and other toxic and metabolic disorders. The aim is to present a peer-reviewed evidence-based statement for the guidance of practice for clinical neurologists, geriatricians, psychiatrists and other specialist physicians responsible for the care of patients with dementing disorders. It represents a statement of minimum desirable standards for practice guidance. METHODS: The task force working group reviewed evidence from original research articles, meta-analyses and systematic reviews, published by June 2011. The evidence was classified (I, II, III, IV) and consensus recommendations graded (A, B, or C) according to the EFNS guidance. Where there was a lack of evidence, but clear consensus, good practice points were provided. RESULTS AND CONCLUSIONS: New recommendations and good practice points are made for clinical diagnosis, blood tests, neuropsychology, neuroimaging, electroencephalography, cerebrospinal fluid (CSF) analysis, genetic testing, disclosure of diagnosis, treatment of behavioural and psychological symptoms in dementia, legal issues, counselling and support for caregivers. All recommendations were revised as compared with the previous EFNS guidelines. The specialist neurologist together with primary care physicians play an important role in the assessment, interpretation and treatment of symptoms, disability and needs of dementia patients.

Avian agnosia: A window into auditory semantics.

The functional and neural organisation of auditory knowledge is relatively poorly understood. The breakdown of conceptual knowledge in semantic dementia has revealed that pre-morbid expertise influences the extent to which knowledge is differentiated. Whether this principle applies to a similar extent in the auditory domain is not yet known. Previous reports of patients with impaired auditory vs. intact visual expert knowledge suggest that expertise may have differential effects upon the organisation of auditory and visual knowledge. An equally plausible alternative, however, is that auditory knowledge is simply more vulnerable to deterioration. Thus, expertise effects in the auditory domain may not yet have been observed because knowledge of auditory expert vs. non-expert knowledge has yet to be compared. We had the opportunity to address this issue by studying SA, a patient with semantic dementia and extensive pre-morbid knowledge of birds. We undertook a systematic investigation of SA's auditory vs. visual knowledge from matched expert vs. non-expert categories. Relative to a group of 10 age, education and IQ matched bird experts, SA showed impaired auditory vs. intact visual avian knowledge, despite intact basic auditory perceptual abilities. This was explained by independent effects of modality and expertise. Thus, he was also disproportionately impaired for auditory vs. visual knowledge of items from non-expert categories. In both auditory and visual modalities, his performance was relatively more impaired on tests of non-expert vs. expert knowledge. These findings suggest that, while auditory knowledge may be more vulnerable to deterioration, expertise modulates visual and auditory knowledge to a similar extent.

Using the presence of visual hallucinations to differentiate Parkinson's disease from atypical parkinsonism.

OBJECTIVES: Visual hallucinations (VH) occur frequently in Parkinson's disease (PD) and dementia with Lewy bodies (DLB) and are much less common in other bradykinetic rigid syndromes. Pathological series suggest that the presence of VH is highly specific for Lewy body pathology. To address the issue of diagnosis in patients with parkinsonism, we developed instructions for a structured interview (Queen Square Visual Hallucination Inventory (QSVHI)), capable of rapidly screening for VH in the outpatient setting. METHODS: 181 consecutive patients from a specialist movement disorders clinic were tested (115 with PD, 23 with progressive supranuclear palsy (PSP), 9 with multiple system atrophy (MSA), 5 with vascular parkinsonism, 19 with unclassifiable parkinsonism (UP) and 8 others), and 15 selected patients from other clinics and 14 neurologically normal controls. The characteristics of hallucinators and non-hallucinators were compared and the sensitivity, specificity and predictive values of VH for a clinical diagnosis of PD calculated. RESULTS: Screening questions identified VH in only 38% of patients with PD. The QSVHI identified VH in 75% of patients with PD and 47% of those with UP. The specificity of VH identified by the QSVHI for PD was 91%, sensitivity was 62%, positive predictive value was 95% and negative predictive value was 48%. CONCLUSIONS: The QSVHI appears to be a sensitive method for identifying VH in a movement disorders clinic. VH occurred predominantly in PD and very rarely in PSP and MSA. Among patients with unclassifiable or undetermined parkinsonism, the presence of VH should be considered a red flag for underlying Lewy body pathology.

The cultural context of visual hallucinations.

Visual hallucinations (VH) are a cardinal neuropsychiatric symptom and often have important diagnostic implications. The interpretation of VH is influenced by the patient's social and cultural milieu, but the impact of socio-cultural factors on the interpretation, presentation and detection of VH has been little studied. When patients exhibit VH and other neuropsychiatric phenomena, appropriate sensitivity to the role of cultural factors is an important determinant of the success of the medical consultation. We discuss this issue using three illustrative cases.

