Endogenous mitochondrial NAD(P)H fluorescence can predict lifespan.

Many aging clocks have recently been developed to predict health outcomes and deconvolve heterogeneity in aging. However, existing clocks are limited by technical constraints, such as low spatial resolution, long processing time, sample destruction, and a bias towards specific aging phenotypes. Therefore, here we present a non-destructive, label-free and subcellular resolution approach for quantifying aging through optically resolving age-dependent changes to the biophysical properties of NAD(P)H in mitochondria through fluorescence lifetime imaging (FLIM) of endogenous NAD(P)H fluorescence.

The Effect of Dysautonomia on Motor, Behavioral, and Cognitive Fluctuations in Parkinson's Disease.

Background: Motor and nonmotor fluctuations adversely impact the quality of life in Parkinson's disease (PD). Dysautonomia, a feature frequently associated with PD and a possible adverse effect of dopaminergic therapy, may be comorbid with fluctuations.

Objective: We sought to evaluate the effect of dysautonomia on motor and nonmotor fluctuations in PD.

The effect of dysautonomia on motor, behavioral and cognitive fluctuations in Parkinson's disease.

Background: Motor and non-motor fluctuations adversely impact quality of life in Parkinson's disease (PD). Dysautonomia, a feature frequently associated with PD and a possible adverse effect of dopaminergic therapy, may be comorbid with fluctuations.

Objectives: We sought to evaluate the effect of dysautonomia on motor and non-motor fluctuations in PD.

Long-term, home-based transcranial direct current stimulation coupled with computerized cognitive training in frontotemporal dementia: A case report.

We present the case of a 62-year-old woman with probable behavioral variant of frontotemporal dementia (bvFTD) with cognitive/language deficits who demonstrated improved performance on cognitive/language testing and in functional tasks following long-term, home-based transcranial direct current stimulation (tDCS) coupled with computerized cognitive training (CCT). The patient underwent home-based tDCS (anode on the left prefrontal cortex and cathode on the right homologue) for 46 sessions over 10 weeks along with CCT. On post-treatment testing, the patient improved by 3 points on the Mini-Mental State Exam (MMSE) (23 to 26).

Classification of Neural Stem Cell Activation State In Vitro using Autofluorescence.

Neural stem cells (NSCs) divide and produce newborn neurons in the adult brain through a process called adult neurogenesis. Adult NSCs are primarily quiescent, a reversible cell state where they have exited the cell cycle (G0) yet remain responsive to the environment. In the first step of adult neurogenesis, quiescent NSCs (qNSCs) receive a signal and activate, exiting quiescence and re-entering the cell cycle.

Exploring Psychosis in Neurodegenerative Dementia: Connecting Symptoms to Neurobiology.

The following commentary discusses a review by Cressot et al. entitled: 'Psychosis in Neurodegenerative Dementias: A Systematic Comparative Review'. The authors describe the epidemiology and phenomenology of psychosis across neurodegenerative dementias.

Impact of Acute Dopamine Replacement on Cognitive Function in Parkinson's Disease.

Background: PD causes striatal dopaminergic denervation in a posterior/dorsal to anterior/ventral gradient, leaving motor and associative cortico-striato-pallido-thalamic loops differentially susceptible to hyperdopaminergic effects with treatment. As the choice and titration of symptomatic PD medications are guided primarily by motor symptoms, it is important to understand their cognitive implications.

Objective: To investigate the effects of acute dopaminergic medication administration on executive function in Parkinson's disease (PD).

The Association of Antidepressant Use and Impulse Control Disorder in Parkinson's Disease.

Objectives: To examine whether initiation of an antidepressant is associated with the development of impulse control disorder (ICD) in patients with Parkinson's disease (PD).

Design: We performed a retrospective analysis utilizing data from the Parkinson's Progression Markers Initiative (PPMI). Two-sample Mann-Whitney tests were used for comparison of continuous variables and Pearson χ tests were used for categorical variables.

Examining the link between impulse control disorder and antidepressant use in Parkinson's disease.

