Category: Neurology

Hot Topics: Dementia Risk Doubled After Stroke

katheride Dementia, Hot Topics in Research, Neurology

Stroke and dementia risk: A systematic review and meta-analysis
Kuźma E, Lourida I, Moore SF, Levine DA, Ukoumunne OC, Llewellyn DJ. Stroke and dementia risk: A systematic review and meta-analysis. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association. . https://doi.org/10.1016/j.jalz.2018.06.3061.
Introduction
Stroke is an established risk factor for all-cause dementia, though meta-analyses are needed to quantify this risk.
Methods
We searched Medline, PsycINFO, and Embase for studies assessing prevalent or incident stroke versus a no-stroke comparison group and the risk of all-cause dementia. Random effects meta-analysis was used to pool adjusted estimates across studies, and meta-regression was used to investigate potential effect modifiers.
Results
We identified 36 studies of prevalent stroke (1.9 million participants) and 12 studies of incident stroke (1.3 million participants). For prevalent stroke, the pooled hazard ratio for all-cause dementia was 1.69 (95% confidence interval: 1.49–1.92; P < .00001; I2 = 87%). For incident stroke, the pooled risk ratio was 2.18 (95% confidence interval: 1.90–2.50; P < .00001; I2 = 88%). Study characteristics did not modify these associations, with the exception of sex which explained 50.2% of between-study heterogeneity for prevalent stroke.
Discussion
Stroke is a strong, independent, and potentially modifiable risk factor for all-cause dementia.

Hot Topics: Drug Effectiveness Predicted by Brain “Fingerprint”

katheride Hot Topics in Research, Neurology, Pharmaceutical Sciences

Multimodal imaging-based therapeutic fingerprints for optimizing personalized interventions: Application to neurodegeneration
Iturria-Medina Y, Carbonell FM, Evans AC. Multimodal imaging-based therapeutic fingerprints for optimizing personalized interventions: Application to neurodegeneration. NeuroImage. 2018;179:40-50. http://dx.doi.org/10.1016/j.neuroimage.2018.06.028.
Personalized Medicine (PM) seeks to assist the patients according to their specific treatment needs and potential intervention responses. However, in the neurological context, this approach is limited by crucial methodological challenges, such as the requirement for an understanding of the causal disease mechanisms and the inability to predict the brain’s response to therapeutic interventions. Here, we introduce and validate the concept of the personalized Therapeutic Intervention Fingerprint (pTIF), which predicts the effectiveness of potential interventions for controlling a patient’s disease evolution. Each subject’s pTIF can be inferred from multimodal longitudinal imaging (e.g. amyloid-β, metabolic and tau PET; vascular, functional and structural MRI). We studied an aging population (N = 331) comprising cognitively normal and neurodegenerative patients, longitudinally scanned using six different neuroimaging modalities. We found that the resulting pTIF vastly outperforms cognitive and clinical evaluations on predicting individual variability in gene expression (GE) profiles. Furthermore, after regrouping the patients according to their predicted primary single-target interventions, we observed that these pTIF-based subgroups present distinctively altered molecular pathway signatures, supporting the across-population identification of dissimilar pathological stages, in active correspondence with different therapeutic needs. The results further evidence the imprecision of using broad clinical categories for understanding individual molecular alterations and selecting appropriate therapeutic needs. To our knowledge, this is the first study highlighting the direct link between multifactorial brain dynamics, predicted treatment responses, and molecular alterations at the patient level. Inspired by the principles of PM, the proposed pTIF framework is a promising step towards biomarker-driven assisted therapeutic interventions, with additional important implications for selective enrollment of patients in clinical trials.

