Medicare expenditures among spouses of persons with dementia.

BACKGROUND: Spouses of persons living with dementia face intense strains on their well-being compared with similarly aged adults and spouses of partners with no dementia. This strain can impact spouses' health and healthcare needs, and therefore affect their healthcare utilization and expenditures. METHODS: Using data from the Health and Retirement Study linked with Medicare claims, we matched dyads of spouses and their partners with dementia (SPWD) to a comparison group of similar spouses and their partners with no dementia (SPWND). We then examined Medicare expenditures for spouses in the 5 years following their partner's dementia onset month using a two-part regression model. RESULTS: SPWD cumulative total Medicare expenditures were, on average, $60,043 in the 5 years post dementia onset, compared to $56,068 for SPWND. This difference ($3974, 95% CI = [-$3,199; $11,477]) was not significant. However, there were significant differences in the 5th year's total expenditures (+$2,748 [$321; $5,447]), driven by inpatient expenditures ($1,562 [$22; $3,277]). CONCLUSIONS: Despite the differences in partner's dementia status, we found no significant difference in the 5-year cumulative Medicare expenditures between SPWD and SPWND. Compared to previous studies, we likely captured an earlier stage of dementia more consistently for a broader population which may be less straining on spouses. Further research should examine patterns of expenditures in later years and around critical timepoints in caregiving, such as partner transitions to formal long-term care settings and death, to better understand healthcare expenditures for spouses of persons living with dementia.

Assessing the Influence of Redlining on Intergenerational Wealth and Body Mass Index Through a Quasi-experimental Framework.

BACKGROUND: Higher levels of body mass index (BMI), particularly for those who have obesity defined as class II and III, are correlated with excess risk of all-cause mortality in the USA, and these risks disproportionately affects marginalized communities impacted by systemic racism. Redlining, a form of structural racism, is a practice by which federal agencies and banks disincentivized mortgage investments in predominantly racialized minority neighborhoods, contributing to residential segregation. The extent to which redlining contributes to current-day wealth and health inequities, including obesity, through wealth pathways or limited access to health-promoting resources, remains unclear. Our quasi-experimental study aimed to investigate the generational impacts of redlining on wealth and body mass index (BMI) outcomes. METHODS: We leveraged the Panel Study of Income Dynamics (PSID) and Home Owners' Loan Corporation (HOLC) maps to implement a geographical regression discontinuity design, where treatment assignment is randomly based on the boundary location of PSID grandparents in yellowlined vs. redlined areas and used outcome measures of wealth and mean BMI of grandchildren. To estimate our effects, we used a continuity-based approach and applied data-driven procedures to identify the most appropriate bandwidths for a valid estimation and inference. RESULTS: In our fully adjusted model, grandchildren with grandparents living in redlined areas had lower average household wealth (ß = - $35,419; 95% CIrbc - $37,423, - $7615) and a notably elevated mean BMI (ß = 7.47; 95% CIrbc - 4.00, 16.60), when compared to grandchildren whose grandparents resided in yellowlined regions. CONCLUSION: Our research supports the idea that redlining, a historical policy rooted in structural racism, is a key factor contributing to disparities in wealth accumulation and, conceivably, body mass index across racial groups.

Caregiving for dementia: trends pre-post onset and predictive factors of family caregiving (2002-2018).

Persons living with Alzheimer's and other related forms of dementia rely heavily on care from family and friends for assistance with daily activities ("family care"), but little is known about care transitions over time. We analyzed data from the Health and Retirement Study to describe caregiving patterns, from 2 years before dementia onset and up to 6 years after. Using sociodemographic data from the interview prior to dementia onset, we determined if there are significant factors that predict receipt of family care at dementia onset. We found that one-third (33%) of people living with dementia were receiving help with daily activities 2 years prior to their first positive dementia screen and this increased to 60% during the first positive screen. Nearly all of those receiving assistance received family care. We found multiple significant predictors of receiving family care at onset, including race, education, access to private health insurance, number of activities of daily living that were difficult, number of chronic conditions, and already receiving help. This demonstrates potential gaps in dementia care, and which subpopulations may benefit most from targeted interventions for household members who do not have adequate caregiving resources or programs that provide additional formal care.

Economic impact on local businesses of road safety improvements in Seattle: implications for Vision Zero projects.

