Faculty Bibliography

OBJECTIVE:We sought to evaluate early clinical differences between cerebral arteriolosclerosis (pARTE), Alzheimer disease (pAD), and AD with arteriolosclerosis (ADARTE). METHODS:Using National Alzheimer's Coordinating Center neuropathology diagnoses, we defined pARTE (n=21), pAD (n=203), and ADARTE (n=158) groups. We compared demographics, medical history, psychometrics, neuropsychiatric symptoms, and apolipoprotein E (APOE) allele variants across neuropathology groups. Retrospective timepoints were first evaluation with Global Clinical Dementia Rating (CDR) score of 0.5 and 1.0, via the CDR Dementia Staging Instrument, corresponding to mild cognitive impairment (MCI) and mild dementia, respectively. RESULTS:In MCI, clinical differences were minimal but pARTE subjects were older, had later onset cognitive decline, and progressed less severely than pAD. In mild dementia, pAD subjects were younger and had earlier onset of decline. Neuropsychiatric (depression) and psychometric (Logical Memory Delayed Recall, Trails B) differences also emerged between the groups. In MCI, APOE4 associated with worse Logical Memory Delayed Recall in pAD and ADARTE. In mild dementia, APOE4 associated with better animal fluency in pAD, but with better Trails A performance and more neuropsychiatric symptoms (Neuropsychiatric Inventory Questionnaire) in ADARTE. CONCLUSIONS:Differences between pARTE, pAD, and ADARTE emerge at mild dementia rather than MCI. APOE4 has varied cognitive and psychiatric impact dependent on neuropathology group and stage.

BACKGROUND:There is an increased effort to better understand neuropsychiatric symptoms of Alzheimer's disease (AD) as an important feature of symptomatic burden as well as potential modi- fiable factors of the disease process. Anxiety is one of the most common neuropsychiatric symptoms in Alzheimer's disease (AD). A growing body of work has emerged that addresses the epidemiology and biological correlations of anxiety in AD. OBJECTIVE AND METHODS/OBJECTIVE:Here, we review human studies in research and clinical cohorts that examined anxiety in AD. We focused on work related to prevalence across AD stages, correlation with established biomarkers, relationship with AD neuropathology and genetic risk factors, and impact on progression. RESULTS:Anxiety is prominent in the early stages and increases across the spectrum of functional stages. Biomarker relationships are strongest at the level of FDG-PET and amyloid measured via PET or cerebrospinal fluid analysis. Neuropathologically, anxiety emerges with early Braak stage tau pathology. The presence of the apolipoprotein E e4 allele is associated with increased anxiety at all stages, most notably at mild cognitive impairment. Anxiety portended a faster progression at all pre-dementia stages. CONCLUSION/CONCLUSIONS:This body of work suggests a close biological relationship between anxiety and AD that begins in early stages and influences functional decline. As such, we discuss future work that would improve our understanding of this relationship and test the validity of anxiolytic treatment as disease modifying therapy for AD.

BACKGROUND:We have described the clinical stages of the brain aging and Alzheimer's disease (AD) continuum. In terms of the pre-dementia stages of AD, we introduced the terminology "mild cognitive impairment" (MCI) for the first pre-dementia stage and "subjective cognitive decline" (SCD) for the pre-MCI stage. We now report the characteristics of a pre-SCD condition eventuating in likely AD. OBJECTIVE:The aim of this study was to characterize a pre-SCD condition eventuating in AD. METHOD/METHODS:Sixty healthy persons with "no cognitive decline" (NCD) were recruited and 47 were followed (mean baseline age, 64.1 ± 8.9 years; mean follow-up time, 6.7 ± 3.1 years). Outcome was determined at the final assessment prior to 2002 as "decliner," if SCD or worse, or "nondecliner" if NCD. RESULTS:After controlling for age, gender, years of education, and follow-up time, there was a between-group difference in the decline rate (p < 0.001). Also, after controlling for demographic variables and follow-up time, the combinatorial psychometric score was lower at baseline in the future decliners (p = 0.035). Of the 9 psychometric variables, after controlling for demographic variables and follow-up time, 3 were significantly lower at baseline in future decliners. Since AD is known to be age related and all subjects in this study were otherwise healthy, we also did an analysis without controlling for age. The combinatorial psychometric score was highly significantly better at baseline in the future nondecliners than in the future decliners (p = 0.008). CONCLUSION/CONCLUSIONS:This is ostensibly the first study to link psychometric cognitive decline to the subsequent SCD stage of eventual AD.