Hot Topics: New Techniques Examine Parkinson’s Damage to Heart

katheride Central Nervous System Disorders, Hot Topics in Research, Neurology

In vivo imaging of inflammation and oxidative stress in a nonhuman primate model of cardiac sympathetic neurodegeneration
Metzger JM, Moore CF, Boettcher CA, et al. In vivo imaging of inflammation and oxidative stress in a nonhuman primate model of cardiac sympathetic neurodegeneration. npj Parkinson’s Disease. 2018;4(1):22. https://doi.org/10.1038/s41531-018-0057-1.
Loss of cardiac postganglionic sympathetic innervation is a characteristic pathology of Parkinson’s disease (PD). It progresses over time independently of motor symptoms and is not responsive to typical anti-parkinsonian therapies. Cardiac sympathetic neurodegeneration can be mimicked in animals using systemic dosing of the neurotoxin 6-hydroxydopamine (6-OHDA). As in PD, 6-OHDA-induced neuronal loss is associated with increased inflammation and oxidative stress. To assess the feasibility of detecting changes over time in cardiac catecholaminergic innervation, inflammation, and oxidative stress, myocardial positron emission tomography with the radioligands [11C]meta-hydroxyephedrine (MHED), [11C]PBR28 (PBR28), and [61Cu]diacetyl-bis(N(4))-methylthiosemicarbazone (ATSM) was performed in 6-OHDA-intoxicated adult, male rhesus macaques (n = 10; 50 mg/kg i.v.). The peroxisome proliferator-activated receptor gamma (PPARγ) agonist pioglitazone, which is known to have anti-inflammatory and anti-oxidative stress properties, was administered to five animals (5 mg/kg, PO); the other five were placebo-treated. One week after 6-OHDA, cardiac MHED uptake was significantly reduced in both groups (placebo, 86% decrease; pioglitazone, 82%); PBR28 and ATSM uptake increased in both groups but were attenuated in pioglitazone-treated animals (PBR28 Treatment × Level ANOVA p < 0.002; ATSM Mann–Whitney p = 0.032). At 12 weeks, partial recovery of MHED uptake was significantly greater in the pioglitazone-treated group, dependent on left ventricle circumferential region and axial level (Treatment × Region × Level ANOVA p = 0.034); 12-week MHED uptake significantly correlated with tyrosine hydroxylase immunoreactivity across cardiac anatomy (p < 0.000002). PBR28 and ATSM uptake returned to baseline levels by 12 weeks. These radioligands thus hold potential as in vivo biomarkers of mechanisms of cardiac neurodegeneration and neuroprotection.

Hot Topics: New Technology Could Allow Dementia Patients to Live Alone Longer

katheride Dementia, Hot Topics in Research, Neurology

Health management and pattern analysis of daily living activities of people with dementia using in-home sensors and machine learning techniques
Enshaeifar S, Zoha A, Markides A, et al. Health management and pattern analysis of daily living activities of people with dementia using in-home sensors and machine learning techniques. PLOS ONE. 2018;13(5):e0195605. https://doi.org/10.1371/journal.pone.0195605.
The number of people diagnosed with dementia is expected to rise in the coming years. Given that there is currently no definite cure for dementia and the cost of care for this condition soars dramatically, slowing the decline and maintaining independent living are important goals for supporting people with dementia. This paper discusses a study that is called Technology Integrated Health Management (TIHM). TIHM is a technology assisted monitoring system that uses Internet of Things (IoT) enabled solutions for continuous monitoring of people with dementia in their own homes. We have developed machine learning algorithms to analyse the correlation between environmental data collected by IoT technologies in TIHM in order to monitor and facilitate the physical well-being of people with dementia. The algorithms are developed with different temporal granularity to process the data for long-term and short-term analysis. We extract higher-level activity patterns which are then used to detect any change in patients’ routines. We have also developed a hierarchical information fusion approach for detecting agitation, irritability and aggression. We have conducted evaluations using sensory data collected from homes of people with dementia. The proposed techniques are able to recognise agitation and unusual patterns with an accuracy of up to 80%.

Hot Topics: New Drug Improves Bladder Function After Spinal Cord Injury

katheride Hot Topics in Research, Neurology, Pharmaceutical Sciences

Role of proNGF/p75 signaling in bladder dysfunction after spinal cord injury
Ryu JC, Tooke K, Malley SE, et al. Role of proNGF/p75 signaling in bladder dysfunction after spinal cord injury. J Clin Invest. 2018;128(5):1772-1786. https://doi.org/10.1172/JCI97837
Loss of bladder control is a challenging outcome facing patients with spinal cord injury (SCI). We report that systemic blocking of pro–nerve growth factor (proNGF) signaling through p75 with a CNS-penetrating small-molecule p75 inhibitor resulted in significant improvement in bladder function after SCI in rodents. The usual hyperreflexia was attenuated with normal bladder pressure, and automatic micturition was acquired weeks earlier than in the controls. The improvement was associated with increased excitatory input to the spinal cord, in particular onto the tyrosine hydroxylase–positive fibers in the dorsal commissure. The drug also had an effect on the bladder itself, as the urothelial hyperplasia and detrusor hypertrophy that accompany SCI were largely prevented. Urothelial cell loss that precedes hyperplasia was dependent on p75 in response to urinary proNGF that is detected after SCI in rodents and humans. Surprisingly, death of urothelial cells and the ensuing hyperplastic response were beneficial to functional recovery. Deleting p75 from the urothelium prevented urothelial death, but resulted in reduction in overall voiding efficiency after SCI. These results unveil a dual role of proNGF/p75 signaling in bladder function under pathological conditions with a CNS effect overriding the peripheral one.

