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.

Lower volume, more impairment: reduced cholinergic basal forebrain grey matter density is associated with impaired cognition in Parkinson disease.

OBJECTIVE: A major contributor to dementia in Parkinson disease (PD) is degeneration of the cholinergic basal forebrain. This study determined whether cholinergic nucleus 4 (Ch4) density is associated with cognition in early and more advanced PD. METHODS: We analysed brain MRIs and neuropsychological test scores for 228 newly diagnosed PD participants from the Parkinson's Progression Markers Initiative (PPMI), 101 healthy controls from the PPMI and 125 more advanced PD patients from a local retrospective cohort. Cholinergic basal forebrain nuclei densities were determined by applying probabilistic maps to MPRAGE T1 sequences processed using voxel-based morphometry methods. Relationships between grey matter densities and cognitive scores were analysed using correlations and linear regression models. RESULTS: In more advanced PD, greater Ch4 density was associated with Montreal Cognitive Assessment (MoCA) score (ß=14.2; 95% CI=1.5 to 27.0; p=0.03), attention domain z-score (ß=3.2; 95% CI=0.8 to 5.5; p=0.008) and visuospatial domain z-score (ß=7.9; 95% CI=2.0 to 13.8; p=0.009). In the PPMI PD cohort, higher Ch4 was associated with higher scores on MoCA (ß=9.2; 95% CI=1.9 to 16.5; p=0.01), Judgement of Line Orientation (ß=20.4; 95% CI=13.8 to 27.0; p<0.001), Letter Number Sequencing (ß=16.5; 95% CI=9.5 to 23.4; p<0.001) and Symbol Digit Modalities Test (ß=41.8; 95% CI=18.7 to 65.0; p<0.001). These same relationships were observed in 97 PPMI PD participants at 4 years. There were no significant associations between Ch4 density and cognitive outcomes in healthy controls. CONCLUSION: In de novo and more advanced PD, lower Ch4 density is associated with impaired global cognition, attention and visuospatial function.

Perceptions of competence: age moderates views of healthy aging and Alzheimer's disease.

UNLABELLED: BACKGROUND/STUDY CONTEXT: Older adults have more complex and differentiated views of aging than do younger adults, but less is known about age-related perceptions of Alzheimer's disease. This study investigated age-related perceptions of competence of an older adult labeled as "in good health" (healthy) or "has Alzheimer's disease" (AD), using a person-perception paradigm. It was predicted that older adults would provide more differentiated assessments of the two targets than would younger adults. METHODS: Younger (n=86; 18-36 years) and older (n=66; 61-95 years) adults rated activities of daily living (ADL), instrumental activities of daily living (IADL), and memory abilities of a female target aged 75 years, described as healthy or with AD. Data on anxiety about aging, knowledge of and experience with aging and AD, knowledge of memory aging, and positive and negative biases toward aging and AD were also collected. RESULTS: Older adults perceived the healthy target as more capable of cognitively effortful activities (e.g., managing finances) and as possessing better memory abilities than the AD target. As predicted, these differences were greater than differences between targets perceived by younger adults. The interaction effect remained significant after statistically controlling for relevant variables, including education and gender. Additionally, exploratory analyses revealed that older adults held less positively biased views of AD than younger adults, but negatively biased views were equivalent between age groups. CONCLUSION: The results demonstrate that mere labels of "healthy" and "Alzheimer's disease" produce significant and subtle age differences in perceived competencies of older adults, and that biases towards AD vary by age group and valence. Our findings extend the person-perception paradigm to an integrative analysis of aging and AD, are consistent with models of adult development, and complement current research and theory on stereotypes of aging. Future directions for research on perceptions of aging are suggested.

The mother as hunter: significant reduction in foraging costs through enhancements of predation in maternal rats.

