Dementia, dementia's risk factors and premorbid brain structure are concentrated in disadvantaged areas: National register and birth-cohort geographic analyses.

INTRODUCTION: Dementia risk may be elevated in socioeconomically disadvantaged neighborhoods. Reasons for this remain unclear, and this elevation has yet to be shown at a national population level. METHODS: We tested whether dementia was more prevalent in disadvantaged neighborhoods across the New Zealand population (N = 1.41 million analytic sample) over a 20-year observation. We then tested whether premorbid dementia risk factors and MRI-measured brain-structure antecedents were more prevalent among midlife residents of disadvantaged neighborhoods in a population-representative NZ-birth-cohort (N = 938 analytic sample). RESULTS: People residing in disadvantaged neighborhoods were at greater risk of dementia (HR per-quintile-disadvantage-increase = 1.09, 95% confidence interval [CI]:1.08-1.10) and, decades before clinical endpoints typically emerge, evidenced elevated dementia-risk scores (CAIDE, LIBRA, Lancet, ANU-ADRI, DunedinARB; ß's 0.31-0.39) and displayed dementia-associated brain structural deficits and cognitive difficulties/decline. DISCUSSION: Disadvantaged neighborhoods have more residents with dementia, and decades before dementia is diagnosed, residents have more dementia-risk factors and brain-structure antecedents. Whether or not neighborhoods causally influence risk, they may offer scalable opportunities for primary dementia prevention.

A blood biomarker of the pace of aging is associated with brain structure: replication across three cohorts.

Biological aging is the correlated decline of multi-organ system integrity central to the etiology of many age-related diseases. A novel epigenetic measure of biological aging, DunedinPACE, is associated with cognitive dysfunction, incident dementia, and mortality. Here, we tested for associations between DunedinPACE and structural MRI phenotypes in three datasets spanning midlife to advanced age: the Dunedin Study (age=45 years), the Framingham Heart Study Offspring Cohort (mean age=63 years), and the Alzheimer's Disease Neuroimaging Initiative (mean age=75 years). We also tested four additional epigenetic measures of aging: the Horvath clock, the Hannum clock, PhenoAge, and GrimAge. Across all datasets (total N observations=3380; total N individuals=2322), faster DunedinPACE was associated with lower total brain volume, lower hippocampal volume, greater burden of white matter microlesions, and thinner cortex. Across all measures, DunedinPACE and GrimAge had the strongest and most consistent associations with brain phenotypes. Our findings suggest that single timepoint measures of multi-organ decline such as DunedinPACE could be useful for gauging nervous system health.

Diagnosis of Delayed Post-Hypoxic Leukoencephalopathy (Grinker's Myelinopathy) with MRI Using Divided Subtracted Inversion Recovery (dSIR) Sequences: Time for Reappraisal of the Syndrome?

Background: Delayed Post-Hypoxic Leukoencephalopathy (DPHL), or Grinker's myelinopathy, is a syndrome in which extensive changes are seen in the white matter of the cerebral hemispheres with MRI weeks or months after a hypoxic episode. T2-weighted spin echo (T2-wSE) and/or T2-Fluid Attenuated Inversion Recovery (T2-FLAIR) images classically show diffuse hyperintensities in white matter which are thought to be near pathognomonic of the condition. The clinical features include Parkinsonism and akinetic mutism. DPHL is generally regarded as a rare condition. Methods and Results: Two cases of DPHL imaged with MRI nine months and two years after probable hypoxic episodes are described. No abnormalities were seen on the T2-FLAIR images with MRI, but very extensive changes were seen in the white matter of the cerebral and cerebellar hemisphere on divided Subtraction Inversion Recovery (dSIR) images. dSIR sequences may produce ten times the contrast of conventional inversion recovery (IR) sequences from small changes in T1. The clinical findings in both cases were of cognitive impairment without Parkinsonism or akinetic mutism. Conclusion: The classic features of DPHL may only represent the severe end of a spectrum of diseases in white matter following global hypoxic injury to the brain. The condition may be much more common than is generally thought but may not be recognized using conventional clinical and MRI criteria for diagnosis. Reappraisal of the syndrome of DPHL to include clinically less severe cases and to encompass recent advances in MRI is advocated.

