Faculty Bibliography

INTRODUCTION/BACKGROUND:This clinical trial evaluates the efficacy and safety of a 6-week course of daily neuroAD™ therapy. METHODS:131 subjects between 60 and 90 years old, unmedicated for Alzheimer's disease (AD), or on stable doses of an acetylcholinesterase inhibitor and/or memantine, with Mini-Mental State Examination scores between 18 and 26, clinical dementia rating scale scores of 1 or 2, enrolled for a prospective, randomized, double-blind, sham-controlled, multicenter clinical trial. Structural brain MRIs were obtained for transcranial magnetic stimulation targeting. Baseline Alzheimer's disease assessment scale-cognitive (ADAS-Cog) and Clinical Global Impression of Change were assessed. 129 participants were randomized to active treatment plus standard of care (SOC) or sham treatments plus SOC. RESULTS:Subjects with baseline ADAS-Cog ≤ 30 (~85% of study population) showed a statistically significant benefit favoring active over sham. Responder analysis showed 31.7% participants in the active group with ≤ -4 point improvement on ADAS-Cog versus 15.4% in the sham group. DISCUSSION/CONCLUSIONS:neuroAD™ Therapy System provides a low-risk therapeutic benefit for patients with milder AD (baseline ADAS-Cog ≤30) beyond pharmacologic SOC.

Aims Noninvasive brain stimulation with trains of repetitive Transcranial Magnetic Stimulation (TMS) can modulate activity in specific cortical brain region and networks, and thus affect cognitive function. The neuroADTM Therapy System delivers brain MRI neuro-navigated, focal TMS concurrently with Cognitive Training exercises. The Cognitive Training tasks are designed to engage the cognitive functions of the brain networks targeted by a preceding train of TMS. Method This pivotal, aimed to gain regulatory clearance (equivalent to pharmaceutical phase III study), randomized, double-blind, sham-controlled clinical trial was designed to evaluate the efficacy and safety of a 6 weeks course of daily neuroADTM Therapy in the treatment of cognitive function in patients with mild to moderate Alzheimer (NIA-AA criteria). In a multi-center study at 10 sites, 131 subjects were enrolled and randomized to neuroADTM versus sham (placebo). Participants were 60-90 years old, with MMSE 18-26, CDR 1-2, and on stable doses of cholinesterase inhibitors or memantine (or un-medicated for AD). Informed Consent was obtained from all participants. All subjects had evaluation of ADAS-Cog and CGI-C baseline, week 7 and week 12. Enrolled patients were randomized to either Active or Sham treatment groups. Both Active and Sham interventions involved 30 daily sessions over six weeks. Each session was approximately one hour long. Results The pivotal, regulatory-targeted study is complete. The safety results will be presented at the meeting. Conclusion Study outcomes support an on-going FDA application for clearance of the neuroADTM Therapy System

Importance: Several large-scale Alzheimer disease (AD) secondary prevention trials have begun to target individuals at the preclinical stage. The success of these trials depends on validated outcome measures that are sensitive to early clinical progression in individuals who are initially asymptomatic. Objective: To investigate the utility of the Cognitive Function Instrument (CFI) to track early changes in cognitive function in older individuals without clinical impairment at baseline. Design, Setting, and Participants: Longitudinal study from February 2002 through February 2007 at participating Alzheimer's Disease Cooperative Study sites. Individuals were followed up annually for 48 months after the baseline visit. The study included 468 healthy older individuals (Clinical Dementia Rating scale [CDR] global scores of 0, above cutoff on the modified Mini-Mental State Examination and Free and Cued Selective Reminding Test) (mean [SD] age, 79.4 [3.6] years; age range, 75.0-93.8 years). All study participants and their study partners completed the self and partner CFIs annually. Individuals also underwent concurrent annual neuropsychological assessment and APOE genotyping. Main Outcomes and Measures: The CFI scores between clinical progressors (CDR score, >/=0.5) and nonprogressors (CDR score, 0) and between APOE epsilon4 carriers and noncarriers were compared. Correlations of change between the CFI scores and neuropsychological performance were assessed longitudinally. Results: At 48 months, group differences between clinical progressors and non-progressors were significant for self (2.13, SE=0.45, P < .001), partner (5.08, SE=0.59, P < .001), and self plus partner (7.04, SE=0.83, P < .001) CFI total scores. At month 48, APOE epsilon4 carriers had greater progression than noncarriers on the partner (1.10, SE=0.44, P < .012) and self plus partner (1.56, SE=0.63, P < .014) CFI scores. Both self and partner CFI change were associated with longitudinal cognitive decline (self, rho=0.32, 95% CI, 0.13 to 0.46; partner, rho=0.56, 95% CI, 0.42 to 0.68), although findings suggest self-report may be more accurate early in the process, whereas accuracy of partner report improves when there is progression to cognitive impairment. Conclusions and Relevance: Demonstrating long-term clinical benefit will be critical for the success of recently launched secondary prevention trials. The CFI appears to be a brief, but informative potential outcome measure that provides insight into functional abilities at the earliest stages of disease.

