With populations ageing, the number of people with dementia worldwide is expected to triple to 152 million by 2050. Seventy percent of cases are due to Alzheimer's disease (AD) pathology and there is a 10-20 year 'pre-clinical' period before significant cognitive decline occurs. We urgently need, cost effective, objective methods to detect AD, and other dementias, at an early stage. Risk factor modification could prevent 40% of cases and drug trials would have greater chances of success if participants are recruited at an earlier stage. Currently, detection of dementia is largely by pen and paper cognitive tests but these are time consuming and insensitive to pre-clinical phases. Specialist brain scans and body fluid biomarkers can detect the earliest stages of dementia but are too invasive or expensive for widespread use. With the advancement of technology, Artificial Intelligence (AI) shows promising results in assisting with detection of early-stage dementia. Existing AI-aided methods and potential future research directions are reviewed and discussed.
Abstract Background Dementia prevention and drug development is hindered by the lack of low‐cost population‐level tests to help identify preclinical Alzheimer’s disease (AD) in the community. Recent evidence suggests that precise analysis of hand movements may detect motor changes indicative of preclinical AD. The objective was to evaluate how TAS Test, a new online automated hand movement test, predicts preclinical AD biomarkers (plasma ptau181 and subtle episodic memory decline) in a cognitively asymptomatic cohort of older adults. Method Participants completed TAS Test online at home using their own computer without researcher assistance: a series of 10‐30 second index finger‐key and index finger‐thumb tapping tests recorded with a keyboard and/or webcam. Movement features including frequency, rhythm, pauses and accuracy were extracted. Participants also completed online tests of episodic memory, CANTAB Paired Associate Learning (CANTAB). A subset provided blood samples for ptau181 analysis. Accuracy of linear regression models comprising hand motor features to predict PAL scores and ptau181 levels, adjusted for confounding, was compared to null models (with only confounders: age, gender, education level, anxiety and depression) using R2adj and AIC. ΔAIC > 2 denotes statistical difference. Result 1,228 adults (mean (SD) age, 65.8 (7.4) years; 73.0% female) completed TAS Test and CANTAB; 459 underwent ptau181 analysis. All keyboard tests improved prediction of asymptomatic episodic memory decline; the 3 step‐ (ΔAIC = 11.2; R2adj = 8.1%) and alternate‐ key (ΔAIC = 3.3; R2adj = 7.5%) tests ranked highest and were the only keyboard tests to improve prediction of ptau181 (3 step ΔAIC = 7.0; R2adj = 17.8%; alternate key ΔAIC = 3.4; R2adj = 17.4%). All finger‐thumb motor measures improved predictions of CANTAB scores and ptau181 levels; the highest performing tests were dominant hand tapping (CANTAB ΔAIC = 2.9; R2adj = 8.2%; ptau181 ΔAIC = 2.4; R2adj = 12.9%) and both hands dual‐task tapping (CANTAB ΔAIC = 3.0; R2adj = 6.8%; ptau181 ΔAIC = 8.7; R2adj = 11.9%). Conclusion TAS Test provides an accessible brief home‐based test for identifying preclinical AD risk. This novel approach holds potential as a pre‐screening/enrichment tool for identifying at risk cohorts for further investigation.
Abstract INTRODUCTION Finding low‐cost methods to detect early‐stage Alzheimer's disease (AD) is a research priority for neuroprotective drug development. Presymptomatic Alzheimer's is associated with gait impairment but hand motor tests, which are more accessible, have hardly been investigated. This study evaluated how home‐based Tasmanian (TAS) Test keyboard tapping tests predict episodic memory performance. METHODS 1169 community participants (65.8 ± 7.4 years old; 73% female) without cognitive symptoms completed online single‐key and alternate‐key tapping tests and episodic memory, working memory, and executive function cognitive tests. RESULTS All single‐key ( R 2 adj = 8.8%, ΔAIC = 5.2) and alternate‐key ( R 2 adj = 9.1%, ΔAIC = 8.8) motor features predicted episodic memory performance relative to demographic and mood confounders only ( R 2 adj = 8.1%). No tapping features improved estimation of working memory. DISCUSSION Brief self‐administered online hand movement tests predict asymptomatic episodic memory impairment. This provides a potential low‐cost home‐based method for stratification of enriched cohorts. Highlights We devised two brief online keyboard tapping tests to assess hand motor function. 1169 cognitively asymptomatic adults completed motor‐ and cognitive tests online. Impaired hand motor function predicted reduced episodic memory performance. This brief self‐administered test may aid stratification of community cohorts.
