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1.

Introduction

Staging preclinical Alzheimer disease (AD) by the expected years to symptom onset (EYO) in autosomal dominant AD (ADAD) through biomarker correlations is important.

Methods

We estimated the correlation matrix between EYO/cognition and imaging/CSF biomarkers, and searched for the EYO cutoff where a change in the correlations occurred before and after the cutoff among the asymptomatic mutation carriers of ADAD. We then estimated the longitudinal rate of change for biomarkers/cognition within each preclinical stage defined by the EYO.

Results

Based on the change in the correlations, the preclinical ADAD was divided by EYOs ?7 and ?13 years. Mutation carriers demonstrated a temporal ordering of biomarker/cognition changes across the three preclinical stages.

Discussion

Duration of each preclinical stage can be estimated in ADAD, facilitating better planning of prevention trials with the EYO cutoffs under the recently released FDA guidance. The generalization of these results to sporadic AD warrants further investigation.  相似文献   

2.

Background

Arousal and sleep represent basic domains of behavior, and alterations are of high clinical importance.

Objective/hypothesis

The aim of this study was to further elucidate the neurobiology of insomnia disorder (ID) and the potential for new treatment developments, based on the modulation of cortical activity through the non-invasive brain stimulation technique transcranial direct current stimulation (tDCS). Specifically, we tested the hypotheses that bi-frontal anodal tDCS shortens and cathodal tDCS prolongs total sleep time in patients with ID, compared to sham stimulation. Furthermore, we tested for differences in indices of arousal between ID patients and healthy controls and explored their potential impact on tDCS effects.

Methods

Nineteen ID patients underwent a within-subject repeated-measures sleep laboratory study with adaptation, baseline and three experimental nights. Bifrontal anodal, cathodal and sham tDCS was delivered in a counterbalanced order immediately prior to sleep. Wake EEG was recorded prior to and after tDCS as well as on the following morning. Subsequently, we compared patients with ID to a healthy control group from an earlier dataset.

Results

Against our hypothesis, we did not observe any tDCS effects on sleep continuity or sleep architecture in patients with ID. Further analyses of nights without stimulation demonstrated significantly increased levels of arousal in ID patients compared to healthy controls, as indexed by subjective reports, reduced total sleep time, increased wake after sleep onset and increased high frequency EEG power during wakefulness and NREM sleep. Of note, indices of increased arousal predicted the lack of effect of tDCS in ID patients.

Conclusions

Our study characterizes for the first time differential effects of tDCS on sleep in patients with ID and healthy controls, presumably related to persistent hyperarousal in ID. These findings suggest that adapted tDCS protocols need to be developed to modulate arousal and sleep dependent on baseline arousal levels.  相似文献   

3.

Introduction

The relative importance of structural magnetic resonance imaging (MRI) and tau positron emission tomography (PET) to predict diagnosis and cognition in Alzheimer's disease (AD) is unclear.

Methods

We tested 56 cognitively unimpaired controls (including 27 preclinical AD), 32 patients with prodromal AD, and 39 patients with AD dementia. Optimal classifiers were constructed using the least absolute shrinkage and selection operator with 18F-AV-1451 (tau) PET and structural MRI data (regional cortical thickness and subcortical volumes).

Results

18F-AV-1451 in the amygdala, entorhinal cortex, parahippocampal gyrus, fusiform, and inferior parietal lobule had 93% diagnostic accuracy for AD (prodromal or dementia). The MRI classifier involved partly the same regions plus the hippocampus, with 83% accuracy, but did not improve upon the tau classifier. 18F-AV-1451 retention and MRI were independently associated with cognition.

Discussion

Optimized tau PET classifiers may diagnose AD with high accuracy, but both tau PET and structural brain MRI capture partly unique information relevant for the clinical deterioration in AD.  相似文献   

4.

