A pilot study to investigate the safety and feasibility of antiretroviral therapy for Alzheimer's disease (ART-AD).

Retrotransposons are viral-like DNA sequences that constitute approximately 41% of the human genome. Studies in Drosophila, mice, cultured cells, and human brain indicate that retrotransposons are activated in settings of tauopathy, including Alzheimer's disease, and causally drive neurodegeneration. The anti-retroviral medication 3TC (lamivudine), a nucleoside analog reverse transcriptase inhibitor, limits retrotransposon activation and suppresses neurodegeneration in tau transgenic Drosophila, two mouse models of tauopathy, and in brain assembloids derived from patients with sporadic Alzheimer's disease. We performed a 24-week phase 2a open-label clinical trial of 300 mg daily oral 3TC (NCT04552795) in 12 participants aged 52-83 years with a diagnosis of mild cognitive impairment due to suspected Alzheimer's disease. Primary outcomes included feasibility, blood brain barrier penetration, effects of 3TC on reverse transcriptase activity in the periphery, and safety. Secondary outcomes included changes in cognition and fluid-based biomarkers of neurodegeneration and neuroinflammation. All participants completed the six-month trial; one event of gastrointestinal bleeding due to a peptic ulcer was reported. 3TC was detected in blood and cerebrospinal fluid (CSF) of all participants, suggestive of adherence to study drug and effective brain penetration. Cognitive measures remained stable throughout the study. Glial fibrillary acidic protein (GFAP) (P=0.03) and Flt1 (P=0.05) were significantly reduced in CSF over the treatment period; Aß42/40 (P=0.009) and IL-15 (P=0.006) were significantly elevated in plasma. While this is an open label study of small sample size, the significant decrease of some neurodegeneration- and neuroinflammation-related biomarkers in CSF, significantly elevated levels of plasma Aß42/40, and a trending decrease of CSF NfL after six months of 3TC exposure suggest a beneficial effect on subjects with mild cognitive impairment due to suspected Alzheimer's disease. Feasibility, safety, tolerability, and central nervous system (CNS) penetration assessments further support clinical evaluation of 3TC in a larger placebo-controlled, multi-dose clinical trial.

Herpes Labialis, Chlamydophila pneumoniae, Helicobacter pylori, and Cytomegalovirus Infections and Risk of Dementia: The Framingham Heart Study.

BACKGROUND: An association between chronic infectious diseases and development of dementia has been suspected for decades, based on the finding of pathogens in postmortem brain tissue and on serological evidence. However, questions remain regarding confounders, reverse causality, and how accurate, reproducible and generalizable those findings are. OBJECTIVE: Investigate whether exposure to Herpes simplex (manifested as herpes labialis), Chlamydophila pneumoniae (C. pneumoniae), Helicobacter pylori (H. pylori), and cytomegalovirus (CMV) modifies the risk of dementia in a populational cohort. METHODS: Questionnaires regarding incidence of herpes infections were administered to Original Framingham Study participants (n = 2,632). Serologies for C. pneumoniae, H. pylori, and CMV were obtained in Original (n = 2,351) and Offspring cohort (n = 3,687) participants. Participants are under continuous dementia surveillance. Brain MRI and neuropsychological batteries were administered to Offspring participants from 1999-2005. The association between each infection and incident dementia was tested with Cox models. Linear models were used to investigate associations between MRI or neuropsychological parameters and serologies. RESULTS: There was no association between infection serologies and dementia incidence, total brain volume, and white matter hyperintensities. Herpes labialis was associated with reduced 10-year dementia risk (HR 0.66, CI 0.46-0.97), but not for the duration of follow-up. H. pylori antibodies were associated with worse global cognition (ß -0.14, CI -0.22, -0.05). CONCLUSION: We found no association between measures of chronic infection and incident dementia, except for a reduction in 10-year dementia risk for patients with herpes labialis. This unexpected result requires confirmation and further characterization, concerning antiviral treatment effects and capture of episodes.

Review of Evidence and Perspectives of Flavonoids on Metabolic Syndrome and Neurodegenerative Disease.

Flavonoids are commonly found in fruits, vegetables, and plant-derived foods and may promote various health benefits when included in the diet. The biological activity of flavonoids is normally associated to their potent antioxidant and anti-inflammatory effects, since oxidative stress is associated to conditions such as diabetes, obesity, cardiovascular and neurodegenerative diseases. Additionally, flavonoids may be related to metabolic diseases through their effects on inflammatory mediators and pathways, barrier integrity and gut microbiota composition. The extensive metabolism undergone by flavonoids in humans and the individual differences in their bioavailability to target organs hinder the interpretation of results from cell and animal models. Prospective human studies therefore provide an important perspective. In the field of neurodegenerative disease, carefully designed cohort studies have uncovered important associations between flavonoid intake and reduction in dementia risk, especially regarding specific flavonols, but also anthocyanins. Alternative mechanisms of action, such as changes in the gut microbiota or modulation of the production of toxic proteins, such as amyloid and tau, likely account for an important component of their positive effects, and their elucidation may lead to public health benefits of large magnitude.

Right hemispatial ipsilesional neglect with chronic right hemisphere strokes.