BACKGROUND: Local transportation agencies implementing Vision Zero road safety improvement projects often face opposition from business owners concerned about the potential negative impact on their sales. Few studies have documented the economic impact of these projects. METHODS: We examined baseline and up to 3 years of postimprovement taxable sales data for retail, food and service-based businesses adjacent to seven road safety projects begun between 2006 and 2014 in Seattle. We used hierarchical linear models to test whether the change in annual taxable sales differed between the 7 intervention sites and 18 nearby matched comparison sites that had no road safety improvements within the study time frame. RESULTS: Average annual taxable sales at baseline were comparable at the 7 intervention sites (US$44.7 million) and the 18 comparison sites (US$56.8 million). Regression analysis suggests that each additional year following baseline was associated with US$1.20 million more in taxable sales among intervention sites and US$1.14 million more among comparison sites. This difference is not statistically significant (p=0.64). Sensitivity analyses including a random slope, using a generalised linear model and an analysis of variance did not change conclusions. DISCUSSION: Results suggest that road safety improvement projects such as those in Vision Zero plans are not associated with adverse economic impacts on adjacent businesses. The absence of negative economic impacts associated with pedestrian and bicycle road safety projects should reassure local business owners and may encourage them to work with transportation agencies to implement Vision Zero road safety projects designed to eliminate traffic-related injuries.

Cerebellar functional connectivity change is associated with motor and neuropsychological function in early stage drug-naïve patients with Parkinson's disease.

Introduction: Parkinson's Disease (PD) is a progressive neurodegenerative disorder affecting both motor and cognitive function. Previous neuroimaging studies have reported altered functional connectivity (FC) in distributed functional networks. However, most neuroimaging studies focused on patients at an advanced stage and with antiparkinsonian medication. This study aims to conduct a cross-sectional study on cerebellar FC changes in early-stage drug-naïve PD patients and its association with motor and cognitive function. Methods: Twenty-nine early-stage drug-naïve PD patients and 20 healthy controls (HCs) with resting-state fMRI data and motor UPDRS and neuropsychological cognitive data were extracted from the Parkinson's Progression Markers Initiative (PPMI) archives. We used seed-based resting-state fMRI (rs-fMRI) FC analysis and the cerebellar seeds were defined based on the hierarchical parcellation of the cerebellum (AAL atlas) and its topological function mapping (motor cerebellum and non-motor cerebellum). Results: The early stage drug-naïve PD patients had significant differences in cerebellar FC when compared with HCs. Our findings include: (1) Increased intra-cerebellar FC within motor cerebellum, (2) increase motor cerebellar FC in inferior temporal gyrus and lateral occipital gyrus within ventral visual pathway and decreased motor-cerebellar FC in cuneus and dorsal posterior precuneus within dorsal visual pathway, (3) increased non-motor cerebellar FC in attention, language, and visual cortical networks, (4) increased vermal FC in somatomotor cortical network, and (5) decreased non-motor and vermal FC within brainstem, thalamus and hippocampus. Enhanced FC within motor cerebellum is positively associated with the MDS-UPDRS motor score and enhanced non-motor FC and vermal FC is negatively associated with cognitive function test scores of SDM and SFT. Conclusion: These findings provide support for the involvement of cerebellum at an early stage and prior to clinical presentation of non-motor features of the disease in PD patients.

Cost of Implementing an Evidence-Based Intervention to Support Safer Use of Antipsychotics in Youth.

To estimate the cost of implementing a clinical program designed to support safer use of antipsychotics in children and adolescents (youth) age 3-17 years at the time of initiating an antipsychotic medication. We calculate the costs of implementing a psychiatric consultation and navigation program for youth prescribed antipsychotic medications across 4 health systems, which included an electronic health record (EHR) decision support tool, consultation with a child and adolescent psychiatrist, and up to 6 months of behavioral health care navigation, as well as telemental health for patients (n = 348). Cost data were collected for both start-up and ongoing intervention phases and are estimated over a 1-year period. Data sources included study records and time-in-motion reports, analyzed from a health system perspective. Costs included both labor and nonlabor costs (2019 US dollars). The average total start-up and ongoing costs per health system were $34,007 and $185,174, respectively. The average total cost per patient was $2,128. The highest average ongoing labor cost components were telemental health ($901 per patient), followed by child and adolescent psychiatrist consultation ($659), and the lowest cost component was primary care/behavioral health provider time to review/respond to the EHR decision support tool and case consultation ($24). For health systems considering programs to promote safer and targeted use of antipsychotics among youth, this study provides estimates of the full start-up and ongoing costs of an EHR decision support tool, psychiatric consultation service, and psychotherapeutic services for patients and families.Trial registration: Clinicaltrials.gov, NCT03448575.

