Publications
172 results found
Sen A, Akinola M, Tai XY, et al., 2021, An Investigation of Levetiracetam in Alzheimer's Disease (ILiAD): a double-blind, placebo-controlled, randomised crossover proof of concept study., Trials, Vol: 22, Pages: 508-508, ISSN: 1745-6215
BACKGROUND: Although Alzheimer's disease affects around 800,000 people in the UK and costs almost £23 billion per year, currently licenced treatments only offer modest benefit at best. Seizures, which are more common in patients with Alzheimer's disease than age matched controls, may contribute to the loss of nerve cells and abnormal brain discharges can disrupt cognition. This aberrant electrical activity may therefore present potentially important drug targets. The anti-seizure medication levetiracetam can reduce abnormal cortical discharges and reverse memory deficits in a mouse model of Alzheimer's disease. Levetiracetam has also been shown to improve memory difficulties in patients with mild cognitive impairment, a precursor to Alzheimer's disease. Clinical use of levetiracetam is well-established in treatment of epilepsy and extensive safety data are available. Levetiracetam thus has the potential to provide safe and efficacious treatment to help with memory difficulties in Alzheimer's disease. METHODS: The proposed project is a proof of concept study to test whether levetiracetam can help cognitive function in people with dementia. We plan to recruit thirty patients with mild to moderate Alzheimer's disease with no history of previous seizures or other significant co-morbidity. Participants will be allocated to a double-blind placebo-controlled crossover trial that tests levetiracetam against placebo. Standardised scales to assess cognition and a computer-based touchscreen test that we have developed to better detect subtle improvements in hippocampal function will be used to measure changes in memory. All participants will have an electroencephalogram (EEG) at baseline. The primary outcome measure is a change in the computer-based touchscreen cognitive task while secondary outcomes include the effect of levetiracetam on mood, quality of life and modelling of the EEG, including time series measures and feature-based analysis to see whether the effect of
Franklin HD, Russell LL, Peakman G, et al., 2021, The Revised Self-Monitoring Scale detects early impairment of social cognition in genetic frontotemporal dementia within the GENFI cohort., Alzheimers Research & Therapy, Vol: 13, Pages: 1-12, ISSN: 1758-9193
BACKGROUND: Although social cognitive dysfunction is a major feature of frontotemporal dementia (FTD), it has been poorly studied in familial forms. A key goal of studies is to detect early cognitive impairment using validated measures in large patient cohorts. METHODS: We used the Revised Self-Monitoring Scale (RSMS) as a measure of socioemotional sensitivity in 730 participants from the genetic FTD initiative (GENFI) observational study: 269 mutation-negative healthy controls, 193 C9orf72 expansion carriers, 193 GRN mutation carriers and 75 MAPT mutation carriers. All participants underwent the standardised GENFI clinical assessment including the 'CDR® plus NACC FTLD' scale and RSMS. The RSMS total score and its two subscores, socioemotional expressiveness (EX score) and modification of self-presentation (SP score) were measured. Volumetric T1-weighted magnetic resonance imaging was available from 377 mutation carriers for voxel-based morphometry (VBM) analysis. RESULTS: The RSMS was decreased in symptomatic mutation carriers in all genetic groups but at a prodromal stage only in the C9orf72 (for the total score and both subscores) and GRN (for the modification of self-presentation subscore) groups. RSMS score correlated with disease severity in all groups. The VBM analysis implicated an overlapping network of regions including the orbitofrontal cortex, insula, temporal pole, medial temporal lobe and striatum. CONCLUSIONS: The RSMS indexes socioemotional impairment at an early stage of genetic FTD and may be a suitable outcome measure in forthcoming trials.
Malpetti M, Jones PS, Tsvetanov KA, et al., 2021, Apathy in presymptomatic genetic frontotemporal dementia predicts cognitive decline and is driven by structural brain changes, Alzheimers & Dementia, Vol: 17, Pages: 969-983, ISSN: 1552-5260
IntroductionApathy adversely affects prognosis and survival of patients with frontotemporal dementia (FTD). We test whether apathy develops in presymptomatic genetic FTD, and is associated with cognitive decline and brain atrophy.MethodsPresymptomatic carriers of MAPT, GRN or C9orf72 mutations (N = 304), and relatives without mutations (N = 296) underwent clinical assessments and MRI at baseline, and annually for 2 years. Longitudinal changes in apathy, cognition, gray matter volumes, and their relationships were analyzed with latent growth curve modeling.ResultsApathy severity increased over time in presymptomatic carriers, but not in non-carriers. In presymptomatic carriers, baseline apathy predicted cognitive decline over two years, but not vice versa. Apathy progression was associated with baseline low gray matter volume in frontal and cingulate regions.DiscussionApathy is an early marker of FTD-related changes and predicts a subsequent subclinical deterioration of cognition before dementia onset. Apathy may be a modifiable factor in those at risk of FTD.