Cerebellar Volume and Disease Staging in Parkinson's Disease: An ENIGMA-PD Study.

BACKGROUND: Increasing evidence points to a pathophysiological role for the cerebellum in Parkinson's disease (PD). However, regional cerebellar changes associated with motor and non-motor functioning remain to be elucidated. OBJECTIVE: To quantify cross-sectional regional cerebellar lobule volumes using three dimensional T1-weighted anatomical brain magnetic resonance imaging from the global ENIGMA-PD working group. METHODS: Cerebellar parcellation was performed using a deep learning-based approach from 2487 people with PD and 1212 age and sex-matched controls across 22 sites. Linear mixed effects models compared total and regional cerebellar volume in people with PD at each Hoehn and Yahr (HY) disease stage, to an age- and sex- matched control group. Associations with motor symptom severity and Montreal Cognitive Assessment scores were investigated. RESULTS: Overall, people with PD had a regionally smaller posterior lobe (dmax = -0.15). HY stage-specific analyses revealed a larger anterior lobule V bilaterally (dmax = 0.28) in people with PD in HY stage 1 compared to controls. In contrast, smaller bilateral lobule VII volume in the posterior lobe was observed in HY stages 3, 4, and 5 (dmax = -0.76), which was incrementally lower with higher disease stage. Within PD, cognitively impaired individuals had lower total cerebellar volume compared to cognitively normal individuals (d = -0.17). CONCLUSIONS: We provide evidence of a dissociation between anterior "motor" lobe and posterior "non-motor" lobe cerebellar regions in PD. Whereas less severe stages of the disease are associated with larger motor lobe regions, more severe stages of the disease are marked by smaller non-motor regions. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A blood biomarker of accelerated aging in the body associates with worse structural integrity in the brain: replication across three cohorts.

Biological aging is the correlated decline of multi-organ system integrity central to the etiology of many age-related diseases. A novel epigenetic measure of biological aging, DunedinPACE, is associated with cognitive dysfunction, incident dementia, and mortality. Here, we tested for associations between DunedinPACE and structural MRI phenotypes in three datasets spanning midlife to advanced age: the Dunedin Study (age=45 years), the Framingham Heart Study Offspring Cohort (mean age=63 years), and the Alzheimer's Disease Neuroimaging Initiative (mean age=75 years). We also tested four additional epigenetic measures of aging: the Horvath clock, the Hannum clock, PhenoAge, and GrimAge. Across all datasets (total N observations=3,380; total N individuals=2,322), faster DunedinPACE was associated with lower total brain volume, lower hippocampal volume, and thinner cortex. In two datasets, faster DunedinPACE was associated with greater burden of white matter hyperintensities. Across all measures, DunedinPACE and GrimAge had the strongest and most consistent associations with brain phenotypes. Our findings suggest that single timepoint measures of multi-organ decline such as DunedinPACE could be useful for gauging nervous system health.

Acquired Stuttering in Parkinson's Disease.

Background: Parkinson's disease frequently causes communication impairments, but knowledge about the occurrence of new-onset stuttering is limited. Objectives: To determine the presence of acquired neurogenic stuttering and its relationship with cognitive and motor functioning in individuals with Parkinson's disease. Method: Conversation, picture description, and reading samples were collected from 100 people with Parkinson's disease and 25 controls to identify the presence of stuttered disfluencies (SD) and their association with neuropsychological test performance and motor function. Results: Participants with Parkinson's disease presented with twice as many stuttered disfluencies during conversation (2.2% ± 1.8%SD) compared to control participants (1.2% ± 1.2%SD; P < 0.01). 21% of people with Parkinson's disease (n = 20/94) met the diagnostic criterion for stuttering, compared with 1/25 controls. Stuttered disfluencies also differed significantly across speech tasks, with more disfluencies during conversation compared to reading (P < 0.01). Stuttered disfluencies in those with Parkinson's disease were associated with longer time since disease onset (P < 0.01), higher levodopa equivalent dosage (P < 0.01), and lower cognitive (P < 0.01) and motor scores (P < 0.01). Conclusion: One in five participants with Parkinson's disease presented with acquired neurogenic stuttering, suggesting that speech disfluency assessment, monitoring and intervention should be part of standard care. Conversation was the most informative task for identifying stuttered disfluencies. The frequency of stuttered disfluencies was higher in participants with worse motor functioning, and lower cognitive functioning. This challenges previous suggestions that the development of stuttered disfluencies in Parkinson's disease has purely a motoric basis.