Beyond the biomedical, towards the agentic: A paradigm shift for population health science.

Life expectancy in the United States is decreasing. Health disparities are widening. Growing evidence for and integration of social and structural determinants into theory and practice has not yet improved outcomes. The COVID-19 pandemic reinforced the fact. In this paper, we argue that the biomedical model and its underlying scientific paradigm of causal determinism, which currently dominate population health, cannot meet population health needs. While criticism of the biomedical model is not new, this paper advances the field by going beyond criticism to recognize the need for a paradigm shift. In the first half of the paper, we present a critical analysis of the biomedical model and the paradigm of causal determinism. In the second half, we outline the agentic paradigm and present a structural model of health based on generalizable, group-level processes. We use the experience of the COVID-19 pandemic to illustrate the practical applications of our model. It will be important for future work to investigate the empirical and pragmatic applications of our structural model of population health.

Medicaid Integrated Purchasing for Physical and Behavioral Health: Early Adopters' Perceptions of Payment Reform Implementation in Washington State.

The Centers for Medicare and Medicaid Innovation (CMMI) gave rise to the State Innovation Models (SIMs). Medicaid Integrated Purchasing for Physical and Behavioral Health, referred to as Payment Model 1 (PM1), was a core payment redesign area of the Washington State SIM project under which our research team was contracted to provide an evaluation. In doing so, we leveraged an open systems conceptual model to assess qualitatively Early Adopter stakeholders' perceived effects of implementation. Between 2017 and 2019, we conducted three rounds of interviews, examining themes of care coordination, common facilitators and barriers to integration, and potential concerns for sustaining the initiative into the future. Further, we noted the initiative's complexity may require the establishment of enduring partnerships, secure funding sources, and committed regional leadership to ensure longer-term success.

A sequential, multiple assignment randomized trial comparing web-based education to mobile video interpreter access for improving provider interpreter use in primary care clinics: the mVOCAL hybrid type 3 study protocol.

BACKGROUND: Individuals who use a language other than English for medical care are at risk for disparities related to healthcare safety, patient-centered care, and quality. Professional interpreter use decreases these disparities but remains underutilized, despite widespread access and legal mandates. In this study, we compare two discrete implementation strategies for improving interpreter use: (1) enhanced education targeting intrapersonal barriers to use delivered in a scalable format (interactive web-based educational modules) and (2) a strategy targeting system barriers to use in which mobile video interpreting is enabled on providers' own mobile devices. METHODS: We will conduct a type 3 hybrid implementation-effectiveness study in 3-5 primary care organizations, using a sequential multiple assignment randomized trial (SMART) design. Our primary implementation outcome is interpreter use, calculated by matching clinic visits to interpreter invoices. Our secondary effectiveness outcome is patient comprehension, determined by comparing patient-reported to provider-documented visit diagnosis. Enrolled providers (n = 55) will be randomized to mobile video interpreting or educational modules, plus standard interpreter access. After 9 months, providers with high interpreter use will continue as assigned; those with lower use will be randomized to continue as before or add the alternative strategy. After another 9 months, both strategies will be available to enrolled providers for 9 more months. Providers will complete 2 surveys (beginning and end) and 3 in-depth interviews (beginning, middle, and end) to understand barriers to interpreter use, based on the Theoretical Domains Framework. Patients who use a language other than English will be surveyed (n = 648) and interviewed (n = 75) following visits with enrolled providers to understand their experiences with communication. Visits will be video recorded (n = 100) to assess fidelity to assigned strategies. We will explore strategy mechanism activation to refine causal pathway models using a quantitative plus qualitative approach. We will also determine the incremental cost-effectiveness of each implementation strategy from a healthcare organization perspective, using administrative and provider survey data. DISCUSSION: Determining how these two scalable strategies, alone and in sequence, perform for improving interpreter use, the mechanisms by which they do so, and at what cost, will provide critical insights for addressing a persistent cause of healthcare disparities. TRIAL REGISTRATION: NCT05591586.

Trial of Globus Pallidus Focused Ultrasound Ablation in Parkinson's Disease.

