Collin Y. Liu

Blood-brain barrier breakdown in the aging human hippocampus.

UNLABELLED The blood-brain barrier (BBB) limits entry of blood-derived products, pathogens, and cells into the brain that is essential for normal neuronal functioning and information processing. Post-mortem tissue analysis indicates BBB damage in Alzheimers disease (AD). The timing of BBB breakdown remains, however, elusive. Using an advanced dynamic contrast-enhanced MRI protocol with high spatial and temporal resolutions to quantify regional BBB permeability in the living human brain, we show an age-dependent BBB breakdown in the hippocampus, a region critical for learning and memory that is affected early in AD. The BBB breakdown in the hippocampus and its CA1 and dentate gyrus subdivisions worsened with mild cognitive impairment that correlated with injury to BBB-associated pericytes, as shown by the cerebrospinal fluid analysis. Our data suggest that BBB breakdown is an early event in the aging human brain that begins in the hippocampus and may contribute to cognitive impairment. VIDEO ABSTRACT

Reliability of two‐dimensional and three‐dimensional pseudo‐continuous arterial spin labeling perfusion MRI in elderly populations: Comparison with 15o‐water positron emission tomography

To investigate the reliability and accuracy of two pseudo‐continuous arterial spin labeling (pCASL) sequences, using two‐dimensional (2D) gradient‐echo echo planar imaging (EPI) and 3D gradient and spin echo (GRASE) as the readout, respectively.

Neuropsychological and neuroimaging markers in early versus late-onset Alzheimer's disease.

Background: Early-onset Alzheimer’s disease (EOAD) has been overshadowed by the more common late-onset AD (LOAD). Yet, the literature indicates EOAD may have less hippocampal-memory presentations and more focal neocortical localization early in the disease. Objective: To evaluate these proposed differences between these 2 forms of AD and to explore what they inform about differences in AD pathophysiology. Methods: In all, 21 patients with EOAD and 24 patients with LOAD matched for disease progression and severity were compared on neurocognitive measures and resting state fluorodeoxy-glucose positron–emission tomography (FDG-PET). Results: Patients with EOAD had worse executive functions with greater hypometabolism in the parietal regions; whereas patients with LOAD had worse confrontation naming and verbal recognition memory with greater hypometabolism in inferior frontotemporal regions. Conclusions: In addition to highlighting significant differences between EOAD and LOAD, these results reveal dissociation between executive deficits in AD and frontal hypometabolism, suggesting early disturbances of the parietal–frontal network in EOAD.

Complexity and synchronicity of resting state blood oxygenation level-dependent (BOLD) functional MRI in normal aging and cognitive decline.

To explore the use of approximate entropy (ApEn) as an index of the complexity and the synchronicity of resting state blood oxygenation level‐dependent (BOLD) functional magnetic resonance imaging (fMRI) in normal aging and cognitive decline associated with familial Alzheimers disease (fAD).Purpose To explore the use of approximate entropy (ApEn) as an index of the complexity and the synchronicity of resting state BOLD fMRI in normal aging and cognitive decline associated with familial Alzheimer’s disease (fAD).

Posterior Cortical Atrophy: Evidence for Discrete Syndromes of Early-Onset Alzheimer’s Disease

Background: Posterior cortical atrophy (PCA) may represent a discrete syndrome of Alzheimer’s disease (AD) rather than amnestic AD with visual deficits. Methods: We separated 30 patients with PCA based on ventral and dorsal visual symptoms using cluster analysis and analyzed the demographic, cognitive, and functional imaging features. Results: This analysis revealed subgroups of 26 dorsal and 4 ventral patients. The ventral subgroup had greater confrontational naming impairment, and the dorsal subgroup had greater hypofunction in the parietal regions. The PCA cohort had memory retrieval rather than encoding deficits, and clinical follow-up showed relative isolation of dorsal and ventral visual manifestations. Conclusion: These results support 2, mostly nonoverlapping syndromes in patients with PCA, with the commonest affecting the dorsal visual pathway; moreover, the memory retrieval difficulty in the patients with PCA was dissimilar to the amnestic pattern in typical AD. These results suggest that, in most cases, PCA syndromes are discrete clinical variants of AD.

Assessing intracranial vascular compliance using dynamic arterial spin labeling

Vascular compliance (VC) is an important marker for a number of cardiovascular diseases and dementia, which is typically assessed in the central and peripheral arteries indirectly by quantifying pulse wave velocity (PWV), and/or pulse pressure waveform. To date, very few methods are available for the quantification of intracranial VC. In the present study, a novel MRI technique for in-vivo assessment of intracranial VC was introduced, where dynamic arterial spin labeling (ASL) scans were synchronized with the systolic and diastolic phases of the cardiac cycle. VC is defined as the ratio of change in arterial cerebral blood volume (ΔCBV) and change in arterial pressure (ΔBP). Intracranial VC was assessed in different vascular components using the proposed dynamic ASL method. Our results show that VC mainly occurs in large arteries, and gradually decreases in small arteries and arterioles. The comparison of intracranial VC between young and elderly subjects shows that aging is accompanied by a reduction of intracranial VC, in good agreement with the literature. Furthermore, a positive association between intracranial VC and cerebral perfusion measured using pseudo-continuous ASL with 3D GRASE MRI was observed independent of aging effects, suggesting loss of VC is associated with a decline in perfusion. Finally, a significant positive correlation between intracranial and central (aortic arch) VC was observed using an ungated phase-contrast 1D projection PWV technique. The proposed dynamic ASL method offers a promising approach for assessing intracranial VC in a range of cardiovascular diseases and dementia.

