A Precision Medicine Approach to Dementia Care: Syndrome, Etiology, and Copathology.

Recognizing multiple neuropathological entities in people with dementia improves understanding of diagnosis, prognosis, and expected outcomes from therapies. Care for the individual with dementia includes the evaluation and management of diseases associated with the aged brain, most commonly neurodegeneration and vascular brain injury (VBI). Terminology has evolved to keep pace with diagnostic, prognostic, and therapeutic advances, and autopsy studies have shown that multiple comorbid neuropathological entities are the rule, not the exception, especially in older individuals.

rs10501087, rs1491850 and rs11030094 polymorphisms associated with delayed progression in early-stage Parkinson's disease.

Parkinson's disease (PD) is heterogenous in its presentation, progression and response to therapies. Genetic polymorphisms may account for some of this variability. Several single nucleotide polymorphisms (SNPs) in the brain-derived neurotrophic factor gene have been associated with differing clinical outcomes from different dopaminergic replacement strategies, and one of these, the rs6265 SNP, has been associated with a milder clinical phenotype in the unmedicated, early-stage of PD.

BDNF rs6265 Variant Alters Outcomes with Levodopa in Early-Stage Parkinson's Disease.

Disease outcomes are heterogeneous in Parkinson's disease and may be predicted by gene variants. This study investigated if the BDNF rs6265 single nucleotide polymorphism (SNP) is associated with differential outcomes with specific pharmacotherapy treatment strategies in the "NIH Exploratory Trials in PD Long-term Study 1" (NET-PD LS-1, n = 540). DNA samples were genotyped for the rs6265 SNP and others (rs11030094, rs10501087, rs1491850, rs908867, and rs1157659).

The BDNF Val66Met polymorphism (rs6265) enhances dopamine neuron graft efficacy and side-effect liability in rs6265 knock-in rats.

Prevalent in approximately 20% of the worldwide human population, the rs6265 (also called 'Val66Met') single nucleotide polymorphism (SNP) in the gene for brain-derived neurotrophic factor (BDNF) is a common genetic variant that can alter therapeutic responses in individuals with Parkinson's disease (PD). Possession of the variant Met allele results in decreased activity-dependent release of BDNF. Given the resurgent worldwide interest in neural transplantation for PD and the biological relevance of BDNF, the current studies examined the effects of the rs6265 SNP on therapeutic efficacy and side-effect development following primary dopamine (DA) neuron transplantation.

Epigenetic factor siRNA screen during primary KSHV infection identifies novel host restriction factors for the lytic cycle of KSHV.

Establishment of viral latency is not only essential for lifelong Kaposi's sarcoma-associated herpesvirus (KSHV) infection, but it is also a prerequisite of viral tumorigenesis. The latent viral DNA has a complex chromatin structure, which is established in a stepwise manner regulated by host epigenetic factors during de novo infection. However, despite the importance of viral latency in KSHV pathogenesis, we still have limited information about the repertoire of epigenetic factors that are critical for the establishment and maintenance of KSHV latency.

BDNF provides many routes toward STN DBS-mediated disease modification.

The concept that subthalamic nucleus deep brain stimulation (STN DBS) may be disease modifying in Parkinson's disease (PD) is controversial. Several clinical trials that enrolled subjects with late-stage PD have come to disparate conclusions on this matter. In contrast, some clinical studies in early- to midstage subjects have suggested a disease-modifying effect.

Quality Over Quantity: Advantages of Using Alpha-Synuclein Preformed Fibril Triggered Synucleinopathy to Model Idiopathic Parkinson's Disease.

Animal models have significantly advanced our understanding of Parkinson's disease (PD). Alpha-synuclein (α-syn) has taken center stage due to its genetic connection to familial PD and localization to Lewy bodies, one pathological hallmark of PD. Animal models developed on the premise of elevated alpha-synuclein via germline manipulation or viral vector-mediated overexpression are used to investigate PD pathophysiology and vet novel therapeutics.

ESTIMATING SHAPE CORRESPONDENCE FOR POPULATIONS OF OBJECTS WITH COMPLEX TOPOLOGY.

Statistical shape analysis captures the geometric properties of a given set of shapes, obtained from medical images, by means of statistical methods. Orthognathic surgery is a type of craniofacial surgery that is aimed at correcting severe skeletal deformities in the mandible and maxilla. Methods assuming spherical topology cannot represent the class of anatomical structures exhibiting complex geometries and topologies, including the mandible.

Correction to: Lewy body-like alpha-synuclein inclusions trigger reactive microgliosis prior to nigral degeneration.

