Faculty Bibliography

Background: We conducted a 28-week, single-blind, randomized, controlled trial of the efficacy of Comprehensive, Individualized, Person-Centered Management (CI-PCM) and memantine treatment (Reisberg et al., Dement Geriatr Cogn Disord, 2017) in advanced AD persons. CI-PCM and memantine was approximately 7.5 times more beneficial to AD persons on the Functional Assessment Staging Tool (FAST) (Kenowsky et. al., Alzheimer"™s and Dementia, 2017) than to AD persons who received memantine alone in the memantine FDA approval pivotal trial conducted by Reisberg et. al., (NEJM 2003). We also conducted a 24-week extension study. Herein, we report the difference in functional outcomes between the CI-PCM and Usual Community Care (UCC+FC) groups at 52-weeks on the FAST and the ADCS-ADLSev-Abv. See Figures 1 and 2. Method: After screening, 20 eligible subject-carepartner dyads were randomized equally to the CI-PCM and UCC+FC groups. All 20 dyads completed the 28-week study and entered the 24-week extension study. One subject in the UCC+FC group died during the extension study. The FAST and ADCS-ADLsev-abv were conducted at baseline, and weeks 4, 12, 28, and 52. P values were calculated using the Wilcoxon Mann Whitney test. Result: The mean FAST total score from baseline (6.6±0.1SE) to week 52 (6.5±0.01SE) showed an improvement of functional limitations in the CI-PCM group. The mean FAST total score for the UCC+FC group showed a functional decline from baseline (6.6±0.1SE) to week 52 (6.8±0.1SE), displaying a robustly significant difference between the two groups (p<0.0014). The mean ADCS-ADL-sev-abv total score for the CI-PCM group demonstrated a 20.9% improvement in functioning from baseline (15.3±2.0SE) to week 52 (18.5±2.5SE). The mean ADCS-ADL-sev-abv total score for the UCC+FC group showed a decline of 48.6% from baseline (14.8±2.1SE) to week 52 (7.6±2.3SE), indicating a significant difference between the two groups (p<0.009). Conclusion: The CI-PCM program is the only evidenced-based treatment to date that can significantly improve and reverse functional deterioration in advanced AD persons. The functional success of the CI-PCM program may primarily be attributed to care partners learning to memory coach AD persons to perform daily activities such as bathing, dressing, feeding and toileting themselves, and to become/maintain urinary and fecal continence.

In large clinical centers a small subset of patients present with hydrocephalus that requires surgical treatment. We aimed to develop a screening tool to detect such cases from the head MRI with performance comparable to neuroradiologists. We leveraged 496 clinical MRI exams collected retrospectively at a single clinical site from patients referred for any reason. This diagnostic dataset was enriched to have 259 hydrocephalus cases. A 3D convolutional neural network was trained on 16 manually segmented exams (ten hydrocephalus) and subsequently used to automatically segment the remaining 480 exams and extract volumetric anatomical features. A linear classifier of these features was trained on 240 exams to detect cases of hydrocephalus that required treatment with surgical intervention. Performance was compared to four neuroradiologists on the remaining 240 exams. Performance was also evaluated on a separate screening dataset of 451 exams collected from a routine clinical population to predict the consensus reading from four neuroradiologists using images alone. The pipeline was also tested on an external dataset of 31 exams from a 2nd clinical site. The most discriminant features were the Magnetic Resonance Hydrocephalic Index (MRHI), ventricle volume, and the ratio between ventricle and brain volume. At matching sensitivity, the specificity of the machine and the neuroradiologists did not show significant differences for detection of hydrocephalus on either dataset (proportions test, p > 0.05). ROC performance compared favorably with the state-of-the-art (AUC 0.90-0.96), and replicated in the external validation. Hydrocephalus cases requiring treatment can be detected automatically from MRI in a heterogeneous patient population based on quantitative characterization of brain anatomy with performance comparable to that of neuroradiologists.