Manera AL, Dadar M, Van Swieten JC, et al., 2021, MRI data-driven algorithm for the diagnosis of behavioural variant frontotemporal dementia, JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, Vol: 92, Pages: 608-616, ISSN: 0022-3050
- Author Web Link
- Cite
- Citations: 7
Poos JM, Russell LL, Peakman G, et al., 2021, Impairment of episodic memory in genetic frontotemporal dementia: A GENFI study, Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, Vol: 13, Pages: 1-14, ISSN: 2352-8729
IntroductionWe aimed to assess episodic memory in genetic frontotemporal dementia (FTD) with the Free and Cued Selective Reminding Test (FCSRT).MethodsThe FCSRT was administered in 417 presymptomatic and symptomatic mutation carriers (181 chromosome 9 open reading frame 72 [C9orf72], 163 progranulin [GRN], and 73 microtubule-associated protein tau [MAPT]) and 290 controls. Group differences and correlations with other neuropsychological tests were examined. We performed voxel-based morphometry to investigate the underlying neural substrates of the FCSRT.ResultsAll symptomatic mutation carrier groups and presymptomatic MAPT mutation carriers performed significantly worse on all FCSRT scores compared to controls. In the presymptomatic C9orf72 group, deficits were found on all scores except for the delayed total recall task, while no deficits were found in presymptomatic GRN mutation carriers. Performance on the FCSRT correlated with executive function, particularly in C9orf72 mutation carriers, but also with memory and naming tasks in the MAPT group. FCSRT performance also correlated with gray matter volumes of frontal, temporal, and subcortical regions in C9orf72 and GRN, but mainly temporal areas in MAPT mutation carriers.DiscussionThe FCSRT detects presymptomatic deficits in C9orf72- and MAPT-associated FTD and provides important insight into the underlying cause of memory impairment in different forms of FTD.
Rojas JC, Wang P, Staffaroni AM, et al., 2021, Plasma neurofilament light for prediction of disease progression in familial frontotemporal lobar degeneration., Neurology, Vol: 96, Pages: e2296-e2312, ISSN: 0028-3878
OBJECTIVE: We tested the hypothesis that plasma neurofilament light chain (NfL) identifies asymptomatic carriers of familial frontotemporal lobar degeneration (FTLD)-causing mutations at risk of disease progression. METHODS: Baseline plasma NfL concentrations were measured with single-molecule array in original (n = 277) and validation (n = 297) cohorts. C9orf72, GRN, and MAPT mutation carriers and noncarriers from the same families were classified by disease severity (asymptomatic, prodromal, and full phenotype) using the CDR Dementia Staging Instrument plus behavior and language domains from the National Alzheimer's Disease Coordinating Center FTLD module (CDR+NACC-FTLD). Linear mixed-effect models related NfL to clinical variables. RESULTS: In both cohorts, baseline NfL was higher in asymptomatic mutation carriers who showed phenoconversion or disease progression compared to nonprogressors (original: 11.4 ± 7 pg/mL vs 6.7 ± 5 pg/mL, p = 0.002; validation: 14.1 ± 12 pg/mL vs 8.7 ± 6 pg/mL, p = 0.035). Plasma NfL discriminated symptomatic from asymptomatic mutation carriers or those with prodromal disease (original cutoff: 13.6 pg/mL, 87.5% sensitivity, 82.7% specificity; validation cutoff: 19.8 pg/mL, 87.4% sensitivity, 84.3% specificity). Higher baseline NfL correlated with worse longitudinal CDR+NACC-FTLD sum of boxes scores, neuropsychological function, and atrophy, regardless of genotype or disease severity, including asymptomatic mutation carriers. CONCLUSIONS: Plasma NfL identifies asymptomatic carriers of FTLD-causing mutations at short-term risk of disease progression and is a potential tool to select participants for prevention clinical trials. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT02372773 and NCT02365922. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in carriers of FTLD-causing mutations, elevation of plasma NfL predicts short-term risk of clinical progression.