Hashimoto's encephalopathy (HE), also known as steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT), is a rare neurological disease that is poorly understood and difficult to diagnose.1 HE may present as an acute, subacute, or even chronic illness that is more common in women than men.1 The condition has been reported in pediatric, adult, and elderly populations throughout the world.1 The course of the disease is typically remitting and relapsing and can include cognitive and memory dysfunction, focal and generalized epileptic seizures, confusion, psychiatric disturbances, stroke-like episodes, myoclonus, ataxia, tremor, and chorea form movements.1 Hashimoto's encephalopathy is generally considered to be an autoimmune encephalopathy; however, the exact pathophysiology of HE is unknown.1 HE is defined by the occurrence of anti-thyroid antibodies (anti-thyroid peroxidase antibody [anti-TPO] and anti-thyroglobulin antibody [anti-TG]) and a positive response to steroids.1 While high titers of anti-thyroid antibodies lead to a diagnosis of HE after other causes of encephalopathy have been excluded, it is not clear if the antibodies are involved in the clinical manifestations of the disease, and some authors suggest that a direct causal relationship between the thyroid antibodies and HE is unlikely.1, 2 Kothbauer-Margreiter et al3 proposed 2 types of HE: a vasculitic type with stroke-like episodes and a diffuse, progressive type. Seizures occur in both types, but more frequently in the diffuse type. Overall, 56% to 80% of patients with HE have seizures,1, 4 and 12% experience status epilepticus.1, 5 The 30-day mortality rate of status epilepticus from any cause ranges from 7.6% to 22%, with the highest rates in the elderly.6 Herein, we present the case of a 14-year-old boy with HE who presented with refractory status epilepticus. The patient responded well to steroids, but required a combination of 4 anti-seizure drugs to control his seizure activity. A 14-year-old boy was admitted to our emergency department (ED) in status epilepticus. Four weeks previously, he was seen at a neurology department because of generalized convulsive status epilepticus (GCSE), myoclonus, and hallucinations. The seizure frequency was about once 10 days, and the onset duration varied from 20 minutes to 60 minutes. He was hospitalized, but no seizures occurred during the hospitalization. Magnetic resonance imaging (MRI) of the brain revealed no obvious abnormalities. Electroencephalogram (EEG) monitoring for 24 hours indicated no epilepsy discharge waves. He was discharged on sodium valproate for seizure control. Twenty-four hours before admission to our ED, he was again seen at the other hospital for GCSE. He had experienced 4 episodes, with an onset duration that varied from 10 minutes to 20 minutes. Sodium valproate, carbamazepine, and diazepam were administrated; however, the status epilepticus was not suspended. He was thus transferred to our ED. This study was approved by the institutional review board (IRB) of the First People's Hospital of Lianyungang City. Written informed consent was obtained from the patient. Written informed consent was obtained from the patient's father for the publication of any potentially identifiable images or data included in this article. On examination in our ED, he was alert and his general examination was without abnormalities. Neurological evaluation only showed a bilateral Babinski sign, and he appeared to have normal cognitive development. He appeared to be of normal weight and height for his age, and his nutritional status appeared sufficient. He had no history of recent infections or flu-like symptoms, injury, toxicosis, or academic achievement decline. He had a history of syncope several years prior, but the details of the event could not be obtained. Routine laboratory tests, including a complete blood count (CBC), erythrocyte sedimentation rate, platelet count, tests of kidney (creatinine, urea nitrogen) and liver function (alanine aminotransferase, aspartate aminotransferase, albumin, direct bilirubin, indirect bilirubin, total bilirubin), and protein, lactate, and ammonia levels were normal. Urine toxicology was unremarkable. However, his glucose was slightly below the lower limit of normal (3.76 mmol/L, reference range: 3.9-6.1 mmol/L). Testing for specific antibodies associated with autoimmune encephalitis including N-methyl-D-aspartate (NMDA) receptor antibody, voltage-gated potassium channel (VGKC) antibody, anti-leucine-rich glioma-inactivated (LGI1) antibody, anti-contactin-associated protein-like 2 (Caspr2) antibody, anti-Hu antibody, and anti-CRMP5/CV2 antibody was negative. Thyroid function tests revealed a low thyroid-stimulating hormone (TSH) level (0.06 mIU/L, reference range: 0.34-5.60 mIU/L), but normal free triiodothyronine (FT3, 4.5 pmol/L, normal range: 3.8-6.47) and free thyroxin (FT4, 1.36 pmol / L, normal range: 7.9-17) levels. However, serum anti-thyroid antibody levels were elevated. His anti-TPO antibody level was 76.7 mIU/L (reference range: 0.25-34 mIU/L), and his anti-TG antibody level was 237.1 mIU/L (reference range: 0-4 mIU/L). Cerebral computed tomography (CT) showed no signs of increased intracranial pressure, hemorrhage, or a space-occupying lesion. MRI, including T1, T2, and diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADC) mapping, and fluid-attenuated inversion recovery (FLAIR) sequences, and contrast-enhanced angiography of the brain also revealed no abnormalities, especially no signs of encephalitis. EEG showed a marked slowing of the background rhythm, suggestive of encephalopathy, and spike waves corresponding with seizure activity (Figure 1). Based on new-onset seizures, an EEG suggestive of encephalopathy, elevated anti-TPO and anti-TG antibody levels, and otherwise extensive and negative workup, a diagnosis of HE was considered. The patient was started methylprednisolone, 500 mg for 5 days, which was then gradually switched to oral prednisone, 60 mg/day during which time his psychiatric symptoms such as hallucinations and agitation were resolved by haloperidol and olanzapine, respectively. Diazepam, midazolam, sodium valproate, chloral hydrate, and phenobarbital were ineffective at controlling his seizures. His seizures were finally controlled with a combination of sodium valproate 2,400 mg/day, clonazepam 4 mg/day, topiramate 350 mg/day, and levetiracetam 1,800 mg/day. At his 18-month follow-up, the patient has remained seizure-free and in good physical condition. Hashimoto's encephalopathy is a rare disease, and the pathophysiology is not known. It can affect people of all ages, but the mean age of onset is about 40 years old, and approximately 75% of cases are in females.1 Past reports suggest that the mean age of presentation in children ranges from 12 to 14 years, and the mean age in adults ranges from 45 to 55 years.7, 8 The clinical presentation of HE is variable; however, the hallmark is a nonspecific encephalopathy characterized by alteration of mental status and consciousness ranging from confusion and/or impaired cognitive function to coma.1, 7 Based on case series in the literature, presentations in adults include cognitive impairment (36% to 100% of cases), altered consciousness (36% to 85%), transient aphasia (73% to 80%), sleep abnormalities (55%), headache (13% to 50%), neurological deficits (18% to 31%), gait ataxia (28% to 65%), tremors (28% to 84%), myoclonus (37% to 65%), seizures (52% to 66%), and status epilepticus (12%).4, 5, 7, 9-14 Acute psychosis is the most common psychiatric presentation of HE (26%), followed by depressive disorders (245).15 Approximately 80% of children with HE present with new-onset seizures without other neurological abnormalities C. Overall, approximately 12% of patients with HE present with new-onset status epilepticus.1 Kothbauer-Magreiter et al3 described 2 distinct presentations of HE and thus proposed 2 subtypes. One subtype, vasculitic HE, is characterized by repetitive stroke-like episodes manifesting as aphasia, hemiparesis, and ataxia with mild cognitive impairment. The other subtype, diffuse HE, is characterized by an insidious and progressive deterioration of mental functions. Seizures can occur in both types.1 A meta-analysis study by de Holanda et al 4 including 130 HE patients from 52 reports found that 77 patients (59%) experienced seizures (63 had generalized seizures and 14 had partial seizures). Of the 130 patients, 60% with normal thyroid function, 62% with subclinical hypothyroidism, 80% with overt hypothyroidism, and 56% of patients with hyperthyroidism had seizures. The importance of diagnosing HE in patients presenting with status epilepticus is essential considering that the etiology of status epilepticus is unknown in 23% of cases, and the short-term mortality rate of status epilepticus 7% to 22%.6 Status epilepticus mostly occurs in adults with HE, while it is not common in children with HE.1 The diagnosis of HE is one of