Faculty Bibliography

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.

Background and Aims: White matter hyperintensities (WMH) on the MRI FLAIR sequence may reflect cerebral small vessel disease, impacting age-related cognitive decline and Alzheimer's disease (AD). However, it is not clear how WMH in normal individuals relates to subjective cognitive decline (SCD), proposed to be a prodromal stage of AD.
Method(s): We performed a cross-sectional analysis of 194 cognitively normal elder volunteers with SCD seen in the NYU Alzheimer's Disease Center from 1/2017-10/2019. Evaluations included medical history, neuropsychological testing, SCD ratings, and MRI. They were divided into two groups based on extent of WMH on MRI axial FLAIR: moderate-to-severe (n=29) and none-to-mild (n=165).
Result(s): The groups performed similarly on cognitive testing, and had equivalent rates of hippocampal atrophy on MRI. Hypertension was more prevalent in the moderate-severe WMH group (67% vs. 25%, p=0.003). Moderate-severe WMH subjects had slightly higher SCD magnitude measured on the Brief Cognitive Rating Scale (21.68 vs. 20.53, p=0.04). They also expressed more concern about nonamnestic cognition on the Cognitive Change Index, questions 13-20 (13.35 vs. 10.92, p=0.003), specifically with everyday decision making (p=0.006) and shifting from one activity to the next (p=0.007). On the Geriatric Depression Scale, they were more likely to endorse emptiness (11% vs. 2%, p=0.04) and not feeling wonderful to be alive now (18% vs. 6%, p=0.049).
Conclusion(s): In SCD, WMH associates with hypertension and contributes to the character of cognitive concern and concomitant affective symptoms. WMH should be further studied as an important vascular modulator of this prodromal stage of AD

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.

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.

Introduction/UNASSIGNED:Severe intracranial stenosis might lead to acute cerebral ischemia. It is imperative to better assess patients who may benefit from immediate reperfusion and blood pressure management to prevent injury to peri-infarct tissue. Methods/UNASSIGNED:We assessed cerebral autoregulation using static and dynamic methods in an 81-year-old woman suffering acute cerebral ischemia from severe intracranial stenosis in the petrous segment of the left internal carotid artery (LICA). Results/UNASSIGNED:Static cerebral autoregulation, which is evaluated by magnetic resonance imaging and magnetic resonance perfusion studies showed a progression of infarcts and a large perfusion-diffusion mismatch in the entire LICA territory between the second and third days after onset despite maximized medical therapy. Dynamic methods, including transfer function analysis and mean velocity index, demonstrated an increasingly impaired dynamic cerebral autoregulation (DCA) on the affected side between these days. Revascularization through acute intracranial stenting resulted in improved perfusion in the LICA territory and normalization of both dynamic and static cerebral autoregulation. Conclusion/UNASSIGNED:Thus, DCA, a noninvasive bedside method, may be useful in helping to identify and select patients with large-vessel flow-failure syndromes that would benefit from immediate revascularization of intracranial atherosclerotic disease.