BACKGROUND: Patients who present with spatial neglect after stroke often perform normally on tests for neglect after a few weeks. Whereas tests for neglect are often performed directly in front of a patient, in their actual environments many important stimuli may be present within their left or right hemispace. The presence and severity of neglect often depends on the hemisphere injured. It is possible, in chronic stroke, for spatial judgments to be influenced by an interaction of stroke laterality and the spatial location of stimuli. The objective of this study was to learn if unilateral hemispheric chronic strokes contribute to a spatial bias with laterally presented stimuli. METHOD: There were 70 participants, 62 with unilateral chronic strokes (>6 months post onset) including 35 with left hemisphere damage (LHD), 27 with right hemisphere damage (RHD), and 8 demographically similar people without history of stroke. Participants were asked to bisect 300 lines presented with distractors on the left, right, or both sides of the line, or no distractor, on a touch-screen monitor in right, center or left hemispace. RESULTS: There was a significant interaction between the side of the hemispheric lesion and the side of the body where these lines were presented. Specifically, in right space, patients with RHD deviated leftward in comparison to the other groups. Furthermore, there was an interaction between group and distractor induced bias. All three groups approached the left distractor, and the patients with LHD also approached the right distractor. CONCLUSIONS: Although spatial neglect is more severe in contralesional than ipsilesional hemispace in the period immediately following a stroke, over time patients with RHD may develop ipsilesional neglect that is more severe in ipsilesional than contralesional space. The mechanism underlying this bias is not known and may be related to attempted compensation or the development of a contralateral attentional/intentional grasp.

Effects of aging on action-intentional programming.

BACKGROUND: Action-intentional programs control "when" we initiate, inhibit, continue, and stop motor actions. The purpose of this study was to learn if there are changes in the action-intentional system with healthy aging, and if these changes are asymmetrical (right versus left upper limb) or related to impaired interhemispheric communication. METHODS: We administered tests of action-intention to 41 middle-aged and older adults (61.9 ± 12.3 years). RESULTS: Regression analyses revealed that older age predicted a decrement in performance for tests of crossed motor response inhibition as well as slower motor initiation with the left hand. CONCLUSION: Changes in action-intention with aging appear to be related to alterations of interhemispheric communication and/or age-related right hemisphere dysfunction; however, further research is needed to identify the mechanisms for age-related changes in the brain networks that mediate action-intention.

Spatial neglect in a patient with logopenic progressive aphasia.

Spatial neglect and extinction are induced by posterior superior temporal and inferior parietal dysfunction. In patients with logopenic progressive aphasia (LPA) these structures are often degenerated, but there are no reports of these disorders being associated. A 53-year-old man with the signs of LPA revealed right-sided spatial neglect on line bisection and drawing tests as well as multimodal extinction. MRI showed left hemispheric posterior temporoparietal atrophy. Since injury to the core structures for these aphasic and attentional syndromes overlaps, patients with LPA should be screened for spatial neglect and extinction.

Allocentric spatial neglect with posterior cortical atrophy.

Patients with posterior cortical atrophy (PCA) have been reported to have neglect in the egocentric/ body-centered reference frame. This report describes a woman with PCA who had a right-sided stimulus-based form of allocentric visual neglect on cancellation, reading, and drawing tests. Her brain imaging revealed left parietal atrophy. The pathophysiology of this disorder may be related to an impairment of the ventral "what" stream's ability to interact with the dorsal "where" stream that mediates the allocation of spatial attention, or a deficit in the systems that allocate contralateral focal attention. Further research is needed to better understand the mechanisms of this disorder and to optimally treat it.

The influence of stimulus proximity on judgments of spatial relationships in patients with chronic unilateral right or left hemisphere stroke.

OBJECTIVE: This was to learn how chronic right hemispheric damage (RHD) versus left hemispheric damage (LHD) may influence attentional biases in proximal and distal space. BACKGROUND: Prior research has suggested that the left hemisphere primarily attends to proximal space and the right hemisphere to distal space. The purpose of this study was to contrast line bisection performed in proximal versus distal space in patients with chronic LHD versus RHD. DESIGN/METHOD: Participants were 32 LHD and 26 RHD patients who sustained a stroke a mean of 3.4 years prior to testing, along with 9 healthy controls. Subjects attempted to bisect 30 lines in proximal space and 30 lines in distal space. RESULTS: Patients with both RHD and LHD had a greater contralesional bias in proximal than distal space (rightward bias for patients with LHD and leftward bias for patients with RHD). Compared to controls, patients with LHD were most different in proximal space, and patients with RHD were most different in distal space. CONCLUSIONS: Proximity appears to influence spatial judgments of patients with RHD and LHD in an opposing manner. Relatively, both patient groups bisect lines contralesionally in proximal space and ipsilesionally (relative to proximal) in distal space. Patients with RHD have the biggest difference between their proximal and distal judgments. The reason for these differences is unknown. However, these biases may be related to an attentional or action-intentional grasp or a learned compensation strategy, and proximity may increase the allocation of attention or intention and thereby enhance this grasp or use of this compensation strategy. Another contributing factor may be dominance of the left and right hemisphere for information presented in proximal and distal space, respectively.

Treating epilepsy in the setting of medical comorbidities.

OPINION STATEMENT: Treatment of epilepsy in patients with medical comorbidities can be challenging. Comorbidities can affect medical management and quality of life. In this review, we discuss treatment options in patients with epilepsy and medical comorbidities. In our opinion, the best way to manage patients with medical comorbidities and epilepsy is to accurately recognize and diagnose medical comorbidities, and to have adequate knowledge and familiarity with antiepileptic drug (AED) metabolism, dosing, side effects, and drug interactions. We believe the trend should move toward using the newer generation of AEDs given their generally reduced rate of adverse effects and interactions. The primary goal of therapy is seizure freedom without side effects.