The neuro-behavioural syndrome of brainstem disease.

We describe two patients with isolated brainstem lesions who exhibited behavioural and cognitive changes that are commonly associated with frontal lobe pathology, as leading clinical features. These cases illustrate the role of distributed neural networks in cognitive and behavioural processes. The brainstem, frontal-subcortical and limbic systems are extensively and reciprocally linked via neurotransmitter projection pathways. We argue that cognitive and behavioural features in patients with brainstem lesions reflect remote effects of brainstem structures on frontal lobe and limbic regions, as a consequence of disruption to ascending neurotransmitter pathways.

Musical hallucinations in a musician.

The experience of music is difficult to study objectively. Here we describe a detailed analysis of musical hallucinations developing after a probable brainstem stroke in an 83 year old musician who was able to describe and notate the hallucinations. The hallucinations comprised simple, repetitive melodic and rhythmic motifs that were combined apparently randomly without definite tonality, large-scale structure, or timbre. This observation is consistent with the proposal that musical hallucinations represent abnormal spontaneous activity in auditory cortical areas beyond the primary auditory cortex. This activity may generate novel musical motifs.

Brain biopsy in dementia.

Brain biopsy has an uncertain role in the diagnosis of dementia. Here we report a retrospective analysis of 90 consecutive cerebral biopsies undertaken for the investigation of dementia in adults at a tertiary referral centre between 1989 and 2003. In most cases (90%), biopsy consisted of a right frontal full thickness resection of cortex, white matter and overlying leptomeninges. Fifty-seven per cent of biopsies were diagnostic: the most frequent diagnoses were Alzheimer's disease (18%), Creutzfeldt-Jakob disease (12%) and inflammatory disorders (9%). Other diagnoses in individual patients included Pick's disease, corticobasal degeneration and other tauopathies, Lewy body dementia, multiple sclerosis, Whipple's disease, progressive multifocal leucoencephalopathy, cerebral autosomal dominant arteriopathy with subcortical ischaemic leucoencephalopathy, vasculopathies and paraneoplastic encephalopathy. The most frequent biopsy finding in the non-diagnostic group and for the series as a whole (37%) was non-specific gliosis variably affecting both cortex and white matter. Complications (11%) included seizures, intracranial and wound infections, and intracranial haemorrhage; there were no deaths or lasting neurological sequelae attributable to the procedure. No trends in diagnostic yield or complication rate over the course of the series were identified. Information obtained at biopsy determined treatment in 11%. A raised cerebrospinal fluid cell count was the only robust predictor of a potentially treatable (inflammatory) process at biopsy. The constellation of behavioural change, raised CSF protein and matched oligoclonal bands in CSF and serum was associated with non-specific gliosis at biopsy. This series underlines the value of cerebral biopsy in the diagnosis of dementia, and suggests that certain clinical and laboratory features may be useful in guiding the decision to proceed to brain biopsy where a treatable disease cannot be excluded by other means.

Distinct mechanisms for processing spatial sequences and pitch sequences in the human auditory brain.

Perception of the acoustic world requires the simultaneous processing of the acoustic patterns associated with sound objects and their location in space. In this functional magnetic resonance experiment, we investigated the human brain areas engaged in the analysis of pitch sequences and sequences of acoustic spatial locations in a paradigm in which both could be varied independently. Subjects were presented with sequences of sounds in which the individual sounds were regular interval noises with variable pitch. Positions of individual sounds were varied using a virtual acoustic space paradigm during scanning. Sound sequences with changing pitch specifically activated lateral Heschl's gyrus (HG), anterior planum temporale (PT), planum polare, and superior temporal gyrus anterior to HG. Sound sequences with changing spatial locations specifically activated posteromedial PT. These results demonstrate directly that distinct mechanisms for the analysis of pitch sequences and acoustic spatial sequences exist in the human brain. This functional differentiation is evident as early as PT: within PT, pitch pattern is processed anterolaterally and spatial location is processed posteromedially. These areas may represent human homologs of macaque lateral and medial belt, respectively.

4-Substituted semicarbazones of mono- and dichlorobenzaldehydes as antihypertensive agents.

Twelve 4-substituted semicarbazone derivatives of o- and p-chloro- as well as 2,6-dichlorobenzaldehyde were synthesized and investigated for antihypertensive activity in spontaneously hypertensive rats. Several of the compounds synthesized (viz. 1, 6, 7, and 15) exhibited potent antihypertensive effects when orally administered. The same compounds were not hypotensive in the normotensive dog.