Background

Transcranial magnetic stimulation (TMS) is a non-invasive method to stimulate localized brain regions. Despite widespread use in motor cortex, TMS is seldom performed in sensory areas due to variable, qualitative metrics.

Objective

Assess the reliability and validity of tracing phosphenes, and to investigate the stimulation parameters necessary to elicit decreased visual cortex excitability with paired-pulse TMS at short inter-stimulus intervals.

Methods

Across two sessions, single and paired-pulse recruitment curves were derived by having participants outline elicited phosphenes and calculating resulting average phosphene sizes.

Results

Phosphene size scaled with stimulus intensity, similar to motor cortex. Paired-pulse recruitment curves demonstrated inhibition at lower conditioning stimulus intensities than observed in motor cortex. Reliability was high across sessions.

Conclusions

TMS-induced phosphenes are a valid and reliable tool for measuring cortical excitability and inhibition in early visual areas. Our results also provide appropriate stimulation parameters for measuring short-latency intracortical inhibition in visual cortex.  相似文献   

5.

Background

Temporal lobe epilepsy is most prevalent among focal epilepsies, and nearly one-third of patients are refractory to pharmacological intervention. Persistent cognitive and neurobehavioral comorbidities also occur due to the recurrent nature of seizures and medication-related side effects.

Hypothesis

Electrical neuromodulation is an effective strategy to reduce seizures both in animal models and clinically, but its efficacy to modulate cognition remains unclear. We hypothesized that theta frequency stimulation of the medial septum would increase septohippocampal oscillations, increase seizure threshold, and improve spatial learning in a rat model of pilocarpine-induced epilepsy.

Methods

Sham and pilocarpine rats were implanted with electrodes in the medial septum, hippocampus and prefrontal cortex. EEG was assessed days prior to and following stimulation. Sham and pilocarpine-treated rats received either no stimulation, continuous (throughout each behavior), or pre-task (one minute prior to each behavior) 7.7?Hz septal stimulation during the Barnes maze spatial navigation test and also during assessment of flurothyl-induced seizures.

Results

Both continuous and pre-task stimulation prevented epilepsy-associated reductions in theta oscillations over time. Additionally, both stimulation paradigms significantly improved spatial navigation in the Barnes maze, reducing latency and improving search strategy. Moreover, stimulation led to significant increases in seizure threshold in pilocarpine-treated rats. There was no evidence of cognitive enhancement or increased seizure threshold in stimulated sham rats.

Conclusion

These findings have profound implications as theta stimulation of the septum represents a single frequency and target that has the potential to both improve cognition and reduce seizures for patients with refractory epilepsy.  相似文献   

6.

Background

Transcutaneous vagus nerve stimulation (tVNS) is a new, non-invasive technique being investigated as an intervention for a variety of clinical disorders, including epilepsy and depression. It is thought to exert its therapeutic effect by increasing central norepinephrine (NE) activity, but the evidence supporting this notion is limited.

Objective

In order to test for an impact of tVNS on psychophysiological and hormonal indices of noradrenergic function, we applied tVNS in concert with assessment of salivary alpha amylase (SAA) and cortisol, pupil size, and electroencephalograph (EEG) recordings.

Methods

Across three experiments, we applied real and sham tVNS to 61 healthy participants while they performed a set of simple stimulus-discrimination tasks. Before and after the task, as well as during one break, participants provided saliva samples and had their pupil size recorded. EEG was recorded throughout the task. The target for tVNS was the cymba conchae, which is heavily innervated by the auricular branch of the vagus nerve. Sham stimulation was applied to the ear lobe.

Results

P3 amplitude was not affected by tVNS (Experiment 1A: N?=?24; Experiment 1B: N?=?20; Bayes factor supporting null model?=?4.53), nor was pupil size (Experiment 2: N?=?16; interaction of treatment and time: p?=?.79). However, tVNS increased SAA (Experiments 1A and 2: N?=?25) and attenuated the decline of salivary cortisol compared to sham (Experiment 2: N?=?17), as indicated by significant interactions involving treatment and time (p?=?.023 and p?=?.040, respectively).