In previous laboratory investigations, we have identified enhanced cognition and reduced stress in parous rats, which are likely adaptations in mothers needing to efficiently exploit resources to maintain, protect and provision their immature offspring. Here, in a series of seven behavioral tests on rats, we examined a natural interface between cognition and resource gathering: predation. Experiment 1 compared predatory behavior (toward crickets) in age-matched nulliparous mothers (NULLs) and postpartum lactating mothers (LACTs), revealing a highly significant enhancement of predation in LACT females (mean = -65s in LACTs, vs. -270s in NULLs). Experiment 2 examined the possibility that LACTs, given their increased metabolic rate, were hungrier, and thus more motivated to hunt; doubling the length of time of food deprivation in NULLs did not decrease their predatory latencies. Experiments 3-5, which examined sensory regulation of the effect, indicated that olfaction (anosmia), audition (blockade with white noise), and somatosensation (trimming the vibrissae) appear to play little role in the behavioral enhancement observed in the LACTs; Experiment 6 examined the possibility that visual augmentations may facilitate the improvements in predation; testing LACTs in a 0-lux environment eliminated the behavioral advantage (increasing their latencies from -65s to -212s), which suggests that temporary augmentation to the visual system may be important, and with hormone-neural alterations therein a likely candidate for further study. In contrast, testing NULLS in the 0-lux environment had the opposite effect, reducing their latency to catch the cricket (from -270s to -200s). Finally, Experiment 7 examined the development of predatory behavior in Early-pregnant (PREG), Mid-PREG, and Late-PREG females. Here, we observed a significant enhancement of predation in Mid-PREG and Late-PREG females--at a time when maternity-associated bodily changes would be expected to diminish predation ability--relative to NULLs. Therefore, as with the increasing reports of enhancements to the maternal brain, it is apparent that meaningful behavioral adaptations occur that likewise promote the survival of the mother and her infants at a crucial stage of their lives.

Cholinergic nucleus 4 grey matter density is associated with apathy in Parkinson's disease.

Objective: The generation and maintenance of goal-directed behavior is subserved by multiple brain regions that receive cholinergic inputs from the cholinergic nucleus 4 (Ch4). It is unknown if Ch4 degeneration contributes to apathy in Parkinson's disease (PD). Method: We analyzed data from 106 pre-surgical patients with PD who had brain MRIs and completed the Frontal Systems Behavior Scales (FrSBe). Eighty-eight patients also completed the Beck Depression Inventory-2nd Edition. Cholinergic basal forebrain grey matter densities (GMD) were measured by applying probabilistic maps to T1 MPRAGE sequences processed using voxel-based morphometry methods. We used linear and hierarchical regression modelling to examine the association between Ch4 GMD and the FrSBe Apathy subscale scores. We used similar methods to assess the specificity of this association and potential associations between Ch4 target regions and apathy. Results: Ch4 GMD (p = .021) and Ch123 GMD (p = .032) were significantly associated with Apathy subscale scores on univariate analysis. Ch4 GMD, but not Ch123 GMD, remained significantly associated with apathy when adjusting for age, sex, levodopa equivalent doses, and disease duration. Centromedial amygdala GMD, which receives cholinergic inputs from Ch4, was also associated with apathy. Ch4 GMD was not associated with depression or disinhibition, nor was it associated with executive dysfunction when adjusting for clinical and demographic variables. Conclusions: Ch4 GMD is specifically associated with apathy in PD. Ch4 degeneration results in cholinergic denervation of multiple cortical and limbic regions, which may contribute to the cognitive and emotional-affective processing deficits that underlie the behavioral symptoms of apathy.

Empowering her guardians to nurture our Ocean's future.

Coastal Indigenous and Traditional communities are starting to see changes to their lives from climate change, whether this is from species range changes or displacement from land changes. For many of these communities, the ability to adequately adapt to these changes is limited by the governance structures they are required to live within, which differ from their customary practices and culture. In November 2019, a group of Indigenous and Traditional Peoples, attended the Future Seas 2030 workshop and discussed the consequences of climate change, the biggest barriers for their communities, and barriers for using traditional knowledge in order to contribute towards a more sustainable future that in the end will benefit all of earth's people. The aim of this workshop was to highlight and give a voice to the various backgrounds and real-life situations impacting on some of the world's Indigenous and Traditional communities whose connection with the oceans and coasts have been disrupted. This paper presents these issues of oppression, colonisation, language and agency, making it difficult for these groups to contribute to the current management of oceans and coasts, and asks scientists and practitioners in this space to be allies and enable the needed shift to earth's guardians taking a leading role in nurturing her for our future.

Cholinergic nucleus 4 atrophy and gait impairment in Parkinson's disease.