Introduction: Impulse control disorders (ICD) in Parkinson's disease (PD) and hypomanic episodes of bipolar disorder show overlapping symptoms, suggesting a shared neurobiology. To explore this, the following hypotheses are tested: (1) larger changes in affective symptoms from OFF to ON medication states will be associated with ICD, (2) antidepressant exposure will be associated with larger OFF to ON affective symptom changes, and (3) antidepressant exposure will be associated with ICD.

Methods: 200 participants (mean age 65, 61 % male) were evaluated in "off" and "on" dopamine states.

Anxiety Change After Dopamine Therapy in Parkinson Disease is Independent of Motor Improvement.

Background: Several anxiety syndromes have been associated with Parkinson disease (PD), but their interactions with dopamine replacement therapy (DRT) and motor function dynamics are not completely understood. We sought to delineate how DRT impacts anxiety phenomenology in PD and whether these changes are dissociable from improved motoric function.

Methods: We compared anxiety responses to DRT in two cohorts: 1) a study of 200 PD participants who completed neuropsychiatric assessments before and after taking their dopaminergic medications ("On-Off"); 2) participants in the Parkinson's Progression Markers Initiative (PPMI) de novo PD cohort who completed the State-Trait Anxiety Inventory (STAI) at the time of DRT initiation and a subsequent study visit (n = 113, mean 8-month interval).

Weight Change and Neuropsychiatric Symptoms in Alzheimer's Disease and Frontotemporal Dementia: Associations with Cognitive Decline.

Weight changes, neuropsychiatric symptoms (NPS), and cognitive decline often coincide in Alzheimer's disease (AD) and frontotemporal dementia (FTD); however, the direction of their relationship remains unclear. This study aims to clarify the connection between weight changes, NPS, and cognition in AD and FTD. We found that cognitive decline was associated with decreased body mass index (BMI) in AD, while BMI gain was associated with increased conversion to FTD.

Age-maintained human neurons demonstrate a developmental loss of intrinsic neurite growth ability.

Injury to adult mammalian central nervous system (CNS) axons results in limited regeneration. Rodent studies have revealed a developmental switch in CNS axon regenerative ability, yet whether this is conserved in humans is unknown. Using human fibroblasts from 8 gestational-weeks to 72 years-old, we performed direct reprogramming to transdifferentiate fibroblasts into induced neurons (Fib-iNs), avoiding pluripotency which restores cells to an embryonic state.

Discovery of a Potent and Orally Bioavailable Zwitterionic Series of Selective Estrogen Receptor Degrader-Antagonists.

Herein, we report the optimization of a meta-substituted series of selective estrogen receptor degrader (SERD) antagonists for the treatment of ER+ breast cancer. Structure-based design together with the use of modeling and NMR to favor the bioactive conformation led to a highly potent series of basic SERDs with promising physicochemical properties. Issues with hERG activity resulted in a strategy of zwitterion formation and ultimately in the identification of .

Genome engineering for estrogen receptor mutations reveals differential responses to anti-estrogens and new prognostic gene signatures for breast cancer.

Mutations in the estrogen receptor (ESR1) gene are common in ER-positive breast cancer patients who progress on endocrine therapies. Most mutations localise to just three residues at, or near, the C-terminal helix 12 of the hormone binding domain, at leucine-536, tyrosine-537 and aspartate-538. To investigate these mutations, we have used CRISPR-Cas9 mediated genome engineering to generate a comprehensive set of isogenic mutant breast cancer cell lines.

Hyperorality in Frontotemporal Dementia: Cognitive and Psychiatric Symptom Profiles in Early-Stage Disease.

Hyperorality is a distinctive feature of the behavioral variant of frontotemporal dementia (bvFTD), but little is known about its significance in early-stage disease. This study examined the cognitive and psychiatric symptom profiles associated with hyperorality, using data from subjects with early-stage bvFTD enrolled in Alzheimer's Disease Research Centers. We found that hyperorality was not associated with cognitive performance, but was associated with psychosis, elation, and disinhibition.

Adult fibroblasts use aggresomes only in distinct cell-states.

The aggresome is a protein turnover system in which proteins are trafficked along microtubules to the centrosome for degradation. Despite extensive focus on aggresomes in immortalized cell lines, it remains unclear if the aggresome is conserved in all primary cells and all cell-states. Here we examined the aggresome in primary adult mouse dermal fibroblasts shifted into four distinct cell-states.