Conclusion

These findings suggest that tVNS modulates hormonal indices but not psychophysiological indices of noradrenergic function.  相似文献   

7.

Background

Accounts of cognitive processes in judgment and decision-making are frequently based on a dual-process framework, which reflects two qualitatively different types of processing: intuitive (Type 1) and analytical (Type 2) processes.

Objective

The present study investigated the effects of bilateral transcranial direct current stimulation (tDCS) to the dorsolateral prefrontal cortex (DLPFC) on judgment and decision-making performance.

Methods

Participants received anodal tDCS stimulation to the right DLPFC, left DLPFC or sham. There were 3 tasks: vignettes measuring heuristic thinking, belief bias syllogisms, and the cognitive reflection test (CRT), a measure of the ability to inhibit automatic responses to reach a correct solution. Fifty-four participants (mean age?=?24.63?±?4.46 years; 29 females) were recruited.

Results

Results showed that anodal tDCS to the right DLPFC was associated with an increase in cognitive reflection performance (Type 2 processing) as compared to left DLPFC and to sham. Logic thinking was reduced following anodal tDCS to the left DLPFC.

Conclusion

These findings are broadly consistent with a dual process framework, and cannot be explained by differences in cognitive ability and thinking style. The results demonstrate the involvement of the right DLPFC in cognitive reflection, and suggest the possibility of improving cognitive performance through tDCS.  相似文献   

8.

Introduction

We evaluated whether hospitalization with or without surgery increases risk for dementia or Alzheimer's disease.

Methods

A clinical sample (843 clinically diagnosed dementia cases; 1686 matched nondemented individuals) was identified from Swedish Twin Registry studies. A register-based sample (4293 cases; 21,465 matched controls) was identified by linkage of Swedish Twin Registry to Swedish Patient Registry records. Apolipoprotein E (APOE) status and within-pair comparisons of dementia discordant twins indicated genetic susceptibility.

Results

Nonsurgical hospitalization is associated with greater dementia risk than hospitalization with surgical intervention. In the register sample, thoracic, abdominal, and major orthopedic procedures entailed dementia risk; in the clinical sample, orthopedic alone. Within-pair analyses indicate that associations in part reflect genetic susceptibility in common to hospitalization and dementia. Potential gene-environment interactions were indicated by greater risk due to hospitalization among APOE ε4 noncarriers.

Discussion

We confirm hospitalization as a risk factor for dementia, with repeated hospitalizations a more important risk factor than surgery.  相似文献   

9.

Introduction

Primary progressive aphasia (PPA) displays variable progression trajectories that require further elucidation.

Methods

Longitudinal quantitation of atrophy and language over 12 months was completed for PPA patients with and without positive amyloid PET (PPAAβ+ and PPAAβ?), an imaging biomarker of underlying Alzheimer’s disease.

Results

Over 12 months, both PPA groups showed significantly greater cortical atrophy rates in the left versus right hemisphere, with a more widespread pattern in PPAAβ+. The PPAAβ+ group also showed greater decline in performance on most language tasks. There was no obligatory relationship between the logopenic PPA variant and amyloid status. Effect sizes from quantitative MRI data were more robust than neuropsychological metrics.

Discussion

Preferential language network neurodegeneration is present in PPA irrespective of amyloid status. Clinical and anatomical progression appears to differ for PPA due to Alzheimer's disease versus non–Alzheimer's disease neuropathology, a distinction that may help to inform prognosis and the design of intervention trials.  相似文献   

10.

Introduction

Recruitment for Alzheimer's disease (AD) prevention research studies is challenging because of lack of awareness among cognitively healthy adults coupled with the high screen fail rate due to participants not having a genetic risk factor or biomarker evidence of the disease. Participant recruitment registries offer one solution for efficiently and effectively identifying, characterizing, and connecting potential eligible volunteers to studies.