Overman MJ, Zamboni G, Butler C, et al., 2021, Splenial white matter integrity is associated with memory impairments in posterior cortical atrophy, Brain Communications, Vol: 3, Pages: 1-15, ISSN: 2632-1297
Posterior cortical atrophy is an atypical form of Alzheimer’s disease characterized by visuospatial impairments and predominant tissue loss in the posterior parieto-occipital and temporo-occipital cortex. Whilst episodic memory is traditionally thought to be relatively preserved in posterior cortical atrophy, recent work indicates that memory impairments form a common clinical symptom in the early stages of the disease. Neuroimaging studies suggest that memory dysfunction in posterior cortical atrophy may originate from atrophy and functional hypoconnectivity of parietal cortex. The structural connectivity patterns underpinning these memory impairments, however, have not been investigated. This line of inquiry is of particular interest, as changes in white matter tracts of posterior cortical atrophy patients have been shown to be more extensive than expected based on posterior atrophy of grey matter. In this cross-sectional diffusion tensor imaging MRI study, we examine the relationship between white matter microstructure and verbal episodic memory in posterior cortical atrophy. We assessed episodic memory performance in a group of posterior cortical atrophy patients (n = 14) and a group of matched healthy control participants (n = 19) using the Free and Cued Selective Reminding Test with Immediate Recall. Diffusion tensor imaging measures were obtained for 13 of the posterior cortical atrophy patients and a second control group of 18 healthy adults. Patients and healthy controls demonstrated similar memory encoding performance, indicating that learning of verbal information was preserved in posterior cortical atrophy. However, retrieval of verbal items was significantly impaired in the patient group compared with control participants. As expected, tract-based spatial statistics analyses showed widespread reductions of white matter integrity in posterior cortical regions of patients compared with healthy adults. Correlation analyses
Panman JL, Venkatraghavan V, van der Ende EL, et al., 2021, Modelling the cascade of biomarker changes in GRN-related frontotemporal dementia, Journal of Neurology, Neurosurgery and Psychiatry, Vol: 92, Pages: 494-501, ISSN: 0022-3050
OBJECTIVE: Progranulin-related frontotemporal dementia (FTD-GRN) is a fast progressive disease. Modelling the cascade of multimodal biomarker changes aids in understanding the aetiology of this disease and enables monitoring of individual mutation carriers. In this cross-sectional study, we estimated the temporal cascade of biomarker changes for FTD-GRN, in a data-driven way. METHODS: We included 56 presymptomatic and 35 symptomatic GRN mutation carriers, and 35 healthy non-carriers. Selected biomarkers were neurofilament light chain (NfL), grey matter volume, white matter microstructure and cognitive domains. We used discriminative event-based modelling to infer the cascade of biomarker changes in FTD-GRN and estimated individual disease severity through cross-validation. We derived the biomarker cascades in non-fluent variant primary progressive aphasia (nfvPPA) and behavioural variant FTD (bvFTD) to understand the differences between these phenotypes. RESULTS: Language functioning and NfL were the earliest abnormal biomarkers in FTD-GRN. White matter tracts were affected before grey matter volume, and the left hemisphere degenerated before the right. Based on individual disease severities, presymptomatic carriers could be delineated from symptomatic carriers with a sensitivity of 100% and specificity of 96.1%. The estimated disease severity strongly correlated with functional severity in nfvPPA, but not in bvFTD. In addition, the biomarker cascade in bvFTD showed more uncertainty than nfvPPA. CONCLUSION: Degeneration of axons and language deficits are indicated to be the earliest biomarkers in FTD-GRN, with bvFTD being more heterogeneous in disease progression than nfvPPA. Our data-driven model could help identify presymptomatic GRN mutation carriers at risk of conversion to the clinical stage.
Baker J, Savage S, Milton F, et al., 2021, The syndrome of transient epileptic amnesia: a combined series of 115 cases and literature review, Brain Communications, Vol: 3, Pages: 1-19, ISSN: 2632-1297
The term transient epileptic amnesia was coined in 1990 to describe a form of epilepsy causing predominantly amnestic seizures which could be confused with episodes of Transient Global Amnesia. Subsequent descriptions have highlighted its association with ‘atypical’ forms of memory disturbance including accelerated long-term forgetting, disproportionate autobiographical amnesia and topographical amnesia. However, this highly treatment-responsive condition remains under-recognized and undertreated. We describe the clinical and neuropsychological features in 65 consecutive cases of transient epileptic amnesia referred to our study, comparing these to our previous cohort of 50 patients and to those reported in 102 literature cases described since our 2008 review. Findings in our two cohorts are substantially consistent: The onset of transient epileptic amnesia occurs at an average age of 62 years, giving rise to amnestic episodes at a frequency of around 1/month, typically lasting 15–30 min and often occurring on waking. Amnesia is the only manifestation of epilepsy in 24% of patients; olfactory hallucinations occur in 43%, motor automatisms in 41%, brief unresponsiveness in 39%. The majority of patients describe at least one of the atypical forms of memory disturbance mentioned above; easily provoked tearfulness is a common accompanying feature. There is a male predominance (85:30). Epileptiform changes were present in 35% of cases, while suspected causative magnetic resonance imaging abnormalities were detected in only 5%. Seizures ceased with anticonvulsant treatment in 93% of cases. Some clinical features were detected more commonly in the second series than the first, probably as a result of heightened awareness. Neuropsychological testing and comparison to two age and IQ-matched control groups (n = 24 and 22) revealed consistent findings across the two cohorts, namely elevated mean IQ, preserved executive function, mi
Tsvetanov KA, Gazzina S, Jones PS, et al., 2021, Brain functional network integrity sustains cognitive function despite atrophy in presymptomatic genetic frontotemporal dementia, Alzheimer's & Dementia, Vol: 17, Pages: 500-514, ISSN: 1552-5260
IntroductionThe presymptomatic phase of neurodegenerative disease can last many years, with sustained cognitive function despite progressive atrophy. We investigate this phenomenon in familial frontotemporal dementia (FTD).MethodsWe studied 121 presymptomatic FTD mutation carriers and 134 family members without mutations, using multivariate data-driven approach to link cognitive performance with both structural and functional magnetic resonance imaging. Atrophy and brain network connectivity were compared between groups, in relation to the time from expected symptom onset.ResultsThere were group differences in brain structure and function, in the absence of differences in cognitive performance. Specifically, we identified behaviorally relevant structural and functional network differences. Structure-function relationships were similar in both groups, but coupling between functional connectivity and cognition was stronger for carriers than for non-carriers, and increased with proximity to the expected onset of disease.DiscussionOur findings suggest that the maintenance of functional network connectivity enables carriers to maintain cognitive performance.
