Home-Based Electronic Cognitive Therapy in Patients With Alzheimer Disease: Feasibility Randomized Controlled Trial.

BACKGROUND: Can home-based computerized cognitive training programs be a useful tool to sustain cognition and quality of life in patients with Alzheimer disease (AD)? To date, the progressive nature of the disease has made this question difficult to answer. Computerized platforms provide more accessibility to cognitive trainings; however, the feasibility of long-term, home-based computerized programs for patients with AD dementia remains unclear. OBJECTIVE: We aimed to investigate the feasibility of a 24-week home-based intervention program using the Constant Therapy app and its preliminary efficacy on cognition in patients with AD. Constant Therapy is a program developed for patients with speech and cognitive deficits. We hypothesized that patients with AD would use Constant Therapy daily over the course of the 24-week period. METHODS: Data were collected over a 48-week period. We recruited participants aged between 50 and 90 years with a diagnosis of mild cognitive impairment due to AD or mild AD dementia. Participants were randomly assigned to either the Constant Therapy (n=10) or active control (n=9) group. The Constant Therapy group completed a tablet-based training during the first 24 weeks; the second 24 weeks of computerized training were optional. The active control group completed paper-and-pencil games during the first 24 weeks and were invited to complete an optional Constant Therapy training during the second 24 weeks. Every 6 weeks, the participants completed the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The participants independently accessed Constant Therapy using an Apple iPad. Our primary feasibility outcomes were the rate of adherence and daily use of Constant Therapy over 24 weeks. Our secondary outcomes were Constant Therapy performance over 24 weeks and change in RBANS scores between the 2 experimental groups. RESULTS: Feasibility analyses were computed for participants who completed 24 weeks of Constant Therapy. We found that long-term use of the Constant Therapy program was feasible in patients with AD over 24 weeks (adherence 80%; program use 121/168 days, for 32 minutes daily). These participants showed an overall improvement in accuracy and latency (P=.005) in the Constant Therapy scores, as well as specific improvements in visual and auditory memory, attention, and arithmetic tasks. The Constant Therapy group showed improvement in the RBANS coding subtest. No unexpected problems or adverse events were observed. CONCLUSIONS: Long-term (eg, 24 weeks) computerized cognitive training using Constant Therapy is feasible in patients with AD in the mild cognitive impairment and mild dementia stages. Patients adhered more to Constant Therapy than to the paper-and-pencil training over 24 weeks and improved their performance over time. These findings support the development of future randomized controlled trials that will investigate the efficacy of Constant Therapy to sustain cognitive function in patients with AD. TRIAL REGISTRATION: ClinicalTrials.gov NCT02521558; https://clinicaltrials.gov/ct2/show/NCT02521558.

Impact of amyloid PET in the clinical care of veterans in a tertiary memory disorders clinic.

Introduction: We aimed to characterize the clinical impact of amyloid PET (APET) in a veteran population with cognitive decline by comparing differences in management between those who did and did not have an APET. Methods: This was a retrospective observational study. Poisson regressions and logistic regression were used for comparisons. Results: Out of 565 veterans, 197 underwent APET; positivity rate was 36.55%. Having an APET was associated with longer follow-up, and increased diagnostic variability; it was not associated with number of additional studies, cholinesterase inhibitors prescription, or referrals to research. A positive APET was associated with less diagnostic variability, fewer additional tests, greater cholinesterase inhibitor prescriptions, and more research referrals. Discussion: In a medically complex, real-world population, APET yielded lower positivity rates and was not associated with classical clinical utility variables when comparing patients with and without an APET. APET may be used more to "rule out" rather than to confirm Alzheimer's disease. Highlights: Amyloid PET was associated with longer follow-up, and higher diagnostic variability.No association was seen with cholinesterase inhibitors prescription, or referrals to research.In complex patients, expected amyloid PET positivity rates are lower than previously described.Amyloid PETs were used to "rule out" AD than to confirm the diagnosis of AD.

Amyloid PET ordering practices in a memory disorders clinic.

Introduction: This study assessed the ordering of amyloid positron emission tomography (PET) scans in a Veterans Affairs (VA) memory disorders clinic as part of routine clinical care, with possible implications for the extent to which ordering may occur outside of the VA in the future if covered by insurance. Methods: Clinical features predictive of ordering amyloid PET scans were retrospectively assessed; the percentage of patients who met appropriate use criteria were evaluated. Results: Among 565 veterans, 34.9% of received an amyloid PET scan and 98.0% of these were consistent with appropriate use criteria. Patients with a PET were younger and more likely to have an initial diagnosis of Alzheimer's disease (AD). Of patients without an amyloid PET scan ordered, 64.4% would have met appropriate use criteria for amyloid PET. Discussion: The majority of scans ordered were consistent with appropriate use criteria and more patients were eligible than received a scan. The current study's findings that approximately one-third of patients in a memory disorders clinic received an amyloid PET scan has implications for memory disorders clinics inside and outside of the US Veterans Health Administration.

