At-Home Administration of Gantenerumab by Care Partners to People with Early Alzheimer's Disease: Feasibility, Safety and Pharmacodynamic Impact.

BACKGROUND: Monoclonal antibodies that target amyloid-beta and remove amyloid plaques can slow cognitive and functional decline in early Alzheimer's disease. Gantenerumab is a subcutaneously administered fully-human anti-amyloid-beta monoclonal antibody with highest affinity for aggregated amyloid-beta. Since the phase 3 GRADUATE trials did not meet the primary endpoint (change from baseline to Week 116 in Clinical Dementia Rating scale - Sum of Boxes), development of gantenerumab in sporadic Alzheimer's disease was stopped and all ongoing trials were terminated early due to sponsor decision. Subcutaneous administration at the clinic or at home by care partner would be an important option for other therapies in this class in order to increase flexibility and reduce overall burden. The insights obtained from the experience with gantenerumab home administration by care partner in the phase 2 GRADUATION trial will serve to guide the ongoing efforts with other anti-amyloid-beta antibodies. OBJECTIVES: To evaluate the pharmacodynamic effects on brain amyloid load of once weekly subcutaneous administration of gantenerumab and the safety and feasibility of home administration by care partners. DESIGN: Phase 2, open-label, single arm study. SETTING: Multicenter trial conducted in 33 sites in 8 countries from November 2020 to March 2023. PARTICIPANTS: Participants aged 50 to 90 with early symptomatic Alzheimer's disease (mild cognitive impairment/mild dementia due to Alzheimer's disease), and evidence of amyloid positron emission tomography positivity. INTERVENTION: Participants could receive up to 255 mg gantenerumab once-weekly, administered subcutaneously at site or at home by healthcare professionals or non-healthcare-professional care partners. MEASUREMENTS: The primary endpoint was the change from baseline to Week 52 and to Week 104 in brain amyloid load as measured by PET centiloid levels. The secondary endpoints were responses to the home administration questionnaire, plasma concentrations and safety. RESULTS: The overall number of participants enrolled was 192, with a mean (standard deviation) amyloid PET load at baseline of 101.80 (29.80) centiloids. At the time of early study termination by sponsor, 149 participants had valid Week 52 amyloid PET data (primary endpoint), and 12 participants had an early termination PET within the pre-defined time range of Week 104. The mean change in amyloid PET from baseline to Week 52 and Week 104 was -26.19 centiloids (range: -75.6-15.8; n=149) and -35.48 centiloids (range: -63.2--7.0; n=12), respectively. Responses to the home administration questionnaire at Week 52 (n=148) indicated that the majority of care partners (88-97%) considered administration of study drug at home easy (30.4%) or very easy (57.4%), and convenient (25.7%) or very convenient (70.9%). Care partners felt confident (31.1%) or very confident (62.2%) and satisfied (29.7%) or very satisfied (64.9%) with giving the injection at home. Responses by care partners at Week 36 (n=72), Week 76 (n=126) and Week 104 (n=29) and participant (patient) assessment of convenience and satisfaction at these time points were similar. There were no new safety findings associated with gantenerumab administered subcutaneously once weekly at 255 mg or safety issues associated with at-home injections by non-healthcare professional care partners. CONCLUSIONS: Once-weekly subcutaneous home administration of the anti-amyloid-beta antibody gantenerumab by non-healthcare-professional care partners to participants with early Alzheimer's disease was feasible, safe, well tolerated, and considered as a convenient option by both the care partners and participants with Alzheimer's disease. Although gantenerumab's development has been stopped due to lack of efficacy, this approach has the potential to reduce the frequency of hospital/outpatient clinic visits required for treatment with other anti-amyloid-ß antibodies and can increase flexibility of drug administration for people living with Alzheimer's disease and their families.

Characteristics of intracerebral haemorrhage associated with COVID-19: a systematic review and pooled analysis of individual patient and aggregate data.