BACKGROUND: Unilateral focused ultrasound ablation of the internal segment of globus pallidus has reduced motor symptoms of Parkinson's disease in open-label studies. METHODS: We randomly assigned, in a 3:1 ratio, patients with Parkinson's disease and dyskinesias or motor fluctuations and motor impairment in the off-medication state to undergo either focused ultrasound ablation opposite the most symptomatic side of the body or a sham procedure. The primary outcome was a response at 3 months, defined as a decrease of at least 3 points from baseline either in the score on the Movement Disorders Society-Unified Parkinson's Disease Rating Scale, part III (MDS-UPDRS III), for the treated side in the off-medication state or in the score on the Unified Dyskinesia Rating Scale (UDysRS) in the on-medication state. Secondary outcomes included changes from baseline to month 3 in the scores on various parts of the MDS-UPDRS. After the 3-month blinded phase, an open-label phase lasted until 12 months. RESULTS: Of 94 patients, 69 were assigned to undergo ultrasound ablation (active treatment) and 25 to undergo the sham procedure (control); 65 patients and 22 patients, respectively, completed the primary-outcome assessment. In the active-treatment group, 45 patients (69%) had a response, as compared with 7 (32%) in the control group (difference, 37 percentage points; 95% confidence interval, 15 to 60; P = 0.003). Of the patients in the active-treatment group who had a response, 19 met the MDS-UPDRS III criterion only, 8 met the UDysRS criterion only, and 18 met both criteria. Results for secondary outcomes were generally in the same direction as those for the primary outcome. Of the 39 patients in the active-treatment group who had had a response at 3 months and who were assessed at 12 months, 30 continued to have a response. Pallidotomy-related adverse events in the active-treatment group included dysarthria, gait disturbance, loss of taste, visual disturbance, and facial weakness. CONCLUSIONS: Unilateral pallidal ultrasound ablation resulted in a higher percentage of patients who had improved motor function or reduced dyskinesia than a sham procedure over a period of 3 months but was associated with adverse events. Longer and larger trials are required to determine the effect and safety of this technique in persons with Parkinson's disease. (Funded by Insightec; ClinicalTrials.gov number, NCT03319485.).

Magnetic resonance imaging-guided focused ultrasound thalamotomy for essential tremor: 5-year follow-up results.

OBJECTIVE: The objective of this study was to evaluate, at 4 and 5 years posttreatment, the long-term safety and efficacy of unilateral MRI-guided focused ultrasound (MRgFUS) thalamotomy for medication-refractory essential tremor in a cohort of patients from a prospective, controlled, multicenter clinical trial. METHODS: Outcomes per the Clinical Rating Scale for Tremor (CRST), including postural tremor scores (CRST Part A), combined hand tremor/motor scores (CRST Parts A and B), and functional disability scores (CRST Part C), were measured by a qualified neurologist. The Quality of Life in Essential Tremor Questionnaire (QUEST) was used to assess quality of life. CRST and QUEST scores at 48 and 60 months post-MRgFUS were compared to those at baseline to assess treatment efficacy and durability. All adverse events (AEs) were reported. RESULTS: Forty-five and 40 patients completed the 4- and 5-year follow-ups, respectively. CRST scores for postural tremor (Part A) for the treated hand remained significantly improved by 73.3% and 73.1% from baseline at both 48 and 60 months posttreatment, respectively (both p < 0.0001). Combined hand tremor/motor scores (Parts A and B) also improved by 49.5% and 40.4% (p < 0.0001) at each respective time point. Functional disability scores (Part C) increased slightly over time but remained significantly improved through the 5 years (p < 0.0001). Similarly, QUEST scores remained significantly improved from baseline at year 4 (p < 0.0001) and year 5 (p < 0.0003). All previously reported AEs remained mild or moderate, and no new AEs were reported. CONCLUSIONS: Unilateral MRgFUS thalamotomy demonstrates sustained and significant tremor improvement at 5 years with an overall improvement in quality-of-life measures and without any progressive or delayed complications. Clinical trial registration no.: NCT01827904 (ClinicalTrials.gov).

A sub-group evaluation of the multi-month dispensing strategy for differentiated HIV care: is personalization of care guidelines warranted in Haiti?