After publication of the original article [1] it was noted that the name of author, D. Luke Fisher, was erroneously typeset in both the PDF and online formats of the manuscript as Luke D. Fisher.

Bdnf variant is associated with milder motor symptom severity in early-stage Parkinson's disease.

Introduction: Parkinson's disease (PD) progression is heterogeneous. Variants in PD-related genes may alter disease progression or severity. We examined if the single nucleotide variant rs6265 in the gene Bdnf alters clinical phenotype in early-stage, unmedicated PD.

Lewy body-like alpha-synuclein inclusions trigger reactive microgliosis prior to nigral degeneration.

Background: Converging evidence suggests a role for microglia-mediated neuroinflammation in Parkinson's disease (PD). Animal models of PD can serve as a platform to investigate the role of neuroinflammation in degeneration in PD. However, due to features of the previously available PD models, interpretations of the role of neuroinflammation as a contributor to or a consequence of neurodegeneration have remained elusive.

External Ventricular Drain Placement Accuracy and Safety When Done by Midlevel Practitioners.

Background: External ventricular drains (EVDs) measure intracranial pressure, divert cerebrospinal fluid, and allow for orthotropic administration of pharmacologic agents. Currently, neurosurgeons and neurosurgery residents are the primary practitioners placing EVDs. Due to the urgency of neurosurgical pathologies and the lack of qualified residents at most hospitals, midlevel practitioner (MLP) placement of EVDs would be advantageous.

Subthalamic Nucleus Deep Brain Stimulation Does Not Modify the Functional Deficits or Axonopathy Induced by Nigrostriatal α-Synuclein Overexpression.

Subthalamic nucleus deep brain stimulation (STN DBS) protects dopaminergic neurons of the substantia nigra pars compacta (SNpc) against 6-OHDA and MPTP. We evaluated STN DBS in a parkinsonian model that displays α-synuclein pathology using unilateral, intranigral injections of recombinant adeno-associated virus pseudotype 2/5 to overexpress wildtype human α-synuclein (rAAV2/5 α-syn). A low titer of rAAV2/5 α-syn results in progressive forelimb asymmetry, loss of striatal dopaminergic terminal density and modest loss of SNpc dopamine neurons after eight weeks, corresponding to robust human-Snca expression and no effect on rat-Snca, Th, Bdnf or Trk2.

Subthalamic Nucleus Deep Brain Stimulation Employs trkB Signaling for Neuroprotection and Functional Restoration.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is the most common neurosurgical treatment for Parkinson's disease motor symptoms. In preclinical models, STN DBS provides neuroprotection for substantia nigra (SN) dopamine neurons and increases BDNF in the nigrostriatal system and primary motor cortex. However, whether BDNF signaling in the SN participates in the neuroprotective effects of DBS remains unknown.

Impact of age and vector construct on striatal and nigral transgene expression.

Therapeutic protein delivery using viral vectors has shown promise in preclinical models of Parkinson's disease (PD) but clinical trial success remains elusive. This may partially be due to a failure to include advanced age as a covariate despite aging being the primary risk factor for PD. We investigated transgene expression following intracerebral injections of recombinant adeno-associated virus pseudotypes 2/2 (rAAV2/2), 2/5 (rAAV2/5), 2/9 (rAAV2/9), and lentivirus (LV) expressing green fluorescent protein (GFP) in aged versus young adult rats.

Viral Vector-Based Modeling of Neurodegenerative Disorders: Parkinson's Disease.

Gene therapy methods are increasingly used to model Parkinson's disease (PD) in animals in an effort to test experimental therapeutics within a more relevant context to disease pathophysiology and neuropathology. We have detailed several criteria that are critical or advantageous to accurately modeling PD in a murine model or in a nonhuman primate. Using these criteria, we then evaluate approaches made to model PD using viral vectors to date, including both adeno-associated viruses and lentiviruses.

High-Frequency Stimulation of the Rat Entopeduncular Nucleus Does Not Provide Functional or Morphological Neuroprotection from 6-Hydroxydopamine.

Deep brain stimulation (DBS) is the most common neurosurgical treatment for Parkinson's disease (PD). Whereas the globus pallidus interna (GPi) has been less commonly targeted than the subthalamic nucleus (STN), a recent clinical trial suggests that GPi DBS may provide better outcomes for patients with psychiatric comorbidities. Several laboratories have demonstrated that DBS of the STN provides neuroprotection of substantia nigra pars compacta (SNpc) dopamine neurons in preclinical neurotoxin models of PD and increases brain-derived neurotrophic factor (BDNF).