Shribman S, Heller C, Burrows M, et al., 2021, Plasma Neurofilament Light as a Biomarker of Neurological Involvement in Wilson's Disease, MOVEMENT DISORDERS, Vol: 36, Pages: 503-508, ISSN: 0885-3185
- Author Web Link
- Cite
- Citations: 15
Benussi A, Premi E, Gazzina S, et al., 2021, Progression of Behavioral Disturbances and Neuropsychiatric Symptoms in Patients With Genetic Frontotemporal Dementia, JAMA NETWORK OPEN, Vol: 4, ISSN: 2574-3805
- Author Web Link
- Cite
- Citations: 34
Ibanez A, Parra MA, Butler C, 2021, The Latin America and the Caribbean Consortium on Dementia (LAC-CD): from networking to research to implementation science, JOURNAL OF ALZHEIMERS DISEASE, Vol: 82, Pages: S379-S394, ISSN: 1387-2877
In comparison with other regions, dementia prevalence in Latin America is growing rapidly, along with the consequent clinical, social, and economic burden upon patients and their families. The combination of fragile health care systems, large social inequalities, and isolated clinical and research initiatives makes the coordination of efforts imperative. The Latin America and the Caribbean Consortium on Dementia (LAC-CD) is a regional organization overseeing and promoting clinical and research activities on dementia. Here, we first provide an overview of the consortium, highlighting the antecedents and current mission. Then, we present the consortium’s regional research, including the multi-partner consortium to expand dementia research in Latin America (ReDLat), which aims to identify the unique genetic, social, and economic factors that drive Alzheimer’s and frontotemporal dementia presentation in LAC relative to the US. We describe an extension of ReDLat which aims to develop affordable markers of disease subtype and severity using high density EEG. We introduce current initiatives promoting regional diagnosis, visibility, and capacity, including the forthcoming launch of the Latin American Brain Health Institute (BrainLat). We discuss LAC-CD-led advances in brain health diplomacy, including an assessment of responses to the impact of COVID-19 on people with dementia and examining the knowledge of public policies among experts in the region. Finally, we present the current knowledge-to-action framework, which paves the way for a future regional action plan. Coordinated actions are crucial to forging strong regional bonds, supporting the implementation of regional dementia plans, improving health systems, and expanding research collaborations across Latin America.
Borrego-Ecija S, Sala-Llonch R, van Swieten J, et al., 2021, Disease-related cortical thinning in presymptomatic granulin mutation carriers, NeuroImage: Clinical, Vol: 29, Pages: 1-8, ISSN: 2213-1582
Mutations in the granulin gene (GRN) cause familial frontotemporal dementia. Understanding the structural brain changes in presymptomatic GRN carriers would enforce the use of neuroimaging biomarkers for early diagnosis and monitoring. We studied 100 presymptomatic GRN mutation carriers and 94 noncarriers from the Genetic Frontotemporal dementia initiative (GENFI), with MRI structural images. We analyzed 3T MRI structural images using the FreeSurfer pipeline to calculate the whole brain cortical thickness (CTh) for each subject. We also perform a vertex-wise general linear model to assess differences between groups in the relationship between CTh and diverse covariables as gender, age, the estimated years to onset and education. We also explored differences according to TMEM106B genotype, a possible disease modifier. Whole brain CTh did not differ between carriers and noncarriers. Both groups showed age-related cortical thinning. The group-by-age interaction analysis showed that this age-related cortical thinning was significantly greater in GRN carriers in the left superior frontal cortex. TMEM106B did not significantly influence the age-related cortical thinning. Our results validate and expand previous findings suggesting an increased CTh loss associated with age and estimated proximity to symptoms onset in GRN carriers, even before the disease onset.