Head Injury Exposure in Veterans Presenting to Memory Disorders Clinic: An Observational Study of Clinical Characteristics and Relationship of Event-Related Potentials and Imaging Markers.

Objective: Traumatic brain injury (TBI) and repetitive head impacts (RHI) related to blasts or contact sports are commonly reported among military service members. However, the clinical implications of remote TBI and RHI in veterans remains a challenge when evaluating older veterans at risk of neurodegenerative conditions including Alzheimer's disease (AD) and Chronic Traumatic Encephalopathy (CTE). This study aimed to test the hypothesis that veterans in a memory disorders clinic with remote head injury would be more likely to have neurodegenerative clinical diagnoses, increased rates of amyloid PET positivity, higher prevalence of cavum septum pellucidi/vergae, and alterations in event-related potential (ERP) middle latency auditory evoked potentials (MLAEPs) and long latency ERP responses compared to those without head injuries. Methods: Older veterans aged 50-100 were recruited from a memory disorders clinic at VA Boston Healthcare system with a history of head injury (n = 72) and without head injury history (n = 52). Patients were classified as reporting prior head injury including TBI and/or RHI exposure based on self-report and chart review. Participants underwent MRI to determine presence/absence of cavum and an ERP auditory oddball protocol. Results: The head injury group was equally likely to have a positive amyloid PET compared to the non-head injury group. Additionally, the head injury group were less likely to have a diagnosis of a neurodegenerative condition than those without head injury. P200 target amplitude and MLAEP amplitudes for standard and target tones were decreased in the head injury group compared to the non-head injury group while P3b amplitude did not differ. Conclusions: Veterans with reported remote head injury evaluated in a memory disorders clinic were not more likely to have a neurodegenerative diagnosis or imaging markers of neurodegeneration than those without head injury. Decreased P200 target and MLAEP target and standard tone amplitudes in the head injury group may be relevant as potential diagnostic markers of remote head injury.

Structural and functional brain changes in hepatic and neurological Wilson disease.

Wilson disease (WD) can manifest with hepatic or neuropsychiatric symptoms. Our understanding of the in vivo brain changes in WD, particularly in the hepatic phenotype, is limited. Thirty subjects with WD and 30 age- and gender-matched controls participated. WD group underwent neuropsychiatric assessment. Unified WD Rating Scale neurological exam scores were used to determine neurological (WDN, score > 0) and hepatic-only (WDH, score 0) subgroups. All subjects underwent 3 Tesla anatomical and resting-state functional MRI. Diffusion tensor imaging (DTI) and susceptibility-weighted imaging (SWI) were performed only in the WD group. Volumetric, DTI, and functional connectivity analyses were performed to determine between-group differences. WDN and WDH groups were matched in demographic and psychiatric profiles. The entire WD group compared to controls showed significant thinning in the bilateral superior frontal cortex. The WDN group compared to control and WDH groups showed prominent structural brain changes including significant striatal and thalamic atrophy, more subcortical hypointense lesions on SWI, and diminished white matter integrity in the bilateral anterior corona radiata and corpus callosum. However, the WDH group also showed significant white matter volume loss compared to controls. The functional connectivity between the frontostriatal nodes was significantly reduced in the WDN group, whereas that of the hippocampus was significantly increased in the WDH group compared to controls. In summary, structural and functional brain changes were present even in neurologically non-manifesting WD patients in this cross-sectional study. Longitudinal brain MRI scans may be useful as biomarkers for prognostication and optimization of treatment strategies in WD.

Patient Companionship in a Movement Disorders Clinic: Outside Assistance Inside the Office.

Objective: We (1) report whether a companion (i.e., spouse, relative, aide) accompanied our consecutive outpatients with a range of movement disorders, (2) identified the set of patient characteristics that was associated with the need for a visit companion, and (3) characterized the role(s) of these companions during the visit. Our overarching goals were to further understand patient needs and the extent of their support networks, and to enrich the clinician-patient interface. Methods: Two-hundred consecutive patients were enrolled from the Movement Disorders Clinic at Yale School of Medicine. We noted whether patients were accompanied by another person during the visit and documented the role of the visit companion during the encounter. Results: One-hundred-twenty-eight of 200 patients (64.0%) brought a companion, with these being spouses (44.8%), adult children (24.1%) or an aide, nurse or social worker (14.5%). Patients who were unemployed (odds ratio [OR] = 5.32, p = 0.019), had a diagnosis of Parkinson's disease or other Parkinsonian syndromes (OR = 10.61, p = 0.001), or were dependent in any instrumental activities of daily living (iADLs) (OR = 4.99, p = 0.005) or basic activities of daily living (bADLs) (OR = 5.81, p = 0.02), had increased odds of presenting to the clinical visit with a visit companion. Visit companions' main roles involved communication (86.7%) and transportation (84.4%). Conclusion: Visit companions were commonly present during movement disorders outpatient visits-two-thirds of patients were accompanied. A number of factors increased the odds of requiring such a companion by 4- or 5-fold.