BACKGROUND AND PURPOSE: There are very few studies of the characteristics and causes of ICH in COVID-19, yet such data are essential to guide clinicians in clinical management, including challenging anticoagulation decisions. We aimed to describe the characteristics of spontaneous symptomatic intracerebral haemorrhage (ICH) associated with COVID-19. METHODS: We systematically searched PubMed, Embase and the Cochrane Central Database for data from patients with SARS-CoV-2 detected prior to or within 7 days after symptomatic ICH. We did a pooled analysis of individual patient data, then combined data from this pooled analysis with aggregate-level data. RESULTS: We included data from 139 patients (98 with individual data and 41 with aggregate-level data). In our pooled individual data analysis, the median age (IQR) was 60 (53-67) years and 64% (95% CI 54-73.7%) were male; 79% (95% CI 70.0-86.9%) had critically severe COVID-19. The pooled prevalence of lobar ICH was 67% (95% CI 56.3-76.0%), and of multifocal ICH was 36% (95% CI 26.4-47.0%). 71% (95% CI 61.0-80.4%) of patients were treated with anticoagulation (58% (95% CI 48-67.8%) therapeutic). The median NIHSS was 28 (IQR 15-28); mortality was 54% (95% CI 43.7-64.2%). Our combined analysis of individual and aggregate data showed similar findings. The pooled incidence of ICH across 12 cohort studies of inpatients with COVID-19 (n = 63,390) was 0.38% (95% CI 0.22-0.58%). CONCLUSIONS: Our data suggest that ICH associated with COVID-19 has different characteristics compared to ICH not associated with COVID-19, including frequent lobar location and multifocality, a high rate of anticoagulation, and high mortality. These observations suggest different underlying mechanisms of ICH in COVID-19 with potential implications for clinical treatment and trials.

Safety and efficacy of oxandrolone in growth hormone-treated girls with Turner syndrome: evidence from recent studies and recommendations for use.

There has been no consensus regarding the efficacy and safety of oxandrolone (Ox) in addition to growth hormone (GH) in girls with Turner syndrome (TS), the optimal age of starting this treatment, or the optimal dose. This collaborative venture between Dutch, UK and US centers is intended to give a summary of the data from three recently published randomized, placebo-controlled, double-blind studies on the effects of Ox. The published papers from these studies were reviewed within the group of authors to reach consensus about the recommendations. The addition of Ox to GH treatment leads to an increase in adult height, on average 2.3­4.6 cm. If Ox dosages<0.06 mg/kg/day are used, side effects are modest. The most relevant safety concerns are virilization(including clitoromegaly and voice deepening) and a transient delay of breast development. We advise monitoring signs of virilization breast development and possibly blood lipids during Ox treatment, in addition to regular follow-up assessments for TS. In girls with TS who are severely short for age, in whom very short adult stature is anticipated,or in whom the growth rate is modest despite good compliance with GH, adjunctive treatment with Ox at a dosage of 0.03­0.05 mg/kg/day starting from the age of 8­10 years onward scan be considered.

Transient ischaemic attacks: mimics and chameleons.

Suspected transient ischaemic attack (TIA) is a common diagnostic challenge for physicians in neurology, stroke, general medicine and primary care. It is essential to identify TIAs promptly because of the very high early risk of ischaemic stroke, requiring urgent investigation and preventive treatment. On the other hand, it is also important to identify TIA 'mimics', to avoid unnecessary and expensive investigations, incorrect diagnostic labelling and inappropriate long-term prevention treatment. Although the pathophysiology of ischaemic stroke and TIA is identical, and both require rapid and accurate diagnosis, the differential diagnosis differs for TIA owing to the transience of symptoms. For TIA the diagnostic challenge is greater, and the 'mimic' rate higher (and more varied), because there is no definitive diagnostic test. TIA heralds a high risk of early ischaemic stroke, and in many cases the stroke can be prevented if the cause is identified, hence the widespread dissemination of guidelines including rapid assessment and risk tools like the ABCD2 score. However, these guidelines do not emphasise the substantial challenges in making the correct diagnosis in patients with transient neurological symptoms. In this article we will mainly consider the common TIA mimics, but also briefly mention the rather less common situations where TIAs can look like something else ('chameleons').

The role of sex steroids in controlling pubertal growth.