exclusion.1 Brain MRI and CT, EEG, lumbar puncture and examination of cerebrospinal fluid (CSF), and blood laboratory testing are all necessary to exclude other causes of encephalopathy and seizures such as space-occupying lesions, Creutzfeldt-Jakob disease, stroke, vasculitis, metabolic disorders, poisoning, and mental/psychiatric disorders.1 The presence of anti-thyroid antibodies is diagnostic of HE; however, their role in the pathophysiology of the disease is not known.1 The first-line treatments for HE include high-dose glucocorticoids, intravenous immunoglobulin, and plasma exchange.1 When a response to first-line treatments is poor, second-line treatments include rituximab and cyclophosphamide.1 In most patients, common anti-seizure medications are ineffective.1 Our patient responded well to steroids for control of his symptoms, but common medications used to control seizures were ineffective. His seizures were ultimately controlled by a combination of sodium valproate, clonazepam, topiramate, and levetiracetam. Visée et al2 reported that phenytoin, phenobarbital, levetiracetam, lacosamide, and midazolam were ineffective at controlling seizures in a patient with HE. Hilberath et al7 reported HE in an adolescent in whom a combination of midazolam, etomidate, thiopental, and diazepam was required to control generalized tonic-clonic seizure activity. McGinley et al16 reported the case of a 42-year-old woman with HE who presented in status epilepticus: An anesthetic dose of sodium thiopentone (20 mg/kg) and intravenous dexamethasone (8 mg every 8 hours) was required to control the seizures. The seizures in our patient may be easier to control if he had been on a higher dosage of steroid therapy and for a longer period.1, 17 Refractory status epilepticus (RSE) refers to continued clinical or electrographic seizures after an adequate initial benzodiazepine dose, followed by a second-line antiepileptic drug (AED). Non-drug treatments can be considered for RSE, such as surgery, and neuromodulation treatment. The purpose of epilepsy surgery is to complete resection of an epileptogenic lesion to control seizures.18 However, the imaging examinations showed no obvious epileptogenic lesions in our patient, and a non-lesion patient may not achieve sustained seizure freedom after surgery.19 Nevertheless, other non-drug treatment, such as vagus nerve stimulation (a neuromodulation method)20 and next-generation sequencing,21 could also be considered for the treatment of seizures in this patient. Importantly, RSE is associated with a worse prognosis and higher morbidity and mortality than non-RSE.6 Our patient was considered to have RSE. When RSE occurs in an individual without a history of epilepsy and no immediate underlying etiology is identified, it is referred to as new-onset RSE.6 New-onset RSE is difficult to treat, and the most commonly identified etiologies of new-onset RSE are autoimmune conditions (19%) and paraneoplastic encephalitis (18%).6 HE should be included in the differential diagnosis of RSE. Hashimoto's encephalopathy is a rare disease that should be considered in patients with new-onset seizures and RSE, and mental status changes when standard investigations are negative. Patients typically respond well to intravenous steroids and anti-seizure drugs. All authors disclose that they have no conflicts of interest. All the data and materials have been presented in the main paper.
There are no low-cost population-level tests to help identify preclinical Alzheimer's disease (AD); this hinders drug development and targeted dementia prevention. New evidence suggests that hand movements change in preclinical AD. We evaluated the predictive accuracy of TAS Test (new online hand movement analysis website) for detecting preclinical AD biomarkers (plasma ptau181 and subtle episodic memory impairment) in cognitively asymptomatic adults.
Methods
Participants completed TAS Test online at home: 10–30 second finger-tapping tests recorded with a keyboard and/or webcam. Movement features (frequency, rhythm, pauses etc) were extracted. Participants also completed online episodic memory tests (CANTAB) and some provided blood samples for ptau181 analysis. Linear regression models comprising hand movement features to predict CANTAB scores and ptau181 levels, adjusted for confounding, was compared to null models (with only confounders: age, gender, education level, anxiety and depression) using R2adj and AIC. ΔAIC > 2 denotes statistical difference.