OBJECTIVE:The aim of this study was to describe the processes and outcomes associated with patients at five sites in the Adult Hydrocephalus Clinical Research Network (AHCRN) who had undergone evaluation and treatment for suspected idiopathic normal pressure hydrocephalus (iNPH) and had 1-year postoperative follow-up. METHODS:Subjects with possible iNPH who had been prospectively enrolled in the AHCRN registry between November 19, 2014, and December 31, 2018, were evaluated by CSF drainage via either lumbar puncture or external lumbar drainage, consistent with recommendations of the international iNPH guidelines. Standardized clinical evaluations of gait, cognition, urinary symptoms, depression, and functional outcomes were conducted at baseline, before and after CSF drainage, and at 4-month intervals after shunt surgery. Complications of CSF drainage and shunt surgery were recorded. RESULTS:Seventy-four percent (424/570) of patients with possible iNPH had CSF drainage, and 46% of them (193/424) underwent shunt surgery. The mean change in gait velocity with CSF drainage was 0.18 m/sec in patients who underwent shunt surgery versus 0.08 m/sec in patients who did not. For shunt surgery patients, gait velocity increased by 54% from 0.67 m/sec before CSF drainage to 0.96 m/sec 8-12 months after surgery, and 80% of patients had an increase of at least 0.1 m/sec by the first postoperative visit. Evaluation of cognition, urinary symptoms, depression, and functional outcomes also revealed improvement after shunt surgery. Of 193 patients who had undergone shunt surgery, 176 (91%) had no complications and 17 (9%) had 28 complications. Eleven patients (6%) had 14 serious complications that resulted in the need for surgery or an extended hospital stay. The 30-day reoperation rate was 3%. CONCLUSIONS:Using criteria recommended by the international iNPH guidelines, the authors found that evaluation and treatment of iNPH are safe and effective. Testing with CSF drainage and treatment with shunt surgery are associated with a high rate of sustained improvement and a low rate of complications for iNPH in the 1st year after shunt surgery. Patients who had undergone shunt surgery for iNPH experienced improvement in gait, cognitive function, bladder symptoms, depression, and functional outcome measures. Gait velocity, which is an easily measured, objective, continuous variable, should be used as a standard outcome measure to test a patient's response to CSF drainage and shunt surgery in iNPH.

PURPOSE/OBJECTIVE:Gait improvement following high-volume lumbar puncture (HVLP) and continuous lumbar drain (cLD) is widely used to predict shunt response in patients with suspected normal pressure hydrocephalus (NPH). Here, we investigate differences in MRI volumetric and traditional measures between HVLP/cLD responders and non-responders to identify imaging features that may help predict HVLP/cLD response. METHODS:Eighty-two patients with suspected NPH were studied retrospectively. Gait testing was performed before and immediately/24 h/72 h after HVLP/cLD. A positive response was defined as improvement in gait post-procedure. Thirty-six responders (26 men; mean age 79.3 ± 6.3) and 46 non-responders (25 men; mean age 77.2 ± 6.1) underwent pre-procedure brain MRI including a 3D T1-weighted sequence. Subcortical regional volumes were segmented using FreeSurfer. After normalizing for total intracranial volume, two-way type III ANCOVA test and chi-square test were used to characterize statistical group differences. Evans' index, callosal angle (CA), and disproportionately enlarged subarachnoid space hydrocephalus were assessed. Multivariable logistic regression models were tested using Akaike information criterion to determine which combination of metrics most accurately predicts HVLP/cLD response. RESULTS:Responders and non-responders demonstrated no differences in total ventricular and white/gray matter volumes. CA (men only) and third and fourth ventricular volumes were smaller; and hippocampal volume was larger in responders (p < 0.05). Temporal horns volume correlated with degree of improvement in gait velocity in responders (p = 0.0006). The regression model was 76.8% accurate for HVLP/cLD response. CONCLUSION/CONCLUSIONS:CA and third and fourth ventricular volumes and hippocampal volume may serve as potentially useful imaging features that may help predict spinal tap response and hence potentially shunt response.