Bocchetta M, Todd EG, Peakman G, et al., 2021, Differential early subcortical involvement in genetic FTD within the GENFI cohort, NEUROIMAGE-CLINICAL, Vol: 30, ISSN: 2213-1582
- Author Web Link
- Cite
- Citations: 28
Russell LL, Greaves CV, Bocchetta M, et al., 2020, Social cognition impairment in genetic frontotemporal dementia within the GENFI cohort, Cortex, Vol: 133, Pages: 384-398, ISSN: 0010-9452
A key symptom of frontotemporal dementia (FTD) is difficulty interacting socially with others. Social cognition problems in FTD include impaired emotion processing and theory of mind difficulties, and whilst these have been studied extensively in sporadic FTD, few studies have investigated them in familial FTD. Facial Emotion Recognition (FER) and Faux Pas (FP) recognition tests were used to study social cognition within the Genetic Frontotemporal Dementia Initiative (GENFI), a large familial FTD cohort of C9orf72, GRN, and MAPT mutation carriers. 627 participants undertook at least one of the tasks, and were separated into mutation-negative healthy controls, presymptomatic mutation carriers (split into early and late groups) and symptomatic mutation carriers. Groups were compared using a linear regression model with bootstrapping, adjusting for age, sex, education, and for the FP recognition test, language. Neural correlates of social cognition deficits were explored using a voxel-based morphometry (VBM) study. All three of the symptomatic genetic groups were impaired on both tasks with no significant difference between them. However, prior to onset, only the late presymptomatic C9orf72 mutation carriers on the FER test were impaired compared to the control group, with a subanalysis showing differences particularly in fear and sadness. The VBM analysis revealed that impaired social cognition was mainly associated with a left hemisphere predominant network of regions involving particularly the striatum, orbitofrontal cortex and insula, and to a lesser extent the inferomedial temporal lobe and other areas of the frontal lobe. In conclusion, theory of mind and emotion processing abilities are impaired in familial FTD, with early changes occurring prior to symptom onset in C9orf72 presymptomatic mutation carriers. Future work should investigate how performance changes over time, in order to gain a clearer insight into social cognitive impairment over the course of the
Toniolo S, Maio MR, Tabi YA, et al., 2020, A novel visual short‐term memory task differentiates MCI and Alzheimer’s patients from healthy ageing, Alzheimer's & Dementia, Vol: 16, ISSN: 1552-5260
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>We developed a novel delayed reproduction task, the “What was where?” task, which obtains a continuous measure of localization error and is more sensitive compared to conventional span measures of Short‐term Memory (STM).</jats:p></jats:sec><jats:sec><jats:title>Method</jats:title><jats:p>We recruited 44 MCI (Mild Cognitive Impairment), 41 AD (Alzheimer’s Disease) patients and 109 healthy elderly controls (EHCs) from memory clinics in Oxford, UK and Jena, Germany, where they performed the “What was where?” task (Figure 1). We extracted the following metrics: <jats:italic>Identification Accuracy</jats:italic> (percentage correctly identified items), <jats:italic>Absolute Localization Error</jats:italic> (how far the object was misplaced), <jats:italic>Misbinding</jats:italic> rate (erroneously localizing an item to the remembered location of another item in memory) and <jats:italic>Guessing</jats:italic> response rate.</jats:p></jats:sec><jats:sec><jats:title>Result</jats:title><jats:p><jats:italic>Absolute Localization Error and Misbinding</jats:italic> rates were greater in MCI and AD patients (p < 0.001) compared to EHCs, while AD and MCI performed similarly on these metrics. However, <jats:italic>Identification Accuracy</jats:italic> as well as <jats:italic>Guessing</jats:italic> (p = 0.003) were greater in MCI (p < 0.001) compared to AD patients. Moreover, EHCs identified the correct object more often (p < 0.001) and guessed less (p < 0.001) than MCI patients.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>This novel task is able to detect STM impairment in MCI cases on a
Convery RS, Bocchetta M, Greaves C, et al., 2020, Abnormal pain perception is associated with thalamo-cortico-striatal atrophy in <i>C9orf72</i> expansion carriers in the GENFI cohort, JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, Vol: 91, Pages: 1325-1328, ISSN: 0022-3050
- Author Web Link
- Cite
- Citations: 10
Poos JM, Russell LL, Peakman G, et al., 2020, The Free Cued Selective Reminding Test detects episodic memory impairment in the presymptomatic period of familial frontotemporal dementia within the GENFI cohort, Alzheimer's & Dementia, Vol: 16, ISSN: 1552-5260