Longitudinal growth, which is primarily due to chondrocytic activity at the level of the epiphyseal growth plate, is influenced by many hormones and growth factors in an endocrine and paracrine manner. Their influence is even more complex during the accelerated growth period of puberty that accounts for about 20% of final adult height. Although abnormalities of growth during puberty are very common, the underlying mechanisms that govern the beginning and cessation of pubertal growth at the level of the growth plate are poorly understood. Sex steroids play a crucial role in pubertal growth both at the systemic level via the GH/IGF-1 axis and at the local level of the epiphyseal growth plate. In both sexes it is now accepted that oestrogen is the critical hormone in controlling growth plate acceleration and fusion. This paper reviews the mechanisms that influence pubertal growth and the problems that are associated with disorders of gonadal function.

Combined ultrasound and isotope scanning is more informative in the diagnosis of congenital hypothyroidism than single scanning.

BACKGROUND: Thyroid imaging is helpful in confirming the diagnosis of congenital hypothyroidism and in establishing the aetiology. Although isotope scanning is the standard method of imaging, ultrasound assessment may be complementary. AIM: To determine the strengths and weaknesses of thyroid ultrasound and isotope scanning in neonates with thyroid stimulating hormone (TSH) elevation. METHODS: Babies from the West of Scotland with raised capillary TSH (>15 mU/l) on neonatal screening between January 1999 and 2004 were recruited. Thyroid dimensions were measured using ultrasonography, and volumes were calculated. Isotope scanning was carried out with a pinhole collimator after an intravenous injection of 99m-technetium pertechnetate. RESULTS: 40 infants (29 female) underwent scanning at a median of 17 days (range 12 days to 15 months). The final diagnosis was athyreosis (n = 11), ectopia (n = 12), hypoplasia (n = 8; 3 cases of hemi-agenesis), dyshormonogenesis (n = 5), transient hypothyroidism (n = 2), transient hyperthyrotropinaemia (n = 1) and uncertain status with gland in situ (n = 1). 6 infants had discordant scans with no isotope uptake but visualisation of thyroid tissue on ultrasound. This was attributed to TSH suppression from thyroxine (n = 3); maternal blocking antibodies (n = 1); cystic degeneration of the thyroid (n = 1); and possible TSH receptor defect (n = 1). CONCLUSIONS: Isotope scanning was superior to ultrasound in the detection of ectopic tissue. However, ultrasound detected tissue that was not visualised on isotope scanning, and showed abnormalities of thyroid volume and morphology. We would therefore advocate dual scanning in newborns with TSH elevation as each modality provides different information.

Steroid cover in dentistry: recommendations following a review of current policy in UK dental teaching hospitals.

This article reports a project that was undertaken to determine current UK dental hospital policy with regard to the management of patients taking therapeutic doses of corticosteroids receiving dental treatment under local anaesthesia. There is variation in the medical management of this patient group, and whether practice should be standardized by means of a national policy document warrants consideration.

The processing of kinetic contours in the brain.

This work investigates whether the brain assigns special cortical areas for the processing of kinetic contours. In human imaging experiments, we compared the brain activity produced in the so-called 'kinetic occipital' area ('KO') when humans perceive shapes generated from kinetic boundaries or from equiluminant colors. 'KO' was activated whenever subjects perceived shapes, no matter how they were derived; it is therefore not specialized for the processing of kinetic contours. The application of independent component analysis (ICA) to imaging data obtained when subjects viewed 22 min of an action movie showed that the time course of activity in 'KO' correlates better with activity in area V3 than with activity in two adjacent areas, V5 and LO. We thus consider 'KO' to be part of the V3 family of areas, and use the terminology of Smith et al. (J Neurosci 18:3816-3830, 1998), to refer to it as area V3B. Recordings from orientation-selective cells in the macaque V3 complex show that the great majority have the same orientational specificity when tested with oriented lines generated from kinetic stimuli or from luminance differences. We conclude that there is no present evidence for a visual area specialized for the processing of kinetic contours in the primate visual brain.

Ultrasound of the thyroid gland in the newborn: normative data.