Functional topography of the neocortex predicts covariation in complex cognitive and basic motor abilities.

Although higher-order cognitive and lower-order sensorimotor abilities are generally regarded as distinct and studied separately, there is evidence that they not only covary but also that this covariation increases across the lifespan. This pattern has been leveraged in clinical settings where a simple assessment of sensory or motor ability (e.g. hearing, gait speed) can forecast age-related cognitive decline and risk for dementia. However, the brain mechanisms underlying cognitive, sensory, and motor covariation are largely unknown. Here, we examined whether such covariation in midlife reflects variability in common versus distinct neocortical networks using individualized maps of functional topography derived from BOLD fMRI data collected in 769 45-year-old members of a population-representative cohort. Analyses revealed that variability in basic motor but not hearing ability reflected individual differences in the functional topography of neocortical networks typically supporting cognitive ability. These patterns suggest that covariation in motor and cognitive abilities in midlife reflects convergence of function in higher-order neocortical networks and that gait speed may not be simply a measure of physical function but rather an integrative index of nervous system health.

Altered nucleus accumbens functional connectivity precedes apathy in Parkinson's disease.

Work in animal and human neuroscience has identified neural regions forming a network involved in the production of motivated, goal-directed behaviour. In particular, the nucleus accumbens and anterior cingulate cortex are recognized as key network nodes underlying decisions of whether to exert effort for reward, to drive behaviour. Previous work has convincingly shown that this cognitive mechanism, known as effort-based decision making, is altered in people with Parkinson's disease with a syndrome of reduced goal-directed behaviour-apathy. Building on this work, we investigated whether the neural regions implementing effort-based decision-making were associated with apathy in Parkinson's disease, and more importantly, whether changes to these regions were evident prior to apathy development. We performed a large, multimodal neuroimaging analysis in a cohort of people with Parkinson's disease (n = 199) with and without apathy at baseline. All participants had ∼2-year follow-up apathy scores, enabling examination of brain structure and function specifically in those with normal motivation who converted to apathy by ∼2-year follow-up. In addition, of the people with normal motivation, a subset (n = 56) had follow-up neuroimaging data, allowing for examination of the 'rate of change' in key nodes over time in those who did, and did not, convert to apathy. Healthy control (n = 54) data were also included to aid interpretation of findings. Functional connectivity between the nucleus accumbens and dorsal anterior cingulate cortex was higher in people with normal motivation who later converted to apathy compared to those who did not, whereas no structural differences were evident between these groups. In contrast, grey matter volume in these regions was reduced in the group with existing apathy. Furthermore, of those with normal motivation who had undergone longitudinal neuroimaging, converters to apathy showed a higher rate of change in grey matter volume within the nucleus accumbens. Overall, we show that changes in functional connectivity between nucleus accumbens and anterior cingulate cortex precedes apathy in people with Parkinson's disease, with conversion to apathy associated with higher rate of grey matter volume loss in nucleus accumbens, despite no baseline differences. These findings significantly add to an accumulating body of transdiagnostic evidence that apathy arises from disruption to key nodes within a network in which normal goal-directed behaviour is instantiated, and raise the possibility of identifying those at risk for developing apathy before overt motivational deficits have arisen.

Associations Between Thinner Retinal Neuronal Layers and Suboptimal Brain Structural Integrity in a Middle-Aged Cohort.