OBJECTIVE:The object of this study was to determine the short- and long-term efficacy of primary endoscopic third ventriculostomy (ETV) on cognition and gait in adults with chronic obstructive hydrocephalus. METHODS:Patients were prospectively accrued through the Adult Hydrocephalus Clinical Research Network patient registry. Patients with previously untreated congenital or acquired obstructive hydrocephalus were included in this study. Gait velocity was assessed using a 10-m walk test. Global cognition was assessed with the Montreal Cognitive Assessment (MoCA). Only patients with documented pre- and post-ETV gait analysis and/or pre- and post-ETV MoCA were included. RESULTS:A total of 74 patients had undergone primary ETV, 42 of whom were analyzed. The remaining 32 patients were excluded, as they could not complete both pre- and post-ETV assessments. The mean age of the 42 patients, 19 (45.2%) of whom were female, was 51.9 ± 17.1 years (range 19-79 years). Most patients were White (37 [88.1%]), and the remainder were Asian. Surgical complications were minor. Congenital etiologies occurred in 31 patients (73.8%), with aqueductal stenosis in 23 of those patients (54.8%). The remaining 11 patients (26.2%) had acquired cases. The gait short-term follow-up cohort (mean 4.7 ± 4.1 months, 35 patients) had a baseline median gait velocity of 0.9 m/sec (IQR 0.7-1.3 m/sec) and a post-ETV median velocity of 1.3 m/sec (IQR 1.1-1.4 m/sec). Gait velocity significantly improved post-ETV with a median within-patient change of 0.3 m/sec (IQR 0.0-0.6 m/sec, p < 0.001). Gait velocity improvements were sustained in the long term (mean 14 ± 2.8 months, 12 patients) with a baseline median velocity of 0.7 m/sec (IQR 0.6-1.3 m/sec), post-ETV median of 1.3 m/sec (IQR 1.1-1.7 m/sec), and median within-patient change of 0.4 m/sec (IQR 0.2-0.6 m/sec, p < 0.001). The cognitive short-term follow-up cohort (mean 4.6 ± 4.0 months, 38 patients) had a baseline median MoCA total score (MoCA TS) of 24/30 (IQR 23-27) that improved to 26/30 (IQR 24-28) post-ETV. The median within-patient change was +1 point (IQR 0-2 points, p < 0.001). However, this change is not clinically significant. The cognitive long-term follow-up cohort (mean 14 ± 3.1 months, 15 patients) had a baseline median MoCA TS of 23/30 (IQR 22-27), which improved to 26/30 (IQR 25-28) post-ETV. The median within-patient change was +2 points (IQR 1-3 points, p = 0.007), which is both statistically and clinically significant. CONCLUSIONS:Primary ETV can safely improve symptoms of gait and cognitive dysfunction in adults with chronic obstructive hydrocephalus. Gait velocity and global cognition were significantly improved, and the worsening of either was rare following ETV.

Background: To describe preliminary results of a multi-center, randomized, blinded, placebo-controlled, pilot trial of shunt surgery in INPH.
Method(s): Five sites randomized 18 patients scheduled for ventriculoperitoneal shunting based on CSF-drainage response. Patients were randomized to a Codman Certas Plus valve with SiphonGuard at either setting 4 (Active, N=9) or setting 8/virtual off (Placebo, N=9). Patients and assessors were blinded to the shunt setting. Outcomes included 10-meter gait velocity, cognitive function, and bladder activity scores. The prespecified primary analysis compared changes in 4-month gait velocity in the Active versus Placebo groups. After the 4 months follow up, all shunts were opened, i.e., adjusted to setting 4 whereafter patients underwent 8 and 12-month post-surgical assessment. At the 8-month follow-up, the Placebo group had had an open shunt for 4 months and the Active group for 8 months.
Result(s): At 4-months, gait velocity increased by 0.28+/-0.28m/s in the Active Group and 0.04+/-0.17m/s in the Placebo Group (p=0.071). Overactive Bladder (OAB-q) scores improved in the Active versus Placebo groups (p=0.007). At 8 months, Placebo gait velocity increased by 0.36+/-0.27m/s and was comparable to the Active Group (0.40+/-0.20m/s p=0.56).
Conclusion(s): This study shows a trend suggesting gait velocity improves more at an Active shunt setting than a Placebo shunt setting and demonstrates the feasibility of a placebo-controlled trial in iNPH