Hot Topics: Treating Depression May Counteract Cognitive Impairments

katheride Alzheimer Disease, Geriatrics, Hot Topics in Research, Mood Disorders

Neuropsychiatric Symptoms and the Diagnostic Stability of Mild Cognitive Impairment
Sugarman MA, Alosco ML, Tripodis Y, Steinberg EG, Stern RA. Neuropsychiatric symptoms and the diagnostic stability of mild cognitive impairment. Journal of Alzheimer’s Disease. 2018:1-15. doi: 10.3233/JAD-170527.
Background:
Mild cognitive impairment (MCI) is an intermediate diagnosis between normal cognition (NC) and dementia, including Alzheimer’s disease (AD) dementia. However, MCI is heterogeneous; many individuals subsequently revert to NC while others remain stable at MCI for several years. Identifying factors associated with this diagnostic instability could assist in defining clinical populations and determining cognitive prognoses.
Objective:
The current study examined whether neuropsychiatric symptoms could partially account for the temporal instability in cognitive diagnoses.
Method:
The sample included 6,763 participants from the National Alzheimer’s Coordinating Center Uniform Data Set. All participants had NC at baseline, completed at least two follow-up visits (mean duration: 5.5 years), and had no recent neurological conditions. Generalized linear models estimated by generalized estimating equations examined associations between changes in cognitive diagnoses and symptoms on the Neuropsychiatric Inventory Questionnaire (NPI-Q) and Geriatric Depression Scale (GDS-15).
Results:
1,121 participants converted from NC to MCI; 324 reverted back to NC and 242 progressed to AD dementia. Higher symptoms on the GDS-15 and circumscribed symptom domains on the NPI-Q were associated with conversion from NC to MCI and a decreased likelihood of reversion from MCI to NC. Individuals with higher symptoms on NPI-Q Hyperactivity and Mood items were more likely to progress to AD dementia.
Discussion:
The temporal instability of MCI can be partially explained by neuropsychiatric symptoms. Individuals with higher levels of specific symptoms are more likely to progress to AD dementia and less likely to revert to NC. Identification and treatment of these symptoms might support cognitive functioning in older adults.
 
 
 

Hot Topics: NIH Releases Big Data for Brain Development Research

katheride Hot Topics in Research, Neurology, Pediatrics, Psychology and Psychiatry

NIH releases first dataset from unprecedented study of adolescent brain development
National Institutes of Health. (2018, February 13). NIH releases first dataset from unprecedented study of adolescent brain development [Press release]. Retrieved from https://www.nih.gov/news-events/news-releases/nih-releases-first-dataset-unprecedented-study-adolescent-brain-development.
The National Institutes of Health Tuesday released to the scientific community an unparalleled dataset from the Adolescent Brain Cognitive Development (ABCD) study. To date, more than 7,500 youth and their families have been recruited for the study, well over half the participant goal.  Approximately 30 terabytes of data (about three times the size of the Library of Congress collection), obtained from the first 4,500 participants, will be available to scientists worldwide to conduct research on the many factors that influence brain, cognitive, social, and emotional development. The ABCD study is the largest long-term study of brain development and child health in the United States.

Hot Topics: Virtual Reality Used to Study How Memories Are Formed

katheride Biomedical Sciences, Hot Topics in Research, Neurology

CA1 and CA3 differentially support spontaneous retrieval of episodic contexts within human hippocampal subfields
Dimsdale-Zucker H, Ritchey M, Ekstrom AD, Yonelinas AP, Ranganath C. CA1 and CA3 differentially support spontaneous retrieval of episodic contexts within human hippocampal subfields. Nature Communications. 2018;9(1):294. https://doi.org/10.1038/s41467-017-02752-1.
The hippocampus plays a critical role in spatial and episodic memory. Mechanistic models predict that hippocampal subfields have computational specializations that differentially support memory. However, there is little empirical evidence suggesting differences between the subfields, particularly in humans. To clarify how hippocampal subfields support human spatial and episodic memory, we developed a virtual reality paradigm where participants passively navigated through houses (spatial contexts) across a series of videos (episodic contexts). We then used multivariate analyses of high-resolution fMRI data to identify neural representations of contextual information during recollection. Multi-voxel pattern similarity analyses revealed that CA1 represented objects that shared an episodic context as more similar than those from different episodic contexts. CA23DG showed the opposite pattern, differentiating between objects encountered in the same episodic context. The complementary characteristics of these subfields explain how we can parse our experiences into cohesive episodes while retaining the specific details that support vivid recollection.