Methods

Individuals aged 55-75 years who live in the United States and self-report not having a diagnosis of cognitive impairment such as MCI or dementia are eligible to join GeneMatch. Participants enroll online and are provided a cheek swab kit for DNA extraction and apolipoprotein E (APOE) genotyping. Participants are not told their APOE results, although the results may be used in part to help match participants to AD prevention studies.

Results

As of August 2018, 75,351 participants had joined GeneMatch. Nearly 30% of participants have one APOE4 allele, and approximately 3% have two APOE4 alleles. The percentages of APOE4 heterozygotes and homozygotes are inversely associated with age (P < .001).

Discussion

GeneMatch, the first trial-independent research enrollment program designed to recruit and refer cognitively healthy adults to AD prevention studies based in part on APOE test results, provides a novel mechanism to accelerate prescreening and enrollment for AD prevention trials.  相似文献   

11.

Background

Repetitive convergent inputs to a single post-synaptic neuron can induce long-term potentiation (LTP) or depression (LTD) of synaptic activity in a spike timing-dependent manner.

Objective

Here we set a protocol of visual paired associative stimulation (vPAS) of the primary visual cortex (V1) in humans to induce persistent changes in the excitatory properties of V1 with a spike timing rule.

Methods

We provided convergent inputs to V1 by coupling transcranial magnetic stimulation (TMS) pulses of the occipital cortex with peripheral visual inputs, at four interstimulus intervals of ?50/-25/+25/+50 ms relative to the visual evoked potential (VEP) P1 latency. We analysed VEP amplitude and delayed habituation before and up to 10 min after each vPAS protocol.

Results

VEP amplitude was reduced after vPAS+25. Delayed VEP habituation was increased after vPAS-25 while it was reduced after vPAS+25.

Conclusions

We provide evidence that associative bidirectional synaptic plasticity is a feature not only of the sensorimotor but also of the human visual system.  相似文献   

12.

Introduction

Subjective cognitive decline (SCD) is a risk factor for mild cognitive impairment (MCI) and Alzheimer's disease (AD). Although sleep has been shown to be altered in MCI and AD, little is known about sleep in SCD.

Methods

Seventy cognitively normal community-dwelling participants were classified as SCD (32) or controls (38) using the Subjective Cognitive Decline Questionnaire. Sleep was assessed using actigraphy and diaries. FreeSurfer was used for performing medial temporal lobes (MTLs) and brain cortical parcellation of 3T magnetic resonance images. Multiple regression models were used to assess the presence of sleep, MTL, or regional cortical differences between groups.

Results

Objective sleep was disrupted in SCD participants, which showed increased nighttime wakefulness and reduced sleep efficiency. No group differences emerged in subjective sleep or magnetic resonance imaging outcomes.

Discussion

Objective sleep resulted disrupted in community-dwelling SCD, without any subjective sleep or cortical change. Sleep assessment/intervention in SCD might help prevent/delay AD onset.  相似文献   

13.

Background

Recent studies have shown that neurophysiological outcomes of transcranial direct current stimulation (TDCS) are influenced by current flow in brain regions between the electrodes, and in particular the orientation of current flow relative to the cortical surface.

Objective

We asked whether the directional effects of TDCS on physiological measures in the motor system would also be observed on motor behaviours.

Methods

We applied TDCS during the practice of a ballistic movement task to test whether it affected learning or the retention of learning 48?h later. TDCS electrodes were oriented perpendicular to the central sulcus and two current orientations were used (posterior-anterior, TDCSPA; and anterior-posterior, TDCSAP). Transcranial magnetic stimulation (TMS) was used to assess whether changes in corticospinal excitability reflected any behavioural changes.

Results

Directional TDCSAP impaired the retention of learning on the ballistic movement task compared to TDCSPA and a sham condition. Although TDCSPA had no effect on learning or retention, it blocked the typical increase in corticospinal excitability after a period of motor practice.