Reports an error in "Tracking early decline in cognitive function in older individuals at risk for Alzheimer disease dementia: The Alzheimer's disease cooperative study Cognitive Function Instrument" by Rebecca E. Amariglio, Michael C. Donohue, Gad A. Marshall, Dorene M. Rentz, David P. Salmon, Steven H. Ferris, Stella Karantzoulis, Paul S. Aisen and Reisa A. Sperling (JAMA Neurology, 2015[Apr], Vol 72[4], 446-454). In the original article, there were typographical errors in Figure.1. The corrected figure was present in the erratum. (The following abstract of the original article appeared in record 2015-18024-013). Importance: Several large-scale Alzheimer disease (AD) secondary prevention trials have begun to target individuals at the preclinical stage. The success of these trials depends on validated outcome measures that are sensitive to early clinical progression in individuals who are initially asymptomatic. Objective: To investigate the utility of the Cognitive Function Instrument (CFI) to track early changes in cognitive function in older individuals without clinical impairment at baseline. Design, Setting, and Participants: Longitudinal study from February 2002 through February 2007 at participating Alzheimer's Disease Cooperative Study sites. Individuals were followed up annually for 48 months after the baseline visit. The study included 468 healthy older individuals (Clinical Dementia Rating scale [CDR] global scores of 0, above cutoff on the modified Mini-Mental State Examination and Free and Cued Selective Reminding Test) (mean [SD] age, 79.4 [3.6] years; age range, 75.0-93.8 years). All study participants and their study partners completed the self and partner CFIs annually. Individuals also underwent concurrent annual neuropsychological assessment and i genotyping. Main Outcomes and Measures: The CFI scores between clinical progressors (CDR score, > 0.5) and nonprogressors (CDR score, 0) and between APOE epsilon4 carriers and noncarriers were compared. Correlations of change between the CFI scores and neuropsychological performance were assessed longitudinally. Results: At 48 months, group differences between clinical progressors and non-progressors were significant for self (2.13, SE = 0.45, P < .001), partner (5.08, SE = 0.59, P < .001), and self plus partner (7.04, SE = 0.83, P < .001) CFI total scores. At month 48, APOE epsilon4 carriers had greater progression than noncarriers on the partner (1.10, SE = 0.44, P < .012) and self plus partner (1.56, SE = 0.63, P < .014) CFI scores. Both self and partner CFI change were associated with longitudinal cognitive decline (self, rho = 0.32, 95%CI, 0.13 to 0.46; partner, rho = 0.56, 95% CI, 0.42 to 0.68), although findings suggest self-report may be more accurate early in the process, whereas accuracy of partner report improves when there is progression to cognitive impairment. Conclusions and Relevance: Demonstrating long-term clinical benefit will be critical for the success of recently launched secondary prevention trials. The CFI appears to be a brief, but informative potential outcome measure that provides insight into functional abilities at the earliest stages of disease.

Current diagnostic criteria for mild cognitive impairment (MCI) due to Alzheimer's disease (AD) require standardized tests that are capable of measuring a range of neurocognitive abilities in healthy elderly individuals and sensitive to detect change over time. There currently is no clearly-established "gold standard" for this purpose. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) is a widely used neuropsychological test battery for the clinical diagnosis/tracking of dementia also recently incorporated into clinical trials of new investigational medications for AD treatment. The RBANS has a number of design features that suggest possible utility in diagnosis/tracking of MCI. Eighty-one patients with MCI completed the RBANS and their scores were compared with 81 demographically matched healthy controls. RBANS Total Scale scores in both groups were normally distributed, demonstrating no floor/ceiling effects. The MCI group was most impaired on the Delayed Memory Index (DMI). Receiver operating characteristic analyses reflected good discrimination, with an area under the curve of 0.88 for the Total Scale score and 0.90 for the DMI score. The profile of performance for the MCI group was similar to that previously reported for mild AD patients. The RBANS may be a suitable neurocognitive battery for the detection and tracking of MCI presumed to be due to AD.

It has been theorized that a career in contact sports may be associated with long-term neurodegenerative changes. This idea dates as far back as the 1920s, was initially reported in boxers, colloquially termed 'punch drunk,' later more formally termed dementia pugilistica (DP), and now coined chronic traumatic encephalopathy (CTE). Despite considerable ongoing interest on this topic, there is so far only limited evidence showing an association between sport-related concussion (SRC) and increased risk for late-life cognitive and neuropsychiatric impairment, with no causality or risk factors yet determined. The modern CTE description is nevertheless proposed as a unique tauopathy with characteristic pathological stages occurring in retired athletes who have experienced previous repetitive brain trauma. This review highlights the principal issues that so far preclude firm conclusions about the association of athletic head trauma and neurodegenerative diseases of any type. We consider alternative interpretations that may contribute to the clinical progressive neurological findings in some athletes and recommend carefully-controlled epidemiological work to overcome current limitations in this area of research and stimulate future research.

Dementia with Lewy bodies (DLB) is the second most common form of dementia after Alzheimer disease (AD). DLB is characterized pathologically by Lewy body and Lewy neuritic pathology, often with variable levels of Alzheimer-type pathology. Core clinical features include fluctuating cognition, visual hallucinations, and parkinsonism resulting in greater impairments of quality of life, more caregiver burden, and higher health-related costs compared with AD. These issues, together with a high sensitivity to adverse events with treatment with antipsychotic agents, make the need for an early and accurate diagnosis of DLB essential. Unfortunately, current consensus criteria are highly specific but lack sufficient sensitivity. Use of composite risk scores may improve accuracy of clinical diagnosis. Imaging findings, particularly targeting dopaminergic systems have shown promise as potential markers to differentiate DLB from AD. A combination of non-pharmacologic treatments and pharmacotherapy interventions may maximize cognitive function and overall quality of life in DLB patients.