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Episodic memory is increasingly reported in frontotemporal dementia (FTD) and it has been suggested to differ between genetic forms of FTD. However, systematic investigations of episodic memory in familial FTD, and specifically the presymptomatic stage, are scarce. This cross‐sectional study investigates performance on the Free Cued and Selective Reminding Test (FCSRT) in the Genetic Frontotemporal Dementia Initiative (GENFI), a large familial FTD cohort.</jats:p></jats:sec><jats:sec><jats:title>Method</jats:title><jats:p>685 participants were tested with the FCSRT (52 presymptomatic and 21 symptomatic <jats:italic>MAPT</jats:italic>, 135 presymptomatic and 42 symptomatic <jats:italic>GRN</jats:italic>, 109 presymptomatic and 63 symptomatic <jats:italic>C9orf72</jats:italic> mutation carriers and 263 non‐carriers). The presymptomatic mutation carriers were split into an early and late presymptomatic period (more than or within ten years of expected symptom onset). Groups were compared using linear regression models, adjusted for age and education, with bootstrapping.</jats:p></jats:sec><jats:sec><jats:title>Result</jats:title><jats:p>Performance on all FCSRT test scores had a negative correlation with age (0.18 > <jats:italic>r</jats:italic> < 0.38) and immediate free recall (<jats:italic>r</jats:italic> = 0.21), immediate total recall (<jats:italic>r</jats:italic> = 0.14) and delayed free recall (<jats:italic>r</jats:italic> = 0.24) had a positive correlation with education. All symptomatic mutation carrier groups scored significantly lower than controls on immediate free recall (<jats:italic>MAPT</jats:italic>: −2.54 ± 1.52; <jats:italic>GRN</j
Braun V, Blackmore J, Cleveland RO, et al., 2020, Transcranial ultrasound stimulation in humans is associated with an auditory confound that can be effectively masked, Brain Stimulation, Vol: 13, Pages: 1527-1534, ISSN: 1876-4754
BackgroundTranscranial ultrasound stimulation (TUS) is emerging as a potentially powerful, non-invasive technique for focal brain stimulation. Recent animal work suggests, however, that TUS effects may be confounded by indirect stimulation of early auditory pathways.ObjectiveWe aimed to investigate in human participants whether TUS elicits audible sounds and if these can be masked by an audio signal.MethodsIn 18 healthy participants, T1-weighted magnetic resonance brain imaging was acquired for 3D ultrasound simulations to determine optimal transducer placements and source amplitudes. Thermal simulations ensured that temperature rises were <0.5 °C at the target and <3 °C in the skull. To test for non-specific auditory activation, TUS (500 kHz, 300 ms burst, modulated at 1 kHz with 50% duty cycle) was applied to primary visual cortex and participants were asked to distinguish stimulation from non-stimulation trials. EEG was recorded throughout the task. Furthermore, ex-vivo skull experiments tested for the presence of skull vibrations during TUS.ResultsWe found that participants can hear sound during TUS and can distinguish between stimulation and non-stimulation trials. This was corroborated by EEG recordings indicating auditory activation associated with TUS. Delivering an audio waveform to participants through earphones while TUS was applied reduced detection rates to chance level and abolished the TUS-induced auditory EEG signal. Ex vivo skull experiments demonstrated that sound is conducted through the skull at the pulse repetition frequency of the ultrasound.ConclusionFuture studies using TUS in humans need to take this auditory confound into account and mask stimulation appropriately.
Tavares TP, Mitchell DG, Coleman KKL, et al., 2020, Early symptoms in symptomatic and preclinical genetic frontotemporal lobar degeneration, Journal of Neurology, Neurosurgery and Psychiatry, Vol: 91, Pages: 975-984, ISSN: 0022-3050
Objectives The clinical heterogeneity of frontotemporal dementia (FTD) complicates identification of biomarkers for clinical trials that may be sensitive during the prediagnostic stage. It is not known whether cognitive or behavioural changes during the preclinical period are predictive of genetic status or conversion to clinical FTD. The first objective was to evaluate the most frequent initial symptoms in patients with genetic FTD. The second objective was to evaluate whether preclinical mutation carriers demonstrate unique FTD-related symptoms relative to familial mutation non-carriers.Methods The current study used data from the Genetic Frontotemporal Dementia Initiative multicentre cohort study collected between 2012 and 2018. Participants included symptomatic carriers (n=185) of a pathogenic mutation in chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN) or microtubule-associated protein tau (MAPT) and their first-degree biological family members (n=588). Symptom endorsement was documented using informant and clinician-rated scales.Results The most frequently endorsed initial symptoms among symptomatic patients were apathy (23%), disinhibition (18%), memory impairments (12%), decreased fluency (8%) and impaired articulation (5%). Predominant first symptoms were usually discordant between family members. Relative to biologically related non-carriers, preclinical MAPT carriers endorsed worse mood and sleep symptoms, and C9orf72 carriers endorsed marginally greater abnormal behaviours. Preclinical GRN carriers endorsed less mood symptoms compared with non-carriers, and worse everyday skills.Conclusion Preclinical mutation carriers exhibited neuropsychiatric symptoms compared with non-carriers that may be considered as future clinical trial outcomes. Given the heterogeneity in symptoms, the detection of clinical transition to symptomatic FTD may be best captured by composite indices integrating the most common initial symptoms for each genetic group.