OBJECTIVE: To establish reference ranges for thyroid length, breadth, depth, and volume in healthy term Scottish infants. DESIGN: Prospective observational study of 100 (49 male) neonates. Length, breadth, and depth were measured, and the volume of each lobe was calculated using the formula for a prolate ellipsoid (volume = length x breadth x depth x pi/6). RESULTS: All measurements showed gaussian distribution, with no significant differences between the right and the left lobes. Values (mean (SD) range) were: length (cm), 1.94 (0.24) 0.9-2.5; breadth (cm), 0.88 (0.16) 0.5-1.4; depth (cm), 0.96 (0.17) 0.6-2.0; volume (ml), 0.81 (0.24) 0.3-1.7; combined volume (ml), 1.62 (0.41) 0.7-3.3. Although there was no difference in mean volume between right and left lobes, there was considerable variation (-0.8 to + 0.7 ml) between the two lobes in individual babies. CONCLUSIONS: Both lobes should be measured to give a combined volume. Our findings provide a reference against which thyroid hypoplasia or goitre can be evaluated.

Cushing's syndrome, growth impairment, and occult adrenal suppression associated with intranasal steroids.

We have previously described iatrogenic Cushing's syndrome secondary to intranasal steroids. This report further highlights the potential deleterious effects of intranasal steroids. Nine cases (including the original two cases) are reviewed to show the varied clinical manifestations of adrenal suppression caused by intranasal steroids. Four presented with Cushing's syndrome, three with growth failure, while two asymptomatic patients were discovered in the course of pituitary function testing. Four children had dysmorphic syndromes--Down's, Treacher-Collins, CHARGE association, and campomelic dysplasia--reflecting the vulnerability of such children to ENT problems, together with the difficulty of interpreting steroid induced growth failure in this context. Adrenal suppression was seen not only with betamethasone but also with budesonide, beclomethasone and flunisolide nasal preparations. A careful enquiry as to the use of intranasal steroids should be routine in children presenting with unexplained growth failure or Cushing's syndrome. Particular vigilance/awareness is required in children with dysmorphic syndromes.

Patterns of brain atrophy in frontotemporal dementia and semantic dementia.

OBJECTIVE: To identify and compare the patterns of cerebral atrophy associated with two clinical variants of frontotemporal lobar degeneration (FTLD): frontotemporal dementia (FTD) and semantic dementia (SemD). METHODS: Twenty patients with FTLD were classified as having FTD (N = 8) or SemD (N = 12) based on current clinical criteria. Both groups showed a similar spectrum of behavioral abnormalities, as indicated by the neuropsychiatric inventory. T1-weighted MRI was obtained for each patient and 20 control subjects. The regions of focal gray matter tissue loss associated with both FTD and SemD, as well as those differing between the two groups were examined using voxel-based morphometry. RESULTS: Regions of significant atrophy seen in both groups were located in the ventromedial frontal cortex, the posterior orbital frontal regions bilaterally, the insula bilaterally, and the left anterior cingulate cortex. The FTD, but not the SemD, group showed atrophy in the right dorsolateral frontal cortex and the left premotor cortex. The SemD, but not the FTD, group showed tissue loss in the anterior temporal cortex and the amygdala/anterior hippocampal region bilaterally. CONCLUSIONS: Although FTD and SemD are associated with different overall patterns of brain atrophy, regions of gray matter tissue loss in the orbital frontal, insular, and anterior cingulate regions are present in both groups. The authors suggest that pathology in the areas of atrophy associated with both FTD and SemD may underlie some the behavioral symptoms seen in the two disorders.

Golgi localization and phosphorylation of oxysterol binding protein in Niemann-Pick C and U18666A-treated cells.