Insula as the Interface Between Body Awareness and Movement: A Neurofeedback-Guided Kinesthetic Motor Imagery Study in Parkinson's Disease.

Intentional movement is an internally driven process that requires the integration of motivational and sensory cues with motor preparedness. In addition to the motor cortical-basal ganglia circuits, the limbic circuits are also involved in the integration of these cues. Individuals with Parkinson's disease (PD) have a particular difficulty with internally generating intentional movements and maintaining the speed, size, and vigor of movements. This difficulty improves when they are provided with external cues suggesting that there is a problem with the internal motivation of movement in PD. The prevailing view attributes this difficulty in PD to the dysfunction of motor cortical-basal ganglia circuits. First, we argue that the standard cortical-basal ganglia circuit model of motor dysfunction in PD needs to be expanded to include the insula which is a major hub within the limbic circuits. We propose a neural circuit model highlighting the interaction between the insula and dorsomedial frontal cortex which is involved in generating intentional movements. The insula processes a wide range of sensory signals arising from the body and integrates them with the emotional and motivational context. In doing so, it provides the impetus to the dorsomedial frontal cortex to initiate and sustain movement. Second, we present the results of our proof-of-concept experiment demonstrating that the functional connectivity of the insula-dorsomedial frontal cortex circuit can be enhanced with neurofeedback-guided kinesthetic motor imagery using functional magnetic resonance imaging in subjects with PD. Specifically, we found that the intensity and quality of body sensations evoked during motor imagery and the emotional and motivational context of motor imagery determined the direction (i.e., negative or positive) of the insula-dorsomedial frontal cortex functional connectivity. After 10-12 neurofeedback sessions and "off-line" practice of the successful motor imagery strategies all subjects showed a significant increase in the insula-dorsomedial frontal cortex functional connectivity. Finally, we discuss the implications of these results regarding motor function in patients with PD and propose suggestions for future studies.

Primary Writing Tremor.

Background: Primary writing tremor (PWT) is a rare condition; tremor occurs primarily while writing rather than during other tasks. Phenomenology Shown: We illustrate the phenomenology of PWT and point out associated subtle dystonic posturing on neurological examination. Educational Value: PWT is a tremor disorder that shares clinical features with both dystonia and essential tremor.

Index Finger Pointing (Likely a Subtle Form of Hand Dystonia): Prevalence Across Movement Disorders.

Objective: To investigate the prevalence of index finger pointing (IFP) while walking, which is likely a subtle form of hand dystonia, in cranio-cervical focal dystonia syndromes, Parkinson's disease (PD), essential tremor (ET), and controls. Methods: We recruited patients with an established diagnosis of PD, dystonia, or ET and healthy controls. All participants were videotaped while walking. Videotapes were evaluated by the authors, blinded to diagnosis, to assess the presence or absence of IFP. Results: Two-hundred-fifty participants included 50 dystonia, 50 PD, 80 ET and 70 controls. IFP was present in 29/250 (11.6%) participants: 10 dystonia (20.0%), 8 PD (16.0%), 8 ET (10.0%), and 3 controls (3.8%) (p = 0.03). There was a significant evidence of a trend in the odds of having this sign among disorders with higher risk of dystonic features (dystonia>PD>ET>control; test for trend = 0.004). Among the 180 patients (dystonia, PD, and ET, i.e., excluding the 70 controls), IFP was present in 26 (14.4% prevalence). Conclusion: IFP during gait, likely a subtle form of hand dystonia, was observed in 14.4% of movement disorder patients. The highest prevalence was in dystonia, the second highest in a disease that is often accompanied by dystonia (PD), a lower prevalence among individuals with a disease that is rarely accompanied by dystonia (ET), and the lowest in controls.

Brain circuits and neurochemical systems in essential tremor: insights into current and future pharmacotherapeutic approaches.

INTRODUCTION: There are few medications that are available for the treatment of essential tremor (ET) and they are only moderately effective. Areas covered: Data were obtained from a PubMed search. Original articles, review articles, and clinical guidelines were included. Two disease models for ET have been proposed: 1) the olivary model, which attributes ET to a pathological pacemaker in the inferior olivary nucleus, and 2) the cerebellar degeneration model, which postulates that ET originates in the cerebellum and could be related to deficient or abnormal Purkinje cell (PC) output. Underlying biochemical dysfunction in T-type calcium channels (T-tCaC) may loosely be linked to the first model and deficiency/abnormality in γ-aminobutyric acid (GABA) neurotransmission, to the second. Expert commentary: Human data points robustly to the role of GABA in ET. Numerous medications that target the GABA system have been tried, with variable success. Given the many different types of GABA-ergic neurons, and the multitude of GABAA receptor subtypes, a given medication could have competing/cancelling effects. It would seem that influencing GABA receptors broadly is not as effective as targeting certain GABAA receptor subtypes. Future research should seek to identify molecular candidates that have a more targeted effect within the GABA system.