Celeste A. Roney

Quinoline-n-butylcyanoacrylate-based nanoparticles for brain targeting for the diagnosis of Alzheimer's disease

A survey of research activity on nanoparticles (NPs) based on polymeric devices that could cross the blood-brain barrier (BBB) is given along with the presentation of our own data on the development of NPs of n-butyl-2-cyanoacrylate (BCA) for brain delivery to aid the early diagnosis of Alzheimers disease (AD), a neurodegenerative disorder of the elderly people, the most prevalent form of dementia. Typical data are presented on in vivo detection of amyloid peptides (A beta) (amyloid plaques) that are used as targets for developing the biological markers for the diagnosis of AD. In order to develop efficient in vivo probes, polymeric n-butyl-2-cyanoacrylate (PBCA) NPs have been prepared and encapsulated with the radio-labeled amyloid affinity drug (125)I-clioquinol (CQ, 5-chloro-7-iodo-8-hydroxyquinoline) to improve the transport to brain and amyloid plaque retention of (125)I-CQ using the NPs of PBCA. The (125)I-CQ discriminately binds to the AD post-mortem brain tissue homogenates versus control. (125)I-CQ-PBCA NPs labeled the A beta plaques from the AD human post-mortem frontal cortical sections on paraffin-fixed slides. Storage phosphor imaging verified preferential uptake by AD brain sections compared to cortical control sections. The (125)I-CQ-PBCA NPs crossed the BBB in wild type mouse, giving an increased brain uptake measured in terms of % ID/g i.e., injected dose compared to (125)I-CQ. Brain retention of (125)I-CQ-PBCA NPs was significantly increased in the AD transgenic mice (APP/PS1) and in mice injected with aggregated A beta 42 peptide versus age-matched wild type controls. The results of this study are verified by in vivo storage phosphor imaging and validated by histopathological staining of plaques and select metal ions, viz. Fe(2+) and Cu(2+). The (125)I-CQ-PBCA NPs had more efficient brain entry and rapid clearance in normal mice and enhanced the retention in AD mouse brain demonstrating the ideal in vivo imaging characteristics. The (125)I-CQ-PBCA NPs exhibited specificity for A beta plaques both in vitro and in vivo. This combination offered radio-iodinated CQ-PBCA NPs as the promising delivery vehicle for in vivo single photon emission tomography (SPECT) ((123)I) or PET ((124)I) amyloid imaging agent. The importance of the topic in relation to brain delivery and other similar type of work published in this area are covered to highlight the importance of this research to medical disciplines.

Convergence of connected language and SPECT in variants of frontotemporal lobar degeneration.

The characterization of frontotemporal lobar degeneration (FTLD) is complicated and not widely recognized. Connected language measures (ie, discourse) and functional neuroimaging may advance knowledge specifying early distinctions among frontal dementias. The present study examined the correspondence of discourse measures with (1) clinical diagnosis and (2) single photon emission computed tomography (SPECT) imaging. Nineteen subjects were selected from Alzheimers Disease Center (ADC) participants if they were diagnosed with early-stage frontotemporal lobar degeneration and also underwent single photon emission computed tomography and discourse evaluation. First, clinical diagnoses given by specialists at an Alzheimers Disease Center were compared with the discourse-based diagnostic profiles. Secondly, compromised brain regions that were predicted from discourse profiles were compared with SPECT findings. Results revealed a significant correspondence between the ADC diagnosis and the discourse-based diagnoses. Also, the discourse profiles across frontotemporal lobar degeneration subtypes were consistently associated with distinctive patterns of SPECT hypometabolism in the right frontal, left frontal, or left temporal lobes. These findings suggest that discourse methods may be systematized to provide an efficient adjunct measure beyond the traditional word and sentential level measures. Objectifying complex language performance may contribute to early detection and differentiation among frontotemporal lobar degeneration variants because consensus in the literature states that language is a core disturbance of frontotemporal lobar degeneration.

Nanoparticulate Radiolabelled Quinolines Detect Amyloid Plaques in Mouse Models of Alzheimer's Disease

Detecting aggregated amyloid peptides (Aβ plaques) presents targets for developing biomarkers of Alzheimers disease (AD). Polymeric n-butyl-2-cyanoacrylate (PBCA) nanoparticles (NPs) were encapsulated with radiolabelled amyloid affinity 125I-clioquinol (CQ, 5-chloro-7-iodo-8-hydroxyquinoline) as in vivo probes. 125I-CQ-PBCA NPs crossed the BBB (2.3 ± 0.9 ID/g) (P < .05) in the WT mouse (N = 210), compared to 125I-CQ (1.0 ± 0.4 ID/g). 125I-CQ-PBCA NP brain uptake increased in AD transgenic mice (APP/PS1) versus WT (N = 38; 2.54 × 105 ± 5.31 × 104 DLU/mm2; versus 1.98 × 105 ± 2.22 × 104 DLU/mm2) and in APP/PS1/Tau. Brain increases were in mice intracranially injected with aggregated Aβ 42 peptide (N = 17; 7.19 × 105 ± 1.25 × 105 DLU/mm2), versus WT (6.07 × 105 ± 7.47 × 104 DLU/mm2). Storage phosphor imaging and histopathological staining of the plaques, Fe2+ and Cu2+, validated results. 125I-CQ-PBCA NPs have specificity for Aβ in vitro and in vivo and are promising as in vivo SPECT (123I), or PET (124I) amyloid imaging agents.

Feature Article: Polymeric Nanoparticulate Drug Delivery Through The Blood Brain Barrier

Abstract Alzheimers disease (AD) is the most common cause of dementia among the elderly, affecting 5% of Americans over age 65, and 20% over age 80. An excess of senile plaques (β-amyloid protein) and neurofibrillary tangles (tau protein), ventricular enlargement, and cortical atrophy characterizes it. Unfortunately, targeted drug delivery to the Central Nervous System (CNS), for the therapeutic advancement of neurodegenerative disorders such as Alzheimers, is complicated by restrictive mechanisms imposed at the blood brain barrier (BBB). Opsonization by plasma proteins in the systemic circulation is an additional impediment to cerebral drug delivery. Here, we attempt to show that biodegradable polymeric nanoparticles (NPs) with appropriate surface modifications can deliver drugs of interest beyond the BBB for diagnostic and therapeutic applications, thus allowing the study of neurological disorders. Particularly, the radiolabelled Cu2+ or Fe3+ metal chelator Clioquinol (CQ), which has a high affinity f...