Two Novel Mutations in the First Transmembrane Domain of Presenilin1 Cause Young-Onset Alzheimer's Disease

BACKGROUND The presenilin-1 protein (PS1) is the catalytic unit of γ-secretase implicated in the production of abnormally long forms of amyloid-β (Aβ), including Aβ42, proteins thought critical in the pathogenesis of Alzheimers disease (AD). In AD of autosomal dominant inheritance, the majority of pathogenic mutations have been found in the PSEN1 gene within which the location of the mutation can provide clues as to the mechanism of pathogenesis. OBJECTIVE To describe clinical features of two novel mutations in the transmembrane portion 1 (TMD-1) of PSEN1 as well as biochemical features in one and neuropathological findings in the other. METHODS Two index patients with young onset AD with an autosomal dominant pattern of inheritance underwent clinical and imaging assessments, as well as PSEN1 sequencing. Postmortem examination was completed in one patient. An artificial construct in which the P88L mutation was introduced was created to examine its effects on γ-secretase cleavage. RESULTS Two novel variants in TMD-1 (P88L and V89L) were identified in affected probands. The neuropathological findings of AD were confirmed in the V89L mutation. Both patients presented around age 40 with early short-term memory deficits followed by seizures and corticospinal tract signs. The P88L mutation additionally featured early myoclonus followed by Parkinsonism. The causal role of the P88L mutation is supported by demonstration that this mutation dramatically increased Aβ42 and decreased APP and Notch intracellular domain production in vitro. CONCLUSION Changes in a single amino acid in codons 88 and 89 of TMD-1 can result in young-onset AD. The TMD-1 of PS1 is a region important for the γ-secretase cleavage of Aβ.

A Multidisciplinary Model of Dementia Care in an Underserved Retirement Community, Made Possible by Telemedicine

The need for memory specialists is increasing as the incidence of dementia rapidly rises across the globe. In rural areas, demand for these specialists far outstrips supply. It is increasingly difficulty for patients to receive care in a timely manner. In this paper, we document our experience using videoconference telemedicine to bring a multidisciplinary model of care to a rural retirement community in Southern California. To our knowledge, we are one of the first to integrate telemedicine into dementia care on this large a scale. Given the relatively remote location, patients and neurologists have previously had to travel great distances and bear with long wait times. With neurological consultation by telemedicine and a local team consisting of a geriatrician, a neuropsychologist, and a case manager, we have been able to provide comprehensive dementia care in this underserved area, comparable to university-affiliated California Alzheimer’s Disease Centers, typically found only in major metropolitan areas. We have shown that telemedicine can be very effective in improving access and quality of dementia care.

Regional association of pCASL-MRI with FDG-PET and PiB-PET in people at risk for autosomal dominant Alzheimer's disease

Autosomal dominant Alzheimers disease (ADAD) is a small subset of Alzheimers disease that is genetically determined with 100% penetrance. It provides a valuable window into studying the course of pathologic processes that leads to dementia. Arterial spin labeling (ASL) MRI is a potential AD imaging marker that non-invasively measures cerebral perfusion. In this study, we investigated the relationship of cerebral blood flow measured by pseudo-continuous ASL (pCASL) MRI with measures of cerebral metabolism (FDG PET) and amyloid deposition (Pittsburgh Compound B (PiB) PET). Thirty-one participants at risk for ADAD (age 39 ± 13 years, 19 females) were recruited into this study, and 21 of them received both MRI and FDG and PiB PET scans. Considerable variability was observed in regional correlations between ASL-CBF and FDG across subjects. Both regional hypo-perfusion and hypo-metabolism were associated with amyloid deposition. Cross-sectional analyses of each biomarker as a function of the estimated years to expected dementia diagnosis indicated an inverse relationship of both perfusion and glucose metabolism with amyloid deposition during AD development. These findings indicate that neurovascular dysfunction is associated with amyloid pathology, and also indicate that ASL CBF may serve as a sensitive early biomarker for AD. The direct comparison among the three biomarkers provides complementary information for understanding the pathophysiological process of AD.

The Role of Neuroimaging in the Assessment of the Cognitively Impaired Elderly

This article reviews the current diagnostic tools that are available for structural, functional, and molecular imaging of the brain, summarizing some of the key findings that have been reported in individuals diagnosed with Alzheimer disease, mild cognitive impairment, prodromal AD, or other prevalent dementias. Given recent advances in the development of amyloid PET tracers, current guidelines for the use of amyloid PET imaging in patients with cognitive complaints are reviewed. In addition, data addressing the potential value of amyloid PET imaging in the clinical setting are highlighted.