Purpose: The retina has potential as a biomarker of brain health and Alzheimer's disease (AD) because it is the only part of the central nervous system which can be easily imaged and has advantages over brain imaging technologies. Few studies have compared retinal and brain measurements in a middle-aged sample. The objective of our study was to investigate whether retinal neuronal measurements were associated with structural brain measurements in a middle-aged population-based cohort. Participants and Methods: Participants were members of the Dunedin Multidisciplinary Health and Development Study (n=1037; a longitudinal cohort followed from birth and at ages 3, 5, 7, 9, 11, 13, 15, 18, 21, 26, 32, 38, and most recently at age 45, when 94% of the living Study members participated). Retinal nerve fibre layer (RNFL) and ganglion cell-inner plexiform layer (GC-IPL) thickness were measured by optical coherence tomography (OCT). Brain age gap estimate (brainAGE), cortical surface area, cortical thickness, subcortical grey matter volumes, white matter hyperintensities, were measured by magnetic resonance imaging (MRI). Results: Participants with both MRI and OCT data were included in the analysis (RNFL n=828, female n=413 [49.9%], male n=415 [50.1%]; GC-IPL n=825, female n=413 [50.1%], male n=412 [49.9%]). Thinner retinal neuronal layers were associated with older brain age, smaller cortical surface area, thinner average cortex, smaller subcortical grey matter volumes, and increased volume of white matter hyperintensities. Conclusion: These findings provide evidence that the retinal neuronal layers reflect differences in midlife structural brain integrity consistent with increased risk for later AD, supporting the proposition that the retina may be an early biomarker of brain health.

Progressive MRI brain volume changes in ovine models of CLN5 and CLN6 neuronal ceroid lipofuscinosis.

Neuronal ceroid lipofuscinoses (Batten disease) are a group of inherited lysosomal storage disorders characterized by progressive neurodegeneration leading to motor and cognitive dysfunction, seizure activity and blindness. The disease can be caused by mutations in 1 of 13 ceroid lipofuscinosis neuronal (CLN) genes. Naturally occurring sheep models of the CLN5 and CLN6 neuronal ceroid lipofuscinoses recapitulate the clinical disease progression and post-mortem pathology of the human disease. We used longitudinal MRI to assess global and regional brain volume changes in CLN5 and CLN6 affected sheep compared to age-matched controls over 18 months. In both models, grey matter volume progressively decreased over time, while cerebrospinal fluid volume increased in affected sheep compared with controls. Total grey matter volume showed a strong positive correlation with clinical scores, while cerebrospinal fluid volume was negatively correlated with clinical scores. Cortical regions in affected animals showed significant atrophy at baseline (5 months of age) and progressively declined over the disease course. Subcortical regions were relatively spared with the exception of the caudate nucleus in CLN5 affected animals that degenerated rapidly at end-stage disease. Our results, which indicate selective vulnerability and provide a timeline of degeneration of specific brain regions in two sheep models of neuronal ceroid lipofuscinoses, will provide a clinically relevant benchmark for assessing therapeutic efficacy in subsequent trials of gene therapy for CLN5 and CLN6 disease.

Magnetic resonance imaging of breast implants: Optimizing tissue contrast.

INTRODUCTION: Patients with breast implants need to undergo regular screening MRI procedures. One of the key requirements of this screening scan is the ability to suppress one or more tissues (water, fat, or silicone) simultaneously. However, the presence of "foreign" implants within the breast biological space affects the MRI scanner's normal operating mode. Often, this requires operator's supervision to make sure the correct image contrast is achieved. METHODS: We built a phantom that represents the commonly encountered tissues (water, fat, and silicone) in breast implant imaging. The phantom was used to optimise imaging parameters and highlight common challenges encountered while imaging breast implants. We scanned the phantom on seven different MRI scanners (including 1.5T and 3T) and produced vendor-specific cheat-sheets on how to image breast implants. Ethical approval was not required for this article type. CONCLUSION: Performing a breast MRI procedure with implants in-situ can be challenging. Employing a purpose-built phantom, we provide easy-to-use cheat sheets, with examples, outlining steps that can be taken to ensure appropriate tissue suppression and image contrast in breast implant MRI. We hope these cheat-sheets will help MRI practitioners to confidently and efficiently achieve accurate image contrasts across a number of implant scenarios which will aid in improving diagnostic accuracy, treatment plans, and thus prognosis for the patient.

Functional Topography of the Neocortex Predicts Covariation in Complex Cognitive and Basic Motor Abilities.