BACKGROUND: Differentiated care strategies are rapidly becoming the norm for HIV care delivery globally. Building upon an interest in tailoring antiretroviral therapy (ART) delivery for client-centered needs, the Ministry of Health and Population in Haiti formally endorsed multiple-month dispenses (MMD) in the 2016 national ART guidelines This study explores heterogeneity in retention in care with MMD for specific Haitian populations living with HIV and evaluates if a targeted algorithm for optimal ART prescription intervals is warranted in Haiti. METHODS: This study included ART-naïve individuals who started ART on or after January 1st, 2017 in Haiti. To identify subgroups in which to explore heterogeneity of retention, we implemented a double-lasso regression method to determine which individual characteristics would define the subgroups. Characteristics evaluated for potential subgroup definition included: sex, age category, WHO clinical stage, and body mass index category. We employed instrumental variable models to estimate the causal effect of increasing ART dispensing length on ART retention, by client subgroup. The outcome of interest was retention in care after one year in treatment. We then estimated the marginal effect of a 30-day increase to ART dispensing length to retention in care for each of these subgroups. RESULTS: There was evidence for heterogeneity in the effect of extending ART dispensing intervals on retention by WHO clinical stage. We observed significant improvements to retention in care at one year with a 30-day increase in ART dispense length for all subgroups defined by WHO clinical stages 1-4. The effects ranged from a 14.7% increase (95% CI: 12.4-17.0) to the likelihood of retention for people with HIV in WHO stage 1 to a 21.6% increase (95% CI: 18.7-24.5) to the likelihood of retention for those in WHO stage 3. CONCLUSIONS: All the subgroups defined by WHO clinical stage experienced a benefit of extending ART intervals to retention in care at one year. Though the effect did differ slightly by WHO stage, the effects went in the same direction and were of similar magnitude. Therefore, a standardized recommendation for MMD among those living with HIV and new on ART is appropriate for Haiti treatment guidelines.

Patterns of Medical Care Cost by Service Type for Patients With Recurrent and De Novo Advanced Cancer.

OBJECTIVES: There is limited knowledge about the cost patterns of patients who receive a diagnosis of de novo and recurrent advanced cancers in the United States. METHODS: Data on patients who received a diagnosis of de novo stage IV or recurrent breast, colorectal, or lung cancer between 2000 and 2012 from 3 integrated health systems were used to estimate average annual costs for total, ambulatory, inpatient, medication, and other services during (1) 12 months preceding de novo or recurrent diagnosis (preindex) and (2) diagnosis month through 11 months after (postindex), from the payer perspective. Generalized linear regression models estimated costs adjusting for patient and clinical factors. RESULTS: Patients who developed a recurrence <1 year after their initial cancer diagnosis had significantly higher total costs in the preindex period than those with recurrence ≥1 year after initial diagnosis and those with de novo stage IV disease across all cancers (all P < .05). Patients with de novo stage IV breast and colorectal cancer had significantly higher total costs in the postindex period than patients with cancer recurrent in <1 year and ≥1 year (all P < .05), respectively. Patients in de novo stage IV and those with recurrence in ≥1 year experienced significantly higher postindex costs than the preindex period (all P < .001). CONCLUSIONS: Our findings reveal distinct cost patterns between patients with de novo stage IV, recurrent <1-year, and recurrent ≥1-year cancer, suggesting unique care trajectories that may influence resource use and planning. Future cost studies among patients with advanced cancer should account for de novo versus recurrent diagnoses and timing of recurrence to obtain estimates that accurately reflect these care pattern complexities.

Effects of Medicaid expansion on self-reported use of dental services in socioeconomically vulnerable subgroups.

OBJECTIVE: Research suggests Medicaid expansion led to modest increases in the use of dental services among low-income adults, especially in states with more generous Medicaid dental benefits. We expand upon this research by examining whether the effect of Medicaid expansion differed across important socioeconomic subgroups. METHODS: Using Behavioral Risk Factor Surveillance System data from 2012 to 2016, we employed a difference-in-differences framework to estimate the effect of Medicaid expansion on annual use of dental services overall and by whether states offered more-than-emergency Medicaid dental benefits. We used generalized linear mixed-effects model trees to estimate effects across socioeconomic subgroups (e.g., age, education, race, income). RESULTS: The effect of Medicaid expansion varied by state's generosity of Medicaid dental coverage and combinations of socioeconomic subgroups. Overall, there was no significant association between Medicaid expansion and probability of using dental services (-0.1 pp percentage points [pp], p = 0.914). Medicaid expansion was associated with a modest increase in the probability of using dental services in states with more-than-emergency Medicaid dental benefits (2.3 pp, p < 0.001) and with a modest decrease in states with no or emergency-only benefits (-4.3 pp, p < 0.001). Among adults aged 21-35 without a high school diploma, Medicaid expansion was associated with an 8.1 pp (p = 0.003) increase in dental use probability, but there were no associated effects of Medicaid expansion for other subgroups. CONCLUSIONS: While Medicaid expansion alone is not sufficient to ensure adults receive recommended dental care, some vulnerable subgroups appear to have benefited. Efforts to mitigate barriers to dental care may be needed to increase uptake of dental services by low-income adults.