OBJECTIVEThe authors describe the demographics and clinical characteristics of the first 517 patients enrolled in the Adult Hydrocephalus Clinical Research Network (AHCRN) during its first 2 years.METHODSAdults ≥ 18 years were nonconsecutively enrolled in a registry at 6 centers. Four categories of adult hydrocephalus were defined: transition (treated before age 18 years), unrecognized congenital (congenital pattern, not treated before age 18 years), acquired (secondary to known risk factors, treated or untreated), and suspected idiopathic normal pressure hydrocephalus (iNPH) (≥ age 65 years, not previously treated). Data include etiology, symptoms, examination findings, neuropsychology screening, comorbidities, treatment, complications, and outcomes. Standard evaluations were administered to all patients by trained examiners, including the Montreal Cognitive Assessment, the Symbol Digit Modalities Test, the Beck Depression Inventory-II, the Overactive Bladder Questionnaire Short Form symptom bother, the 10-Meter Walk Test, the Boon iNPH gait scale, the Lawton Activities of Daily Living/Instrumental Activities of Daily Living (ADL/IADL) questionnaire, the iNPH grading scale, and the modified Rankin Scale.RESULTSOverall, 517 individuals were enrolled. Age ranged from 18.1 to 90.7 years, with patients in the transition group (32.7 ± 10.0 years) being the youngest and those in the suspected iNPH group (76.5 ± 5.2 years) being the oldest. The proportion of patients in each group was as follows: 16.6% transition, 26.5% unrecognized congenital, 18.2% acquired, and 38.7% suspected iNPH. Excluding the 86 patients in the transition group, who all had received treatment, 79.4% of adults in the remaining 3 groups had not been treated at the time of enrollment. Patients in the suspected iNPH group had the poorest performance in cognitive evaluations, and those in the unrecognized congenital group had the best performance. The same pattern was seen in the Lawton ADL/IADL scores. Gait velocity was lowest in patients in the suspected iNPH group. Categories that had the most comorbidities (suspected iNPH) or etiologies of hydrocephalus that directly cause neurological injury (transition, acquired) had greater degrees of impairment compared to unrecognized congenital, which had the fewest comorbidities or etiologies associated with neurological injury.CONCLUSIONSThe clinical spectrum of hydrocephalus in adults comprises more than iNPH or acquired hydrocephalus. Only 39% of patients had suspected iNPH, whereas 43% had childhood onset (i.e., those in the transition and unrecognized congenital groups). The severity of symptoms and impairment was worsened when the etiology of the hydrocephalus or complications of treatment caused additional neurological injury or when multiple comorbidities were present. However, more than half of patients in the transition, unrecognized congenital, and acquired hydrocephalus groups had minimal or no impairment. Excluding the transition group, nearly 80% of patients in the AHCRN registry were untreated at the time of enrollment. A future goal for the AHCRN is to determine whether patients with unrecognized congenital and acquired hydrocephalus need treatment and which patients in the suspected iNPH cohort actually have possible hydrocephalus and should undergo further diagnostic testing. Future prospective research is needed in the diagnosis, treatment, outcomes, quality of life, and macroeconomics of all categories of adult hydrocephalus.

BACKGROUND:Little is known with respect to behavioral markers of subjective cognitive decline (SCD), a condition initially described in association with Global Deterioration Scale (GDS) stage 2. OBJECTIVE:Two-year interval behavioral markers were investigated herein. METHODS:Subjects from a published 7-year outcome study of GDS stage 2 subjects were selected. This study had demonstrated a hazard ratio of 4.5 for progression of GDS stage 2, in comparison with GDS stage 1 (no subjective or objective cognitive decline) subjects, after controlling for demographic and temporal variables. Because GDS 2 subjects have previously demonstrated impairment in comparison with healthy persons free of complaints, we herein suggest the terminology "SCD(I)" for these persons. 98 SCD(I) persons, 63 women and 35 men, mean baseline age, 67.12±8.75 years, with a mean educational background of 15.55±2.60 years, and mean baseline MMSE scores of 28.9±1.24 were followed for 2.13±0.30 years. RESULTS:Observed annual decline on the GDS was 6.701% per annum, very close to a 1986 published estimate. At follow up, the MMSE, and 7 of 8 psychometric tests did not decline significantly. Of 21 Hamilton Depression Scale items, 2 improved and the remainder were unchanged. Anxieties declined from multiple perspectives. The Brief Cognitive Rating Scale (BCRS) declined significantly (p < 0.001), with component declines in Remote memory (p < 0.01), and Functioning/self-care (p = 0.01). CONCLUSION/CONCLUSIONS:SCD(I) persons decline at an annual rate of approximately 6.7% /year from several recent studies. The BCRS assessments and the Digit Symbol Substitution Test can be sensitive measures for future studies of progression mitigation.

BACKGROUND AND PURPOSE/OBJECTIVE:Normal Pressure Hydrocephalus is a reversible form of dementia characterized by enlarged ventricles, which can deform and cause disruptions to adjacent white matter fibers. The purpose of this work was to examine how diffusion and kurtosis parameters vary along the corticospinal tract and determine where along this path microstructure is compromised in patients diagnosed with normal pressure hydrocephalus. We hypothesized that disruption of the corticospinal tract from ventricular enlargement can be measured using diffusion MR imaging and this will be quantified in periventricular regions. MATERIALS AND METHODS/METHODS:We developed a method to analyze diffusion parameters at discrete points along neural tracts. We then used diffusion MR imaging data from patients with Alzheimer disease and healthy controls to compare whether diffusion along the corticospinal tract differs from that of patients with normal pressure hydrocephalus. RESULTS:< .05) in an area located close to the superior internal capsule and corona radiata but below the cortex. CONCLUSIONS:A lower axonal water fraction indicates a lower axonal density in the corticospinal tract, which may indicate permanent damage. Lower axial kurtosis may imply that axons are being more aligned due to compression.