Antitumor agents. 2. Bisguanylhydrazones of anthracene-9,10-dicarboxaldehydes.

9,10-Anthracenedicarboxaldehyde bis[(4,5-dihydro-1H-imidazol-2-yl)hydrazone] (bisantrene, VI-1) showed anticancer activity in mice vs. both leukemias and solid tumors. Increases in life span vs. the following neoplasms were: P-388 leukemia, 137%; B-16 melanoma, 122%; Lieberman plasma cell tumor, greater than 85%; colon tumor 26, 150%; Ridgway osteogenic sarcoma, 85%. There were significant numbers of long-term survivors. Both DNA and RNA synthesis were strongly inhibited. The drug was resistant to biodegradation and was bound strongly to tissues; in monkeys the half-life for disappearance from serum was 6 days. Related hydrazones were synthesized, and structure-activity relationships are discussed. Two routes to ring-substituted anthracene-9,10-dicarboxaldehyde intermediates were developed.

Donor organ preservation fluids differ in their effect on endothelial cell function.

Successful organ transplantation depends on adequate preservation of cellular function. We tested the effect of four commonly used donor organ preservation fluids on the ability of cultured bovine pulmonary artery endothelial cells to release endothelium-derived relaxing factor (EDRF). Columns of endothelial cells grown on microcarrier beads were exposed to either University of Wisconsin (Belzer's) solution, Marshall's preservation fluid, Euro-Collins solution, or a blood-based preservation fluid at 4 degrees C for 6 hours, and then to Krebs-Henseleit buffer at 37 degrees C for 1 hour. They were then stimulated with boluses of bradykinin, and the EDRF released was detected by bioassay. The release of EDRF from endothelial cells previously exposed to a preservation fluid was compared with the release of EDRF from control columns of cells perfused throughout at 37 degrees C with Krebs-Henseleit buffer. Previous exposure to any of the three non-blood-based preservation fluids did not attenuate bradykinin-stimulated EDRF release. By contrast, previous perfusion with the blood-based solution completely inhibited EDRF release (p less than 0.01, ANOVA), an effect attributable to the acidity of the solution. Donor organ preservation fluids differ in their effect on endothelial cell function, and this has important implications for lung and for other organ transplantation.

Thalamic syndrome caused by unruptured cerebral aneurysm. Case report.

A case is reported of a 63-year-old woman with thalamic syndrome as the presenting feature of an unruptured cerebral aneurysm. Unruptured aneurysm is a rare cause of thalamic syndrome; the possible mechanisms of production of the sensory disturbance are discussed.

Quinazolinylformamidines and quinazolinediylbisformamidines as antihypertensive agents.

Eleven quinazolinylformamidines and quinazolinediylbisformamidines were synthesized and investigated for antihypertensive activity in spontaneous hypertensive rats. Several compounds showed moderate antihypertensive activity at 100 mg/kg po. The same compounds were not hypotensive in the normotensive dog.

Long-term follow-up and recent observations on 305 cases of orbital decompression for dysthyroid orbitopathy.

Dysthyroid exophthalmopathy (orbitopathy) results from an enlargement of extraglobal orbital structures, producing ocular proptosis, optic nerve compression, and corneal exposure. Treatment with corticosteroids and radiation may be beneficial; refractory cases require surgical decompression of the orbit. Transantral orbital decompression was described by Walsh and Ogura and has been performed in over 350 patients at this institution. A review of 305 patients with long-term follow-up was performed. Visual acuity improved or was maintained at preoperative levels in over 95% of the patients, with ocular recession ranging from 1 to 12 mm (average: 4 mm). Postoperative ocular balance of relative exophthalmos was to within 1 mm in 76% of the patients and to within 2 mm in approximately 90% of the patients. Normal postoperative extraocular muscle balance was present in 99 patients. Immediate postoperative diplopia was noted in 206 patients. Long-term follow-up revealed that in 137 of these patients, diplopia resolved or responded to conservative management. Extraocular muscle surgery was required for correction in 69 patients. Twenty-seven patients had postoperative complications. These included 16 patients with hypesthesia of the infraorbital nerve, 5 patients with sinusitis, 3 patients who had incomplete decompression, 2 patients with oral antral fistulae, and 1 patient who had CSF rhinorrhea. Five patients, despite surgery, radiation, and steroid therapy progressed to blindness. We conclude that this procedure is effective and carries few complications. Orbital imaging, using computed tomography or magnetic resonance sequence with reconstructive capabilities, permits early diagnosis and treatment of dysthyroid compression optic neuropathy.