Conclusions

Our results extend on previous reports of TDCS producing directionally specific changes in neurophysiological outcomes by showing that current direction through a cortical target also impacts upon behavioural outcomes. In addition, changes in corticospinal excitability after a period of motor practice are not causally linked to behavioural learning.  相似文献   

14.
15.

Background

When single pulse transcranial magnetic stimulation (TMS) is applied over the primary motor cortex (M1) with sufficient intensity, it evokes muscular contractions (motor-evoked potentials, MEPs) and muscle twitches (TMS-evoked movements). Participants may also report various hand sensations related to TMS, but the perception elicited by TMS and its relationship to MEPs and evoked movements has not been systematically studied.

Objective

The main aim of this work is to evaluate participants' kinesthetic and somatosensory hand perceptions elicited by single-pulse TMS over M1-hand area at different intensities of stimulation and their relation with MEPs and TMS-evoked movements.

Methods

We compared the number of MEPs (measured by electromyography), TMS-evoked movements (measured by an accelerometer) and participants' hand perception (measured by verbal report) elicited by TMS at different intensity of stimulation. This way, we estimated the amplitude of MEPs and the acceleration of TMS-evoked movements sufficient to trigger TMS evoked hand perceptions.

Results

We found that TMS-evoked hand perceptions are induced at 105% of the individual resting motor threshold, a value significantly different from the threshold inducing MEPs (about 100%) and TMS-evoked movements (about 110%). Our data indicate that only MEPs with an amplitude higher than 0.62 mV and TMS-evoked movements with acceleration higher than 0.42 m/s2 were associated with hand perceptions at threshold.

Conclusions

Our data reveal the main features of TMS-evoked hand perception and show that in addition to MEPs and TMS-evoked movements, this is a separate discernible response associated to single-pulse TMS over M1.  相似文献   

16.

Introduction

Psychogenic non-epileptic seizures (PNES) are paroxysms of either altered subjective or objective manifestations that may mimic epileptic seizures (ES), without abnormal neuronal epileptiform activity. In this report, we present the case of a 39-year-old woman with PNES and functional movement disorders, who was successfully treated with neuro-guided transcranial direct current stimulation (tDCS).

Methods

We used a PET-guided tDCS approach, as a hypometabolism of the frontal region was revealed by FDG TEP scan. TDCs was performed 5 days/week, 2 times/day, during 3 weeks. All clinical manifestations were reported in a seizure diary. We also assessed dissociation, depression, alexithymia, psychotraumatic scales, and involuntary movements.

Results

The treatment was followed by a decrease of both psychogenic involuntary movements and PNES at 5 weeks. At the same time, PTSD symptoms, dissociative symptoms, depression and alexithymia improved.

Conclusion

PET-scan and tDCS seems to be promising tools for the evaluation and treatment of PNES in clinical practice, and may have a specific role on dissociative symptoms.  相似文献   

17.

Introduction

We examined reasons for low mild cognitive impairment (MCI)-to-cognitively normal (CN) reversion rates in the Alzheimer's Disease Neuroimaging Initiative (ADNI).

Methods

CN and MCI participants were identified as remaining stable, progressing, or reverting at 1-year of follow-up (Year 1). Application of ADNI's MCI criteria at Year 1 in addition to Alzheimer's disease biomarkers by group were examined.

Results

The MCI-to-CN reversion rate was 3.0%. When specific components were examined, 22.5% of stable MCI participants had normal memory performance at Year 1 and their Alzheimer's disease biomarkers were consistent with the stable CN group. At Year 1, when all MCI criteria were not met, the more subjective Clinical Dementia Rating rather than objective memory measure appeared to drive continuation of the MCI diagnosis.

Discussion

Results demonstrate an artificially low 1-year MCI-to-CN reversion rate in ADNI-diagnosed participants. If the Logical Memory cutoffs had been consistently applied, the reversion rate would have been at least 21.8%.  相似文献   

18.