Although higher-order cognitive and lower-order sensorimotor abilities are generally regarded as distinct and studied separately, there is evidence that they not only covary but also that this covariation increases across the lifespan. This pattern has been leveraged in clinical settings where a simple assessment of sensory or motor ability (e.g., hearing, gait speed) can forecast age-related cognitive decline and risk for dementia. However, the brain mechanisms underlying cognitive, sensory, and motor covariation are largely unknown. Here, we examined whether such covariation in midlife reflects variability in common versus distinct neocortical networks using individualized maps of functional topography derived from BOLD fMRI data collected in 769 45-year old members of a population-representative cohort. Analyses revealed that variability in basic motor but not hearing ability reflected individual differences in the functional topography of neocortical networks typically supporting cognitive ability. These patterns suggest that covariation in motor and cognitive abilities in midlife reflects convergence of function in higher-order neocortical networks and that gait speed may not be simply a measure of physical function but rather an integrative index of nervous system health.

Reproducibility and repeatability of magnetic resonance imaging in dementia.

PURPOSE: Individualised predictive models of cognitive decline require disease-monitoring markers that are repeatable. For wide-spread adoption, such markers also need to be reproducible at different locations. This study assessed the repeatability and reproducibility of MRI markers derived from a dementia protocol. METHODS: Six participants were scanned at three different sites with a 3T MRI scanner. The protocol employed: T1-weighted (T1w) imaging, resting state functional MRI (rsfMRI), arterial spin labelling (ASL), diffusion-weighted imaging (DWI), T2-weighted fluid attenuation inversion recovery (FLAIR), T2-weighted (T2w) imaging, and susceptibility weighted imaging (SWI). Participants were scanned repeatedly, up to six times over a maximum period of five years. One participant was also scanned a further three times on sequential days on one scanner. Fifteen derived metrics were computed from the seven different modalities. RESULTS: Reproducibility (coefficient of variation; CoV, across sites) was best for T1w derived grey matter, white matter and hippocampal volume (CoV < 1.5%), compared to rsfMRI and SWI derived metrics (CoV, 19% and 21%). For a given metric, long-term repeatability (CoV across time) was comparable to reproducibility, with short-term repeatability considerably better. CONCLUSIONS: Reproducibility and repeatability were assessed for a suite of markers calculated from a dementia MRI protocol. In general, structural markers were less variable than functional MRI markers. Variability over time on the same scanner was comparable to variability measured across different scanners. Overall, the results support the viability of multi-site longitudinal studies for monitoring cognitive decline.

Spatial variation of perfusion MRI reflects cognitive decline in mild cognitive impairment and early dementia.

Cerebral blood flow (CBF) measured with arterial spin labelling (ASL) magnetic resonance imaging (MRI) reflects cerebral perfusion, related to metabolism, and arterial transit time (ATT), related to vascular health. Our aim was to investigate the spatial coefficient of variation (sCoV) of CBF maps as a surrogate for ATT, in volunteers meeting criteria for subjective cognitive decline (SCD), amnestic mild cognitive impairment (MCI) and probable Alzheimer's dementia (AD). Whole-brain pseudo continuous ASL MRI was performed at 3 T in 122 participants (controls = 20, SCD = 44, MCI = 45 and AD = 13) across three sites in New Zealand. From CBF maps that included all grey matter, sCoV progressively increased across each group with increased cognitive deficit. A similar overall trend was found when examining sCoV solely in the temporal lobe. We conclude that sCoV, a simple to compute imaging metric derived from ASL MRI, is sensitive to varying degrees of cognitive changes and supports the view that vascular health contributes to cognitive decline associated with Alzheimer's disease.

Association of subcortical gray-matter volumes with life-course-persistent antisocial behavior in a population-representative longitudinal birth cohort.