Observational study of patient characteristics associated with a timely diagnosis of dementia and mild cognitive impairment without dementia.

BACKGROUND: Timely diagnosis of cognitive impairment is a key goal of the National Plan to Address Alzheimer's Disease, but studies of factors associated with a timely diagnosis are limited. OBJECTIVE: To identify patient characteristics associated with a timely diagnosis of dementia and mild cognitive impairment (MCI). DESIGN: Retrospective observational study using survey data from the Health and Retirement Study (HRS) from 1995-2016 (interview waves 3-13). PARTICIPANTS: 4,760 respondents with incident dementia and 1,864 with incident MCI identified using longitudinal measures of cognitive functioning. MAIN MEASURES: Timely or delayed diagnosis based on the timing of a self or proxy report of a healthcare provider diagnosis in relation to respondents first dementia or MCI-qualifying cognitive score, sociodemographic characteristics, health status, health care utilization, insurance provider, and year of first qualifying score. KEY RESULTS: Only 26.0% of the 4,760 respondents with incident dementia and 11.4% of the 1,864 respondents with incident MCI received a timely diagnosis. Non-Hispanic Black respondents and respondents with less than a college degree were significantly less likely to receive a timely diagnosis of either dementia or MCI than Non-Hispanic White respondents (dementia odds ratio (OR): 0.61, 95% CI: 0.50, 0.75; MCI OR: 0.40, 95% CI: 0.23, 0.70) and those with a college degree (dementia OR for less than high school degree: 0.30, 95% CI: 0.23, 0.38; MCI OR: 0.36, 95% CI: 0.22, 0.60). Respondents that lived alone were also less likely to receive a timely diagnosis of dementia (OR: 0.69, 95% CI: 0.59, 0.81), though not MCI. Timely diagnosis of both conditions increased over time. CONCLUSIONS: Targeting resources for timely diagnosis of cognitive impairment to individuals from racial and ethnic minorities, lower educational attainment, and living alone may improve detection and reduce disparities around timely diagnosis of dementia and MCI.

Focused Ultrasound Mediated Opening of the Blood-Brain Barrier for Neurodegenerative Diseases.

The blood brain barrier (BBB) is an obstacle for the delivery of potential molecular therapies for neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). Although there has been a proliferation of potential disease modifying therapies for these progressive conditions, strategies to deliver these large agents remain limited. High intensity MRI guided focused ultrasound has already been FDA approved to lesion brain targets to treat movement disorders, while lower intensity pulsed ultrasound coupled with microbubbles commonly used as contrast agents can create transient safe opening of the BBB. Pre-clinical studies have successfully delivered growth factors, antibodies, genes, viral vectors, and nanoparticles in rodent models of AD and PD. Recent small clinical trials support the safety and feasibility of this strategy in these vulnerable patients. Further study is needed to establish safety as MRI guided BBB opening is used to enhance the delivery of newly developed molecular therapies.

A Multifaceted Approach to Optimizing AAV Delivery to the Brain for the Treatment of Neurodegenerative Diseases.

Despite major advancements in gene therapy technologies, there are no approved gene therapies for diseases which predominantly effect the brain. Adeno-associated virus (AAV) vectors have emerged as the most effective delivery vector for gene therapy owing to their simplicity, wide spread transduction and low immunogenicity. Unfortunately, the blood-brain barrier (BBB) makes IV delivery of AAVs, to the brain highly inefficient. At IV doses capable of widespread expression in the brain, there is a significant risk of severe immune-mediated toxicity. Direct intracerebral injection of vectors is being attempted. However, this method is invasive, and only provides localized delivery for diseases known to afflict the brain globally. More advanced methods for AAV delivery will likely be required for safe and effective gene therapy to the brain. Each step in AAV delivery, including delivery route, BBB transduction, cellular tropism and transgene expression provide opportunities for innovative solutions to optimize delivery efficiency. Intra-arterial delivery with mannitol, focused ultrasound, optimized AAV capsid evolution with machine learning algorithms, synthetic promotors are all examples of advanced strategies which have been developed in pre-clinical models, yet none are being investigated in clinical trials. This manuscript seeks to review these technological advancements, and others, to improve AAV delivery to the brain, and to propose novel strategies to build upon this research. Ultimately, it is hoped that the optimization of AAV delivery will allow for the human translation of many gene therapies for neurodegenerative and other neurologic diseases.