BACKGROUND: There is evidence that cortical cholinergic denervation contributes to gait and balance impairment in Parkinson's Disease (PD), especially reduced gait speed. OBJECTIVES: The objective of this study was to determine the relationship between cholinergic basal forebrain gray matter density (GMD) and gait in PD patients. METHODS: We investigated 66 PD patients who underwent a pre-surgical evaluation for a neurosurgical procedure to treat motor symptoms of PD. As part of this evaluation patients had a brain MRI and formal gait assessments. By applying probabilistic maps of the cholinergic basal forebrain to voxel-based morphometry of brain MRI, we calculated gray matter density (GMD) for cholinergic nucleus 4 (Ch4), cholinergic nucleus 1, 2, and 3 (Ch123), and the entire cortex. RESULTS: Reduced Ch4 GMD was associated with reduced Fast Walking Speed in the "on" medication state (FWSON, p = 0.004). Bilateral cortical GMD was also associated with FWSON (p = 0.009), but Ch123 GMD was not (p = 0.1). Bilateral cortical GMD was not associated with FWSON after adjusting for Ch4 GMD (p = 0.44). While Ch4 GMD was not associated with improvement in Timed Up and Go (TUG) or Cognitive TUG in the "on" medication state, reduced Ch4 GMD was associated with greater percent worsening based on dual tasks (p = 0.021). CONCLUSIONS: Reduced Ch4 GMD is associated with slower gait speed in PD and greater percent worsening in TUG during dual tasks in patients with PD. These findings have implications for planning of future clinical trials investigating cholinergic therapies to improve gait impairment in PD.

Olfaction, cholinergic basal forebrain degeneration, and cognition in early Parkinson disease.

INTRODUCTION: Impaired olfaction and reduced cholinergic nucleus 4 (Ch4) volume both predict greater cognitive decline in Parkinson's disease (PD). We examined the relationship between olfaction, longitudinal change in cholinergic basal forebrain nuclei and their target regions, and cognition in early PD. METHODS: We analyzed a cohort of 97 PD participants from the Parkinson's Progression Markers Initiative with brain MRIs at baseline, 1 year, 2 years, and 4 years. Using probabilistic maps, regional grey matter density (GMD) was calculated for Ch4, cholinergic nuclei 1, 2, and 3 (Ch123), and their target regions. RESULTS: Baseline University of Pennsylvania Smell Identification Test score correlated with change in GMD of all regions of interest (all p < 0.05). Rate of change of Ch4 GMD was correlated with rate of change of Ch123 (p = 0.034), cortex (p = 0.001), and amygdala GMD (p < 0.001), but not hippocampus GMD (p = 0.38). Rate of change of Ch123 GMD was correlated with rate of change of cortex (p = 0.001) and hippocampus (p < 0.001), but not amygdala GMD (p = 0.133). In a linear regression model including change in GMD of all regions of interest and age as predictors, change in cortex GMD (߈slope= 38.2; 95 % CI: [0.47, 75.9]) and change in hippocampus GMD (߈slope= 24.8; 95 % CI: [0.80, 48.8]) were significant predictors of Montreal Cognitive Assessment score change over time. CONCLUSION: Impaired olfaction is associated with degeneration of the cholinergic basal forebrain and bilateral cortex, amygdala, and hippocampus in PD. The relationship between impaired olfaction and cognitive decline may be mediated by greater atrophy of the cortex and hippocampus.

Cytoarchitectonic Mapping of MRI Detects Rapid Changes in Alzheimer's Disease.

The clinical and pathological progression of Alzheimer's disease often proceeds rapidly, but little is understood about its structural characteristics over short intervals. This study evaluated the short temporal characteristics of the brain structure in Alzheimer's disease through the application of cytoarchitectonic probabilistic brain mapping to measurements of gray matter density, a technique which may provide advantages over standard volumetric MRI techniques. Gray matter density was calculated using voxel-based morphometry of T1-weighted MRI obtained from Alzheimer's disease patients and healthy controls evaluated at intervals of 0.5, 1.5, 3.5, 6.5, 9.5, 12, 18, and 24 months by the MIRIAD study. The Alzheimer's disease patients had 19.1% less gray matter at 1st MRI, and this declined 81.6% faster than in healthy controls. Atrophy in the hippocampus, amygdala, and basal forebrain distinguished the Alzheimer's disease patients. Notably, the CA2 of the hippocampus was found to have atrophied significantly within 1 month. Gray matter density measurements were reliable, with intraclass correlation coefficients exceeding 0.8. Comparative atrophy in the Alzheimer's disease group agreed with manual tracing MRI studies of Alzheimer's disease while identifying atrophy on a shorter time scale than has previously been reported. Cytoarchitectonic mapping of gray matter density is reliable and sensitive to small-scale neurodegeneration, indicating its use in the future study of Alzheimer's disease.