The population activity of CA1 pyramidal neurons (PNs) segregates along anatomical axes with different behaviors, suggesting that CA1 PNs are functionally subspecialized based on somatic location. In dorsal CA1, spatial encoding is biased towards CA2 (CA1c) and in deep layers of the radial axis. In contrast, non-spatial coding peaks towards subiculum (CA1a) and in superficial layers. While preferential innervation by spatial versus non-spatial input from entorhinal cortex (EC) may contribute to this specialization, it cannot fully explain the range of in vivo responses. Differences in intrinsic properties thus may play a critical role in modulating such synaptic input differences. Here we examine the postsynaptic integrative properties of dorsal CA1 PNs in six subpopulations along the transverse (CA1c, CA1b, CA1a) and radial (deep, superficial) axes. Our results suggest that active and passive properties of deep and superficial neurons evolve over the transverse axis to promote the functional specialization of CA1c versus CA1a as dictated by their cortical input. We also find that CA1b is not merely an intermediate mix of its neighbors, but uniquely balances low excitability with superior input integration of its mixed input, as may be required for its proposed role in sequence encoding. Thus, synaptic input and intrinsic properties combine to functionally compartmentalize CA1 processing into at least three transverse axis regions defined by the processing schemes of their composite radial axis subpopulations.

BACKGROUND:Early identification of vasospasm prior to symptom onset would allow prevention of delayed cerebral ischemia (DCI) in aneurysmal subarachnoid hemorrhage (aSAH). Dynamic cerebral autoregulation (DCA) is a noninvasive means of assessing cerebral blood flow regulation by determining independence of low-frequency temporal oscillations of systemic blood pressure (BP) and cerebral blood flow velocities (CBFV). METHODS:Eight SAH patients underwent prospectively a median of 7 DCA assessments consisting of continuous measurements of BCFV and BP. Transfer function analysis was applied to calculate average phase shift (PS) in low (0.07-0.2 Hz) frequency range for each hemisphere as continuous measure of DCA. Lower PS indicated poorer regulatory response. DCI was defined as a 2-point decrease in Glasgow Coma Score and/or infarction on CT. RESULTS:Three subjects developed symptomatic vasospasm with median time-to-DCI of 9 days. DCI was significantly associated with lower PS over the entire recording period (Wald = 4.28; p = 0.039). Additionally, there was a significant change in PS over different recording periods after adjusting for DCI (Wald = 15.66; p = 0.001); particularly, a significantly lower mean PS day 3-5 after bleed (14.22 vs 27.51; p = 0.05). CONCLUSIONS:DCA might be useful for early detection of symptomatic vasospasm. A larger cohort study of SAH patients is currently underway.

Vision, which requires extensive neural involvement, is often impaired in Alzheimer's disease (AD). Over the last few decades, accumulating evidence has shown that various visual functions and structures are compromised in Alzheimer's dementia and when measured can detect those with dementia from those with normal aging. These visual changes involve both the afferent and efferent parts of the visual system, which correspond to the sensory and eye movement aspects of vision, respectively. There are fewer, but a growing number of studies, that focus on the detection of predementia stages. Visual biomarkers that detect these stages are paramount in the development of successful disease-modifying therapies by identifying appropriate research participants and in identifying those who would receive future therapies. This review provides a summary and update on common afferent and efferent visual markers of AD with a focus on mild cognitive impairment (MCI) and preclinical disease detection. We further propose future directions in this area. Given the ease of performing visual tests, the accessibility of the eye, and advances in ocular technology, visual measures have the potential to be effective, practical, and non-invasive biomarkers of AD.