Oxysterol binding protein (OSBP) translocation between Golgi and vesicular/cytoplasmic compartments is affected by conditions that alter cholesterol and sphingomyelin homeostasis, indicating a role in lipid and sterol regulation in this organelle. In this study, we show that OSBP dissociation from the Golgi apparatus was inhibited when LDL cholesterol efflux from lysosomes was blocked in Niemann-Pick C (NPC) or U18666A [3-beta-[2-(diethylamino)ethoxy]androst-5-en-17-one]-treated fibroblasts. Dissociation of OSBP from the Golgi apparatus in response to LDL was independent of de novo cholesterol biosynthesis. OSBP did not localize with filipin-stained lysosomal cholesterol, and the NPC defect did not alter OSBP expression or phosphorylation. However, OSBP in the Golgi apparatus was progressively dephosphorylated (as assessed by a molecular mass shift on SDS-PAGE) in U18666A-treated fibroblasts or Chinese hamster ovary cells as a result of combined inhibition of LDL cholesterol transport and de novo cholesterol synthesis. In vivo phosphopeptide mapping and mutagenesis of OSBP was used to identify the cholesterol-sensitive phosphorylation sites at serines 381, 384, and 387 that were responsible for the altered mobility on SDS-PAGE. NPC-1 protein-mediated release of LDL-derived cholesterol and de novo biosynthesis regulates OSBP localization and phosphorylation. This indicates that OSBP responds to or senses altered cellular sterol content and transport.

Behavior and treatment in frontotemporal dementia.

Behavioral syndromes are central to the clinical presentation of frontotemporal dementia. The authors review the behavioral changes seen in frontotemporal dementia and describe pharmacologic interventions for these behavioral syndromes.

Hemispheric dominance for emotions, empathy and social behaviour: evidence from right and left handers with frontotemporal dementia.

Although evidence from primates suggests an important role for the anterior temporal cortex in social behaviour, human research has to date concentrated almost solely on the orbitofrontal cortex and amygdala. By describing four cases of the temporal variant of frontotemporal dementia we show how this degenerative condition provides an excellent model for investigating the role of the anterior temporal lobe, especially the right, in emotions, empathy and social behaviour. Assessments of semantic memory, processing of emotional facial expression and emotional prosody were made, empathy was measured, and facial expressions of emotion were coded. Of the two right handers described, one subject with predominantly left temporal lobe atrophy had severe semantic impairment but normal performance on all emotional tasks. In contrast, the subject with right temporal lobe atrophy showed severely impaired recognition of emotion from faces and voices that was not due to semantic or perceptual difficulties. Empathy was lost, interpersonal skills were severely affected and facial expression of emotion was characterized by a fixed expression that was unresponsive to situations. Additionally, two left handers with right temporal lobe atrophy are described. One demonstrated the same pattern of hemispheric lateralization as the right handers and had emotional impairment. The other left hander showed the opposite pattern of deficits, suggesting a novel presentation of anomalous dominance with reversed hemispheric specialization of semantic memory and emotional processing.

Perception, attention, and working memory are disproportionately impaired in dementia with Lewy bodies compared with Alzheimer's disease.

OBJECTIVE: To test the hypotheses that visuoperceptual and attentional ability are disproportionately impaired in patients having dementia with Lewy Bodies (DLB) compared with Alzheimer's disease (AD). METHODS: A comprehensive battery of neuropsychological tasks designed to assess working, episodic, and semantic memory, and visuoperceptual and attentional functions was given to groups of patients with DLB (n=10) and AD (n=9), matched for age, education, and mini mental state examination (MMSE), and to normal controls (n=17). RESULTS: Both patient groups performed equally poorly on tests of episodic and semantic memory with the exception of immediate and delayed story recall, which was worse in the AD group. Digit span was by contrast spared in AD. The most striking differences were on tests of visuoperceptual/spatial ability and attention. Whereas patients with AD performed normally on several subtests of the visual object and space perception battery, the DLB group showed substantial impairments. In keeping with previous studies, the AD group showed deficits in selective attention and set shifting, but patients with DLB were more impaired on virtually every test of attention with deficits in sustained, selective, and divided attention. CONCLUSIONS: Patients with DLB have substantially greater impairment of attention, working memory, and visuoperceptual ability than patients with AD matched for overall dementia severity. Semantic memory seems to be equally affected in DLB and AD, unlike episodic memory, which is worse in AD. These findings may have relevance for our understanding of the genesis of visual hallucinations, and the differential diagnosis of AD and DLB.

Fate of patients with questionable (very mild) Alzheimer's disease: longitudinal profiles of individual subjects' decline.