Brain MRI Reveals Ascending Atrophy in Parkinson's Disease Across Severity.

Models which assess the progression of Lewy pathology in Parkinson's disease have proposed ascending spread in a caudal-rostral pattern. In-vivo human evidence for this theory is limited, in part because there are no biomarkers that allow for direct assessment of Lewy pathology. Here, we measured neurodegeneration via MRI, an outcome which may serve as a proxy for a more direct assessment of ascending models using a combination of (1) MRI-based measures of gray matter density and (2) regions of interest (ROIs) corresponding to cortical and subcortical loci implicated in past MRI and stereological studies of Parkinson's disease. Gray matter density was measured using brain MRI voxel-based morphometry from three cohorts: (1) early Parkinson's disease, (2) more advanced Parkinson's disease and (3) healthy controls. Early Parkinson's disease patients (N = 228, mean age = 61.9 years, mean disease duration = 0.6 years) were newly diagnosed by the Parkinson's Progression Markers Initiative (PPMI). Advanced Parkinson's disease patients (N = 136, mean age = 63.5 years, mean disease duration = 8.0 years) were collected retrospectively from a local cohort undergoing evaluation for functional neurosurgery. Control subjects (N = 103, mean age = 60.2 years) were from PPMI. Comparative analyses focused on gray matter regions ranging from deep gray subcortical structures to the neocortex. ROIs were defined with existing probabilistic cytoarchitectonic brain maps. For subcortical regions of the basal forebrain, amygdala, and entorhinal cortex, advanced Parkinson's disease patients had significantly lower gray matter density when compared to both early Parkinson's disease and healthy controls. No differences were seen in neocortical regions that are "higher" in any proposed ascending pattern. Across early and advanced Parkinson's disease, gray matter density from nearly all subcortical regions significantly decreased with disease duration; no neocortical regions showed this effect. These results demonstrate that atrophy in advanced Parkinson's patients compared to early patients and healthy controls is largely confined to subcortical gray matter structures. The degree of atrophy in subcortical brain regions was linked to overall disease duration, suggesting an organized pattern of atrophy across severity.

Baseline symptoms and basal forebrain volume predict future psychosis in early Parkinson disease.

OBJECTIVE: Determining baseline predictors of future psychosis in Parkinson disease (PD) may identify those at risk for more rapidly progressive disease, i.e., a more malignant PD subtype. METHODS: This cohort study evaluated 423 patients with newly diagnosed PD collected as part of the Parkinson's Progression Markers Initiative. Psychotic symptoms were assessed with the Movement Disorders Society-Unified Parkinson Disease Rating Scale item 1.2, which assesses hallucinations and psychosis over the past week. At baseline, participants completed the Scales for Outcomes in Parkinson's Disease-Autonomic, the REM Sleep Behavior Disorder (RBD) Screening Questionnaire, and the Epworth Sleepiness Scale. Cholinergic nucleus 4 (Ch4) density was calculated for 228 participants with PD and 101 healthy controls. RESULTS: Multivariate logistic regression adjusted for age and sex found that greater autonomic symptoms (p = 0.002), RBD (p = 0.021), and excessive daytime sleepiness (EDS) (p = 0.003) at baseline were associated with increased risk of reporting psychotic symptoms on ≥2 occasions. Having 2 or 3 of these baseline symptoms was associated with lower Ch4 density (p = 0.007). In a logistic regression model adjusted for age and sex, higher Ch4 gray matter density was associated with lower risk of reporting psychotic symptoms on ≥2 occasions (odds ratio 0.96 [for an increase in density of 1 unit], p = 0.03). CONCLUSIONS: This study confirms that RBD, EDS, and greater autonomic symptom burden are associated with greater risk of future psychotic symptoms in PD. Reduced Ch4 density at baseline is associated with future psychotic symptoms and a greater burden of RBD, EDS, and autonomic symptoms.

