Objective Neuroimaging and other biomarker assays suggest that the pathological processes of Alzheimer’s disease (AD) initiate years prior to clinical dementia onset. However some 30%–50% of older individuals that harbor AD pathology do not become symptomatic in their lifetime. It is hypothesized that such individuals exhibit cognitive resilience that protects against AD dementia. We hypothesized that in cases with AD pathology structural changes in dendritic spines would distinguish individuals that had or did not have clinical dementia. Methods We compared dendritic spines within layers II and III pyramidal neuron dendrites in Brodmann Area 46 dorsolateral prefrontal cortex using the Golgi-Cox technique in 12 age-matched pathology-free controls, 8 controls with AD pathology (CAD), and 21 AD cases. We used highly optimized methods to trace impregnated dendrites from brightfield microscopy images which enabled accurate three-dimensional digital reconstruction of dendritic structure for morphologic analyses. Results Spine density was similar among control and CAD cases but reduced significantly in AD. Thin and mushroom spines were reduced significantly in AD compared to CAD brains, whereas stubby spine density was decreased significantly in CAD and AD compared to controls. Increased spine extent distinguished CAD cases from controls and AD. Linear regression analysis of all cases indicated that spine density was not associated with neuritic plaque score but did display negative correlation with Braak staging. Interpretation These observations provide cellular evidence to support the hypothesis that dendritic spine plasticity is a mechanism of cognitive resilience that protects older individuals with AD pathology from developing dementia.

Background Depression is common in Parkinson’s disease (PD) and adversely affects quality of life. Both unilateral and bilateral subthalamic (STN) deep brain stimulation (DBS) effectively treat the motor symptoms of PD, but questions remain regarding the impact of unilateral STN DBS on non-motor symptoms, such as depression. Methods We report changes in depression, as measured by the Hamilton Depression Rating Scale (HAMD-17), in 50 consecutive PD patients who underwent unilateral STN DBS. Participants were also evaluated with UPDRS part III, Parkinson’s Disease Questionnaire-39, and Pittsburgh Sleep Quality Index. The primary outcome was change in HAMD-17 at 6 months versus pre-operative baseline, using repeated measures analysis of variance (ANOVA). Secondary outcomes included the change in HAMD-17 at 3, 12, 18, and 24 months post-operatively and correlations amongst outcome variables using Pearson correlation coefficients. As a control, we also evaluated changes in HAMD-17 in 25 advanced PD patients who did not undergo DBS. Results Participants with unilateral STN DBS experienced significant improvement in depression 6 months post-operatively (4.94±4.02) compared to preoperative baseline (7.90±4.44) (mean±SD) (p=<0.0001). HAMD-17 scores did not correlate with UPDRS part III at any time-point. Interestingly, the HAMD-17 was significantly correlated with sleep quality and quality of life at baseline, 3 months, and 6 months post-operatively. Participants without DBS experienced no significant change in HAMD-17 over the same interval. Conclusion Unilateral STN DBS improves depression 6 months post-operatively in patients with PD. Improvement in depression is maintained over time and correlates with improvement in sleep quality and quality of life.

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