Results
1,228 adults (mean (SD) age, 65.8 (7.4) years; 73.0% female) completed TAS Test and CANTAB; 459 underwent ptau181 analysis. The 3 step-key and alternate-key tapping tests improved prediction of asymptomatic episodic memory impairment; (ΔAICs=11.2 and 3.3; R2adjs=8.1% and 7.5% respectively) and ptau181 (3 step ΔAIC=7.0; R2adj=17.8%; alternate key ΔAIC=3.4; R2adj=17.4%). The highest performing webcam tests were dominant hand tapping (CANTAB ΔAIC= 2.9; R2adj=8.2%; ptau181 ΔAIC=2.4; R2adj=12.9%) and both hands dual-task tapping (CANTAB ΔAIC=3.0; R2adj=6.8%; ptau181 ΔAIC=8.7; R2adj=11.9%).
Conclusions
TAS Test provides a home-based test for identifying preclinical AD risk and holds potential as a pre-screening tool for identifying cohorts for further investigation.
Diffusion magnetic resonance imaging (dMRI) is a crucial technique in neuroimaging studies, allowing for the non-invasive probing of the underlying structures of brain tissues. Clinical dMRI data is susceptible to various artifacts during acquisition, which can lead to unreliable subsequent analyses. Therefore, dMRI preprocessing is essential for improving image quality, and manual inspection is often required to ensure that the preprocessed data is sufficiently corrected. However, manual inspection requires expertise and is time-consuming, especially with large-scale dMRI datasets. Given these challenges, an automated dMRI artifact detection tool is necessary to increase the productivity and reliability of dMRI data analysis. To this end, we propose a novel unsupervised deep learning framework called $\textbf{U}$nsupervised $\textbf{d}$MRI $\textbf{A}$rtifact $\textbf{D}$etection via $\textbf{A}$ngular Resolution Enhancement and $\textbf{C}$ycle Consistency Learning (UdAD-AC). UdAD-AC leverages dMRI angular resolution enhancement and cycle consistency learning to capture the effective representation of artifact-free dMRI data during training, and it identifies data containing artifacts using designed confidence score during inference. To assess the capability of UdAD-AC, several commonly reported dMRI artifacts, including bias field, susceptibility distortion, and corrupted volume, were added to the testing data. Experimental results demonstrate that UdAD-AC achieves the best performance compared to competitive methods in unsupervised dMRI artifact detection.
Abstract Objectives Unequal access to cognitive assessments is a major barrier to timely diagnosis, especially for those living in rural or remote areas. ‘One‐stop’ cognitive clinic models are a proposed solution, but few such clinics exist. We evaluate the implementation of a new one‐stop State‐wide clinic model in Tasmania, Australia, where 27% of people live in rural/remote areas. Methods A novel single‐visit protocol has been developed, comprising interdisciplinary medical and cognitive assessments, research participation, consensus diagnosis and management plan. A cross‐sectional evaluation was undertaken using the RE‐AIM (reach, effectiveness, adoption, implementation, maintenance) framework and results benchmarked against the national Australian Dementia Network Registry. Results Over the first 52 consecutive weekly clinics: Reach : 130 adults were assessed (mean age [SD] 70.12 years [10.31]; 59.2% female) with 40 (36.8%) from rural/remote areas. Effectiveness : 98.5% (128/130) received a same‐day diagnosis: 30.1% (n = 40) Subjective Cognitive Decline, 35.4% (46) Mild Cognitive Impairment, 33.1% (43) dementia and one case inconclusive. Adoption : 22.9% (156) of General Practitioners referred patients. Implementation : Nearly all ‘ideal’ diagnostic clinical practices were met and >90% of surveyed patients reported ‘good/very good’ clinic experience. The wait from referral to diagnosis was 2 months shorter than other national Registry clinics (78 vs. 133 days). Conclusions This ‘one‐stop’ model provides an interdisciplinary consensus cognitive diagnosis quickly and is well accepted; this may reduce health inequities especially for people living in rural/remote areas. This cognitive clinic model may be of relevance to other centres worldwide and also provides a rich data source for research studies.
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