Should We Use Preoperative Epoetin-α in the Mildly Anemic Patient Undergoing Simultaneous Total Knee Arthroplasty?

Simultaneous knee arthroplasty is associated with significant blood loss. To prevent transfusion, three preoperative doses of epoetin-α were offered to mildly anemic simultaneous knee arthroplasty patients. A retrospective review, using ICD-9 codes, identified twenty patients from 2007-2009. Epoetin-α increased hemoglobin levels preoperatively (12.6 to 13.9, p<0.01). Twenty patients who did not receive epoetin-α were matched to study patients. Study patients were transfused less (55% vs 95%, p=0.012) and had similar inpatient length of stay. The average blood loss without transfusion was 4.6g/dL. The mildly anemic patient is at high-risk for packed red cell transfusion during simultaneous knee arthroplasty. Three preoperative doses of epoetin-α in the mildly anemic patient decreased total transfusions; however, it did not affect inpatient length of stay.

The Use of Preoperative Epoetin-α in Revision Hip Arthroplasty.

PURPOSE: To evaluate the efficacy of preoperative epoetin-α on the revision hip arthroplasty patient. We hypothesized that epoetin-α will reduce blood transfusion. A pertinent review of the literature is provided. METHODS: Forty-six patients were retrospectively reviewed. Sixteen patients received epoetin-α. Patients were case matched by age, preoperative hemoglobin, surgery, gender, and BMI. The clinical triggers for blood transfusion during or after the procedure were determined based on peri- and postoperative hemoglobin levels, ASA score, and/or clinical symptoms consistent with anemia. Blood salvage was not used. RESULTS: Blood transfusion and length of stay were decreased in the epoetin-α group. Hemoglobin in the intervention group increased from 12.0 to 14.5, preoperatively. Patients who received epoetin-α were 0.78 (RR=0.225) times as likely to receive a transfusion. Number Needed to Treat (NNT) to avoid one allogeneic transfusion was 1.84. Age, Gender, BMI, ASA, total and hidden blood loss, preoperative Iron supplements, preop Hct, preop PLT, PT, PTT, and INR were similar. One (6.0%) patient developed an uncomplicated deep venous thrombosis in the intervention group. CONCLUSIONS: The mildly anemic revision hip arthroplasty patient is at increased risk for transfusion. Epoetin-α increased preoperative hemoglobin counts and reduced transfusions in this study; it also decreased patient length of hospital stay likely allowing for an earlier readiness to resume normal activities and/or meet short-term milestones. A randomized study to evaluate the direct and indirect costs of such a treatment methodology in the mildly anemic revision patient may be warranted.

The Use of Epoetin-α in Revision Knee Arthroplasty.

Introduction. To evaluate the efficacy of epoetin-α prior to revision total knee arthroplasty, we hypothesized that epoetin-α will reduce blood transfusion. Methods. Eighty-one patients were compared in this retrospective review; twenty-eight patients received our dosing regimen. All patients were mildly anemic. Epoetin-α to control (1 : 2) patient matching occurred so that one of two attending surgeons, gender, BMI, complexity of surgery, ASA score, and age were similar between groups. The clinical triggers for blood transfusion during or after the procedure were determined based on peri- and postoperative hemoglobin levels, ASA score, and/or clinical symptoms consistent with anemia. Blood salvage was not used. Results. Blood transfusion and length of stay were lower in the study group. None of the patients who received epoetin-α underwent transfusion. Hemoglobin increased from 11.97 to 13.8, preoperatively. Hemoglobin at day of surgery and time of discharge were higher. Gender, BMI, ASA score, total and hidden blood losses, calculated blood loss, preop PLT, PT, PTT, and INR were similar between groups. One Epogen patient had an uncomplicated DVT (3.6%). Conclusions. Epoetin-α may have a role in the mildly anemic revision knee patient. It may also decrease patient length of stay allowing for earlier readiness to resume normal activities and/or meet short-term milestones. A randomized study to evaluate the direct and indirect costs of such a treatment methodology in the mildly anemic revision patient may be warranted.