Ahmed S, Culley S, Blanco-Duque C, et al., 2020, Pronounced Impairment of Activities of Daily Living in Posterior Cortical Atrophy, DEMENTIA AND GERIATRIC COGNITIVE DISORDERS, Vol: 49, Pages: 48-55, ISSN: 1420-8008
- Author Web Link
- Cite
- Citations: 7
Altmann A, Cash DM, Bocchetta M, et al., 2020, Analysis of brain atrophy and local gene expression in genetic frontotemporal dementia, Brain Communications, Vol: 2, Pages: 1-13, ISSN: 2632-1297
Frontotemporal dementia is a heterogeneous neurodegenerative disorder characterized by neuronal loss in the frontal and temporal lobes. Despite progress in understanding which genes are associated with the aetiology of frontotemporal dementia, the biological basis of how mutations in these genes lead to cell loss in specific cortical regions remains unclear. In this work, we combined gene expression data for 16 772 genes from the Allen Institute for Brain Science atlas with brain maps of grey matter atrophy in symptomatic C9orf72, GRN and MAPT mutation carriers obtained from the Genetic Frontotemporal dementia Initiative study. No significant association was seen between C9orf72, GRN and MAPT expression and the atrophy patterns in the respective genetic groups. After adjusting for spatial autocorrelation, between 1000 and 5000 genes showed a negative or positive association with the atrophy pattern within each individual genetic group, with the most significantly associated genes being TREM2, SSBP3 and GPR158 (negative association in C9Orf72, GRN and MAPT respectively) and RELN, MXRA8 and LPA (positive association in C9Orf72, GRN and MAPT respectively). An overrepresentation analysis identified a negative association with genes involved in mitochondrial function, and a positive association with genes involved in vascular and glial cell function in each of the genetic groups. A set of 423 and 700 genes showed significant positive and negative association, respectively, with atrophy patterns in all three maps. The gene set with increased expression in spared cortical regions was enriched for neuronal and microglial genes, while the gene set with increased expression in atrophied regions was enriched for astrocyte and endothelial cell genes. Our analysis suggests that these cell types may play a more active role in the onset of neurodegeneration in frontotemporal dementia than previously assumed, and in the case of the positively associated cell marker genes, potential
Torso M, Ahmed S, Butler C, et al., 2020, Cortical diffusivity investigation in posterior cortical atrophy and typical Alzheimer's disease, Journal of Neurology, Vol: 268, Pages: 227-239, ISSN: 0340-5354
ObjectivesTo investigate the global cortical and regional quantitative features of cortical neural architecture in the brains of patients with posterior cortical atrophy (PCA) and typical Alzheimer’s disease (tAD) compared with elderly healthy controls (HC).MethodsA novel diffusion MRI method, that has been shown to correlate with minicolumnar organization changes in the cerebral cortex, was used as a surrogate of neuropathological changes in dementia. A cohort of 15 PCA patients, 23 tAD and 22 healthy elderly controls (HC) were enrolled to investigate the changes in cortical diffusivity among groups. For each subject, 3 T MRI T1-weighted images and diffusion tensor imaging (DTI) scans were analysed to extract novel cortical DTI derived measures (AngleR, PerpPD and ParlPD). Receiver operating characteristics (ROC) curve analysis and the area under the curve (AUC) were used to assess the group discrimination capability of the method.ResultsThe results showed that the global cortical DTI derived measures were able to detect differences, in both PCA and tAD patients compared to healthy controls. The AngleR was the best measure to discriminate HC from tAD (AUC = 0.922), while PerpPD was the best measure to discriminate HC from PCA (AUC = 0.961). Finally, the best global measure to differentiate the two patient groups was ParlPD (AUC = 0.771). The comparison between PCA and tAD patients revealed a different pattern of damage within the AD spectrum and the regional comparisons identified significant differences in key regions including parietal and temporal lobe cortical areas. The best AUCs were shown by PerpPD right lingual cortex (AUC = 0.856), PerpPD right superior parietal cortex (AUC = 0.842) and ParlPD right lateral occipital cortex (AUC = 0.826).ConclusionsDiagnostic group differences were found, suggesting that the new cortical DTI analysis method may be useful to investigat
Le Blanc G, Pomerleau VJ, McCarthy J, et al., 2020, Faster Cortical Thinning and Surface Area Loss in Presymptomatic and Symptomatic <i>C9orf72</i> Repeat Expansion Adult Carriers, ANNALS OF NEUROLOGY, Vol: 88, Pages: 113-122, ISSN: 0364-5134
- Author Web Link
- Cite
- Citations: 19