Background

Psychiatric conditions currently treated with deep brain stimulation (DBS), such as obsessive-compulsive disorder (OCD), are heterogeneous diseases with different symptomatic dimensions, indicating that fixed neuroanatomical DBS targets for all OCD cases may not be efficacious.

Objective/hypothesis

We tested whether the optimal DBS target for OCD is fixed for all patients or whether it is individualized and related to each patient's symptomatic content. Further, we explored if the optimal target can be predicted by combining functional neuroimaging and structural connectivity.

Methods

In a prospective, randomized, double-blinded study in 7 OCD patients, symptomatic content was characterized pre-operatively by clinical interview and OCD symptom-provocation during functional MRI. DBS electrode implantation followed a trajectory placing 4 contacts along a striatal axis (nucleus accumbens to caudate). Patients underwent three-month stimulation periods for each contact (and sham), followed by clinical evaluation. Probabilistic tractography, applied to diffusion-weighted images acquired pre-operatively, was used to study the overlap between projections from the prefrontal areas activated during symptom provocation and the volume of activated tissue of each electrode contact.

Results

Six patients were classified responders, with median symptomatic reduction of 50% achieved from each patient's best contact. This was located at the caudate in 4 cases and at the accumbens in 2. Critically, the anatomical locus of the best contact (accumbens or caudate) was related to an index derived by combining functional MRI responses to prevailing symptom provocation and prefronto-cortico-striatal projections defined by probabilistic tractography.

Conclusion

Our results therefore represent a step towards personalized, content-specific DBS targets for OCD.  相似文献   

19.

Introduction

Associations between the Mediterranean-DASH diet Intervention for Neurological Delay (MIND) diet and incidence of cognitive impairment have not been evaluated outside the United States.

Methods

We investigated MIND and Mediterranean diet relations with 12-year incidence of Alzheimer's disease/Vascular dementia (National Institute of Neurological Disorders criteria) and mild cognitive impairment (Winbald criteria) in the Personality and Total Health (PATH) Through Life cohort (n = 1220) set in Canberra, Australia: wave-1 2001-2002; wave-2 2005-2006; wave-3 2009-2010; and wave-4 2013-2014.MIND diet and two alternate Mediterranean diet scores were calculated from the baseline food frequency questionnaire responses. Higher dietary scores signified greater adherence.

Results

In adjusted logistic regression models, MIND diet (OR = 0.47, 95% CI 0.24, 0.91), but not Mediterranean diet, was associated with reduced odds of 12-year cognitive impairment.

Discussion

Preliminary evidence suggests that protective effects of the MIND diet are geographically generalizable. Additional prospective studies are needed in diverse samples to determine the relative effects of the MIND and the Mediterranean diets against cognitive decline.  相似文献   

20.

Introduction

Little is known about dementia incidence in diverse populations of oldest-old, the age group with highest dementia incidence.

Methods

Incident dementia diagnoses from 1/1/2010 to 9/30/2015 were abstracted from medical records for 2350 members of an integrated health care system in California (n = 1702 whites, n = 375 blacks, n = 105 Latinos, n = 168 Asians) aged ≥90 in 2010. We estimated race/ethnicity-specific age-adjusted dementia incidence rates and implemented Cox proportional hazards models and Fine and Gray competing risk of death models adjusted for demographics and comorbidities in midlife and late-life.

Results

Dementia incidence rates (n = 771 cases) were lowest among Asians (89.9/1000 person-years), followed by whites (96.9/1000 person-years), Latinos (105.8/1000 person-years), and blacks (121.5/1000 person-years). Cox regression and competing risk models estimated 28% and 36% higher dementia risk for blacks versus whites adjusting for demographics and comorbidities.

Discussion

Patterns of racial/ethnic disparities in dementia seen in younger older adults continue after the age of 90 years, though smaller in magnitude.  相似文献   

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