Neuropsychological evidence supports the developmental taxonomy theory of antisocial behavior, suggesting that abnormal brain development distinguishes life-course-persistent from adolescence-limited antisocial behavior. Recent neuroimaging work confirmed that prospectively-measured life-course-persistent antisocial behavior is associated with differences in cortical brain structure. Whether this extends to subcortical brain structures remains uninvestigated. This study compared subcortical gray-matter volumes between 672 members of the Dunedin Study previously defined as exhibiting life-course-persistent, adolescence-limited or low-level antisocial behavior based on repeated assessments at ages 7-26 years. Gray-matter volumes of 10 subcortical structures were compared across groups. The life-course-persistent group had lower volumes of amygdala, brain stem, cerebellum, hippocampus, pallidum, thalamus, and ventral diencephalon compared to the low-antisocial group. Differences between life-course-persistent and adolescence-limited individuals were comparable in effect size to differences between life-course-persistent and low-antisocial individuals, but were not statistically significant due to less statistical power. Gray-matter volumes in adolescence-limited individuals were near the norm in this population-representative cohort and similar to volumes in low-antisocial individuals. Although this study could not establish causal links between brain volume and antisocial behavior, it constitutes new biological evidence that all people with antisocial behavior are not the same, supporting a need for greater developmental and diagnostic precision in clinical, forensic, and policy-based interventions.

International Multicenter Analysis of Brain Structure Across Clinical Stages of Parkinson's Disease.

BACKGROUND: Brain structure abnormalities throughout the course of Parkinson's disease have yet to be fully elucidated. OBJECTIVE: Using a multicenter approach and harmonized analysis methods, we aimed to shed light on Parkinson's disease stage-specific profiles of pathology, as suggested by in vivo neuroimaging. METHODS: Individual brain MRI and clinical data from 2357 Parkinson's disease patients and 1182 healthy controls were collected from 19 sources. We analyzed regional cortical thickness, cortical surface area, and subcortical volume using mixed-effects models. Patients grouped according to Hoehn and Yahr stage were compared with age- and sex-matched controls. Within the patient sample, we investigated associations with Montreal Cognitive Assessment score. RESULTS: Overall, patients showed a thinner cortex in 38 of 68 regions compared with controls (dmax  = -0.20, dmin  = -0.09). The bilateral putamen (dleft  = -0.14, dright  = -0.14) and left amygdala (d = -0.13) were smaller in patients, whereas the left thalamus was larger (d = 0.13). Analysis of staging demonstrated an initial presentation of thinner occipital, parietal, and temporal cortices, extending toward rostrally located cortical regions with increased disease severity. From stage 2 and onward, the bilateral putamen and amygdala were consistently smaller with larger differences denoting each increment. Poorer cognition was associated with widespread cortical thinning and lower volumes of core limbic structures. CONCLUSIONS: Our findings offer robust and novel imaging signatures that are generally incremental across but in certain regions specific to disease stages. Our findings highlight the importance of adequately powered multicenter collaborations. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Disparities in the pace of biological aging among midlife adults of the same chronological age have implications for future frailty risk and policy.

Some humans age faster than others. Variation in biological aging can be measured in midlife, but the implications of this variation are poorly understood. We tested associations between midlife biological aging and indicators of future frailty-risk in the Dunedin cohort of 1037 infants born the same year and followed to age 45. Participants' Pace of Aging was quantified by tracking declining function in 19 biomarkers indexing the cardiovascular, metabolic, renal, immune, dental, and pulmonary systems across ages 26, 32, 38, and 45 years. At age 45 in 2019, participants with faster Pace of Aging had more cognitive difficulties, signs of advanced brain aging, diminished sensory-motor functions, older appearance, and more pessimistic perceptions of aging. People who are aging more rapidly than same-age peers in midlife may prematurely need supports to sustain independence that are usually reserved for older adults. Chronological age does not adequately identify need for such supports.

Midlife Cardiovascular Fitness Is Reflected in the Brain's White Matter.