Hot Topics: CTE Caused by Head Impact, Not Concussions

katheride Hot Topics in Research, Neurology, Sports Medicine

Concussion, microvascular injury, and early tauopathy in young athletes after impact head injury and an impact concussion mouse model
Tagge C,A., Fisher A,M., Minaeva O,V., et al. Concussion, microvascular injury, and early tauopathy in young athletes after impact head injury and an impact concussion mouse model. Brain. 2018. doi: 10.1093/brain/awx350.
The mechanisms underpinning concussion, traumatic brain injury, and chronic traumatic encephalopathy, and the relationships between these disorders, are poorly understood. We examined post-mortem brains from teenage athletes in the acute-subacute period after mild closed-head impact injury and found astrocytosis, myelinated axonopathy, microvascular injury, perivascular neuroinflammation, and phosphorylated tau protein pathology. To investigate causal mechanisms, we developed a mouse model of lateral closed-head impact injury that uses momentum transfer to induce traumatic head acceleration. Unanaesthetized mice subjected to unilateral impact exhibited abrupt onset, transient course, and rapid resolution of a concussion-like syndrome characterized by altered arousal, contralateral hemiparesis, truncal ataxia, locomotor and balance impairments, and neurobehavioural deficits. Experimental impact injury was associated with axonopathy, blood–brain barrier disruption, astrocytosis, microgliosis (with activation of triggering receptor expressed on myeloid cells, TREM2), monocyte infiltration, and phosphorylated tauopathy in cerebral cortex ipsilateral and subjacent to impact. Phosphorylated tauopathy was detected in ipsilateral axons by 24 h, bilateral axons and soma by 2 weeks, and distant cortex bilaterally at 5.5 months post-injury. Impact pathologies co-localized with serum albumin extravasation in the brain that was diagnostically detectable in living mice by dynamic contrast-enhanced MRI. These pathologies were also accompanied by early, persistent, and bilateral impairment in axonal conduction velocity in the hippocampus and defective long-term potentiation of synaptic neurotransmission in the medial prefrontal cortex, brain regions distant from acute brain injury. Surprisingly, acute neurobehavioural deficits at the time of injury did not correlate with blood–brain barrier disruption, microgliosis, neuroinflammation, phosphorylated tauopathy, or electrophysiological dysfunction. Furthermore, concussion-like deficits were observed after impact injury, but not after blast exposure under experimental conditions matched for head kinematics. Computational modelling showed that impact injury generated focal point loading on the head and seven-fold greater peak shear stress in the brain compared to blast exposure. Moreover, intracerebral shear stress peaked before onset of gross head motion. By comparison, blast induced distributed force loading on the head and diffuse, lower magnitude shear stress in the brain. We conclude that force loading mechanics at the time of injury shape acute neurobehavioural responses, structural brain damage, and neuropathological sequelae triggered by neurotrauma. These results indicate that closed-head impact injuries, independent of concussive signs, can induce traumatic brain injury as well as early pathologies and functional sequelae associated with chronic traumatic encephalopathy. These results also shed light on the origins of concussion and relationship to traumatic brain injury and its aftermath.

Hot Topics: Virtual Reality Games Can Help Stroke Recovery

katheride Hot Topics in Research, Neurology, Physical Therapy

Virtual Reality Training for Upper Extremity in Subacute Stroke (VIRTUES): A multicenter RCT
Brunner, I., Skouen, J. S., Hofstad, H., Aßmus, J., Becker, F., Sanders, A., . . . Verheyden, G. (2017). Virtual reality training for upper extremity in subacute stroke (VIRTUES). Neurology, doi:10.1212/WNL.0000000000004744
Objective: To compare the effectiveness of upper extremity virtual reality rehabilitation training
(VR) to time-matched conventional training (CT) in the subacute phase after stroke.
Methods: In this randomized, controlled, single-blind phase III multicenter trial, 120 participants
with upper extremity motor impairment within 12 weeks after stroke were consecutively included
at 5 rehabilitation institutions. Participants were randomized to either VR or CT as an adjunct to
standard rehabilitation and stratified according to mild to moderate or severe hand paresis,
defined as $20 degrees wrist and 10 degrees finger extension or less, respectively. The training
comprised a minimum of sixteen 60-minute sessions over 4 weeks. The primary outcome measure
was the Action Research Arm Test (ARAT); secondary outcome measures were the Box and
Blocks Test and Functional Independence Measure. Patients were assessed at baseline, after
intervention, and at the 3-month follow-up.
Results: Mean time from stroke onset for the VR group was 35 (SD 21) days and for the CT group
was 34 (SD 19) days. There were no between-group differences for any of the outcome measures.
Improvement of upper extremity motor function assessed with ARAT was similar at the
postintervention (p 5 0.714) and follow-up (p 5 0.777) assessments. Patients in VR improved
12 (SD 11) points from baseline to the postintervention assessment and 17 (SD 13) points from
baseline to follow-up, while patients in CT improved 13 (SD 10) and 17 (SD 13) points, respectively.
Improvement was also similar for our subgroup analysis with mild to moderate and severe
upper extremity paresis.
Conclusions: Additional upper extremity VR training was not superior but equally as effective as
additional CT in the subacute phase after stroke. VR may constitute a motivating training alternative
as a supplement to standard rehabilitation.