Currently used criteria for the diagnosis of probable Alzheimer's disease requires the presence of cognitive deficit in addition to loss of episodic memory. The recent developments in drug treatments for Alzheimer's disease have highlighted the importance of early diagnosis and the need to characterise the cognitive profile of the earliest stages of the disease. We set out to examine the pattern of decline in terms of individual cognitive domains in non-demented subjects with clinically isolated progressive amnesia which we have termed questionable Alzheimer's disease. Twelve subjects who fulfill criteria for a clinical diagnosis of possible Alzheimer's disease by NINCDS-ADRDA criteria were compared to 20 age-matched controls in a longitudinal study. All subjects had MMSE scores of 24 or greater at entry to study. Individual profiles were measured by impairment in the cognitive domains of episodic memory, attention, semantic memory, visuospatial function and auditory verbal short-term (working) memory. Even after subjects were given this intensive neuropsychological battery, 8 of 12 subjects had episodic memory deficits only. Within 12 months just 3 patients were only amnesic and the other patients with pure amnesia at year 1 developed either semantic or attentional deficits. Impairment in both these cognitive domains preceded impairment in visuospatial function and auditory-verbal short-term memory. Our findings are consistent with the pattern of cognitive impairment in Alzheimer's disease increasing in accordance with neuropathological correlates of cognitive function with amnesia linked to the initial medial temporal pathology before the pattern of spread affects critical neural substrates for attention and semantic memory. Tests of selective attention and semantic memory appear to be the most sensitive markers of decline beyond the amnestic phase of early Alzheimer's disease.

The neurology of saccades and covert shifts in spatial attention: an event-related fMRI study.

Visual neglect occurs most frequently and persistently after lesions that include the right supramarginal gyrus (SMG), a part of the inferior parietal lobule. Patients with this syndrome make very few saccades to the left, and show abnormal performance on tasks in which they must covertly shift their attention to the left, suggesting that the right SMG is involved in the generation of saccades and attention shifts. Functional imaging studies of saccades and covert attention shifts in the normal brain, however, have shown weak or absent responses in both SMGs. We used event-related functional MRI to re-examine the responses to saccades and attention shifts within a single experiment, and to assess responses to left- and right-sided stimuli independently. When subjects made saccades to peripheral stimuli, the expected responses were seen in striate and prestriate cortex, the superior parietal lobules, the frontal eye fields, the supplementary motor area and the anterior insulae. In addition there was a response in the right SMG but not in the left SMG, as predicted from the clinical literature. When subjects made a covert visual assessment of the peripheral stimulus without any saccade, greater activity was seen in all of the areas in the frontoparietal network. Each area showed a bias towards contralateral stimuli, with two exceptions: the anterior insulae gave mainly ipsilateral responses, whilst the right SMG gave equal responses to right- and left-sided stimuli. These findings are discussed in the context of current theories pertaining to the clinical syndrome of neglect.

Differentiating frontal and temporal variant frontotemporal dementia from Alzheimer's disease.

OBJECTIVE/BACKGROUND: To determine whether difficulty in the early differentiation between frontotemporal dementia (FTD) and AD may arise from a failure to discriminate between the temporal and frontal variants of FTD. METHODS: Neuropsychological profiles of patients with early dementia of Alzheimer type (DAT; n = 10), the temporal variant of FTD (tv-FTD or semantic dementia; n = 5), and the frontal variant of FTD (fv-FTD; n = 10) were compared to each other and normal controls (n = 10). Structural MRI demonstrated temporal lobe atrophy in the tv-FTD patients and frontal lobe atrophy in the fv-FTD group. RESULTS: Subjects with tv-FTD showed severe deficits in semantic memory with preservation of attention and executive function. Subjects with fv-FTD showed the reverse pattern. Attention and executive function impairment separated the fv-FTD patients from the early DAT subjects, who were densely amnesic. CONCLUSION: The double dissociation in performance on semantic memory and attention/executive function clearly separated the temporal and frontal variants of FTD and aids the early differentiation of FTD from AD. The characteristic cognitive profiles reflect the distribution of pathology within each syndrome and support the putative role of the inferolateral temporal neocortex in semantic memory, the medial temporal lobe structures of the hippocampal complex in episodic memory, and the frontal lobes in executive function.