Disappointing results from clinical trials designed to delay structural brain decline and the accompanying increase in risk for dementia in older adults have precipitated a shift in testing promising interventions from late in life toward midlife before irreversible damage has accumulated. This shift, however, requires targeting midlife biomarkers that are associated with clinical changes manifesting only in late life. Here we explored possible links between one putative biomarker, distributed integrity of brain white matter, and two intervention targets, cardiovascular fitness and healthy lifestyle behaviors, in midlife. At age 45, fractional anisotropy (FA) derived from diffusion weighted MRI was used to estimate the microstructural integrity of distributed white matter tracts in a population-representative birth cohort. Age-45 cardiovascular fitness (VO2Max; N = 801) was estimated from heart rates obtained during submaximal exercise tests; age-45 healthy lifestyle behaviors were estimated using the Nyberg Health Index (N = 854). Ten-fold cross-validated elastic net predictive modeling revealed that estimated VO2Max was modestly associated with distributed FA. In contrast, there was no significant association between Nyberg Health Index scores and FA. Our findings suggest that cardiovascular fitness levels, but not healthy lifestyle behaviors, are associated with the distributed integrity of white matter in the brain in midlife. These patterns could help inform future clinical intervention research targeting ADRDs.

Neuropsychiatric Symptoms Are Associated with Dementia in Parkinson's Disease but Not Predictive of it.

BACKGROUND: Neuropsychiatric symptoms in Parkinson's disease (PD) may increase dementia (PDD) risk. The predictive value of these symptoms, however, has not been compared to clinical and demographic predictors of future PDD. OBJECTIVES: Determine if neuropsychiatric symptoms are useful markers of PDD risk. METHODS: 328 PD participants completed baseline neuropsychiatric and MDS-Task Force-Level II assessments. Of these, 202 non-demented individuals were followed-up over a four-years period to detect conversion to PDD; 51 developed PDD. ROC analysis tested associations between baseline neuropsychiatric symptoms and future PDD. The probability of developing PDD was also modeled as a function of neuropsychiatric inventory (NPI)-total score, PD Questionnaire (PDQ)-hallucinations, PDQ-anxiety, and contrasted to cognitive ability, age, and motor function. Leave-one-out information criterion was used to evaluate which models provided useful information when predicting future PDD. RESULTS: The PDD group experienced greater levels of neuropsychiatric symptoms compared to the non-PDD groups at baseline. Few differences were found between the PD-MCI and PD-N groups. Six neuropsychiatric measures were significantly, but weakly, associated with future PDD. The strongest was NPI-total score: AUC = 0.66 [0.57-0.75]. There was, however, no evidence it contained useful out-of-sample predictive information of future PDD (delta ELPD = 1.8 (SD 2.5)); Similar results held for PDQ-hallucinations and PDQ-anxiety. In contrast, cognitive ability (delta ELPD = 36 (SD 8)) and age (delta ELPD = 11 (SD 5)) provided useful predictive information of future PDD. CONCLUSIONS: Cognitive ability and age strongly out-performed neuropsychiatric measures as markers of developing PDD within 4 years. Therefore, neuropsychiatric symptoms do not appear to be useful markers of PDD risk.

Intravitreal gene therapy protects against retinal dysfunction and degeneration in sheep with CLN5 Batten disease.

Neuronal ceroid lipofuscinoses (NCL; Batten disease) are a group of inherited neurodegenerative diseases primarily affecting children. A common feature across most NCLs is the progressive loss of vision. We performed intravitreal injections of self-complementary AAV9 vectors packaged with either ovine CLN5 or CLN6 into one eye of 3-month-old CLN5-/- or CLN6-/- animals, respectively. Electroretinography (ERG) was performed every month following treatment, and retinal histology was assessed post-mortem in the treated compared to untreated eye. In CLN5-/- animals, ERG amplitudes were normalised in the treated eye whilst the untreated eye declined in a similar manner to CLN5 affected controls. In CLN6-/- animals, ERG amplitudes in both eyes declined over time although the treated eye showed a slower decline. Post-mortem examination revealed significant attenuation of retinal atrophy and lysosomal storage body accumulation in the treated eye compared with the untreated eye in CLN5-/- animals. This proof-of-concept study provides the first observation of efficacious intravitreal gene therapy in a large animal model of NCL. In particular, the single administration of AAV9-mediated intravitreal gene therapy can successfully ameliorate retinal deficits in CLN5-/- sheep. Combining ocular gene therapy with brain-directed therapy presents a promising treatment strategy to be used in future sheep trials aiming to halt neurological and retinal disease in CLN5 Batten disease.