van der Ende EL, Xiao M, Xu D, et al., 2020, Neuronal pentraxin 2: a synapse-derived CSF biomarker in genetic frontotemporal dementia, JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, Vol: 91, Pages: 612-621, ISSN: 0022-3050
- Author Web Link
- Cite
- Citations: 36
Argyropoulos GPD, Butler CR, 2020, Does hippocampal atrophy explain anterograde and retrograde amnesia following autoimmune limbic encephalitis?, The Hippocampus, Vol: 30, Pages: 1013-1017, ISSN: 1050-9631
Argyropoulos GPD, Moore L, Loane C, et al., 2020, Pathologic tearfulness after limbic encephalitis: A novel disorder and its neural basis, Neurology, Vol: 94, Pages: E1320-E1335, ISSN: 0028-3878
Objective We investigated the nature and neural foundations of pathologic tearfulness in a uniquely large cohort of patients who had presented with autoimmune limbic encephalitis (aLE).Methods We recruited 38 patients (26 men, 12 women; median age 63.06 years; interquartile range [IQR] 16.06 years) in the postacute phase of aLE who completed questionnaires probing emotion regulation. All patients underwent structural/functional MRI postacutely, along with 67 age- and sex-matched healthy controls (40 men, 27 women; median age 64.70 years; IQR 19.87 years). We investigated correlations of questionnaire scores with demographic, clinical, neuropsychological, and brain imaging data across patients. We also compared patients diagnosed with pathologic tearfulness and those without, along with healthy controls, on gray matter volume, resting-state functional connectivity, and activity.Results Pathologic tearfulness was reported by 50% of the patients, while no patient reported pathologic laughing. It was not associated with depression, impulsiveness, memory impairment, executive dysfunction in the postacute phase, or amygdalar abnormalities in the acute phase. It correlated with changes in specific emotional brain networks: volume reduction in the right anterior hippocampus, left fusiform gyrus, and cerebellum, abnormal hippocampal resting-state functional connectivity with the posteromedial cortex and right middle frontal gyrus, and abnormal hemodynamic activity in the left fusiform gyrus, right inferior parietal lobule, and ventral pons.Conclusions Pathologic tearfulness is common following aLE, is not a manifestation of other neuropsychiatric features, and reflects abnormalities in networks of emotion regulation beyond the acute hippocampal focus. The condition, which may also be present in other neurologic disorders, provides novel insights into the neural basis of affective control and its dysfunction in disease.
Braun V, Blackmore J, Cleveland RO, et al., 2020, Transcranial ultrasound stimulation in humans is associated with an auditory confound that can be effectively masked
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Transcranial ultrasound stimulation (TUS) is emerging as a potentially powerful, non-invasive technique for focal brain stimulation. Recent animal work suggests, however, that TUS effects may be confounded by indirect stimulation of early auditory pathways.</jats:p></jats:sec><jats:sec><jats:title>Objective</jats:title><jats:p>We aimed to investigate in human participants whether TUS elicits audible sounds and if these can be masked by an audio signal.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>In 18 healthy participants, T1-weighted magnetic resonance brain imaging was acquired for 3D ultrasound simulations to determine optimal transducer placements and source amplitudes. Thermal simulations ensured that temperature rises were <0.5 °C at the target and <3 °C in the skull. To test for non-specific auditory activation, TUS (500 kHz, 300 ms burst, modulated at 1 kHz with 50% duty cycle) was applied to primary visual cortex and participants were asked to distinguish stimulation from non-stimulation trials. EEG was recorded throughout the task. Furthermore, ex-vivo skull experiments tested for the presence of skull vibrations during TUS.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>We found that participants can hear sound during TUS and can distinguish between stimulation and non-stimulation trials. This was corroborated by EEG recordings indicating auditory activation associated with TUS. Delivering an audio waveform to participants through earphones while TUS was applied reduced detection rates to chance level and abolished the TUS-induced auditory EEG signal. Ex vivo skull experiments demonstrated that sound is conducted through the skull at the pulse repetition frequen
Heller C, Foiani MS, Moore K, et al., 2020, Plasma glial fibrillary acidic protein is raised in progranulin-associated frontotemporal dementia, JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, Vol: 91, Pages: 263-270, ISSN: 0022-3050
- Author Web Link
- Cite
- Citations: 92
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.