Diagnosis of AD
The initial manifestations of Alzheimer’s Disease (AD) frequently encompass cognitive domains beyond memory, encompassing challenges in lexical retrieval, visual processing, spatial orientation, compromised reasoning abilities, and impaired judgment. Memory deficits represent a salient and discernible manifestation of Alzheimer’s disease1.
In the realm of dementia diagnosis, encompassing Alzheimer’s disease (AD) as well, a multitude of imaging techniques are employed6,7. The utilization of CT scans facilitates the examination of alterations in the dimensions of cerebral regions, which are subsequently juxtaposed with either prior scans or projected cerebral sizes corresponding to individuals of commensurate age and physique. Magnetic Resonance Imaging (MRI) plays a pivotal role in the identification and characterization of anomalous cerebral alterations, notably brain atrophy. Fluorodeoxyglucose positron emission tomography (FDG-PET) scans are employed to quantify glucose uptake within the cerebral region, exhibiting diminished levels in specific regions among individuals afflicted with dementia. Consequently, these scans have proven to be valuable tools for diagnostic endeavors. The utilization of amyloid positron emission tomography (PET) scans enables the identification and quantification of anomalous accumulations of beta-amyloid protein, a distinctive characteristic associated with Alzheimer’s disease (AD). The utilization of amyloid PET scans in clinical practice often involves the administration of various tracers, such as florbetapir, flutemetamol, florbetaben, and Pittsburgh compound B. Tau positron emission tomography (PET) scans, which employ tracers such as AV-1451, PI-2620, and MK-6240, have demonstrated their efficacy in identifying pathological tau protein aggregates, thereby serving as a valuable tool for monitoring the progression of Alzheimer’s disease (AD)6,7.
Lumbar punctures are commonly utilized in the identification of cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease (AD), including beta-amyloid 42, tau, and phospho-tau6,7. Blood tests represent an additional modality for the diagnosis of Alzheimer’s disease (AD), with the primary objective of detecting brain-derived biomarker proteins such as beta-amyloid 42/beta-amyloid 40 and phospho-tau 181. The present diagnostic methods for Alzheimer’s disease (AD) exhibit a degree of predictability; however, their sensitivity and accuracy may be enhanced to enable more precise and early detection of AD. This can be achieved through the integration of advanced technologies, such as nanoparticles, with existing imaging agents and tracers. The aforementioned advancements possess the potential to expedite the initiation of therapeutic interventions, thereby potentially impeding the progression of the disease and mitigating the symptoms associated with Alzheimer’s disease (AD)6,7.
Recent studies have been focused on developing integrative methods with nanoparticles to enhance current diagnostic procedures. One study by Razzino et al., synthesized gold-polyamidoamine dendrimer nanocomposites conjugated with screen-printed carbon electrodes (SPCE) to facilitate enhanced diagnosis of AD. The nanocomposites were also functionalized with anti-tau antibodies, allowing tau tangles to aid as the target for diagnosis of AD. In the study by Kim et al., long gold-nanoparticle based nanorods were found to detect tau levels at a significantly low dose of 23.6 fM. One limitation of tau-targeting gold-nanoparticle biosensors is the difficulty of the tau epitopes to be accessible to the biosensor. The hydrophobic bonds between tau proteins and the hydrogen bonding between tau epitopes often limit the ability of nanoparticle-based biosensors to detect the tau protein. This challenge can be overcome by coupling the nanoparticle-based biosensor with chaotropic agents to hinder tau-tau interactions. With this, the nanoparticles-based biosensors were able to detect significantly low tau concentrations of 0.1 pM, compared to the 1.0 pM tau concentration detected by the nanoparticle-based biosensor without the chaotropic agents. Although these studies have found success in implementing gold nanoparticles as in vitro biosensing platforms, further research is necessary to establish their biocompatibility, administration, and bioaccumulation in vivo. Another recent study fabricated magnetic nanoparticles coated with dextran to detect significant AD blood biomarkers, such as amyloid-beta and phosphorylated tau. This was accomplished by functionalizing the surface of the magnetic nanoparticles with antibodies against amyloid-beta and phosphorylated tau. Further studies showed that the synthesized magnetic nanoparticles had high specificity and sensitivity when differentiating between the healthy control group and groups with mild cognitive impairment and AD dementia. However, the magnetic nanoparticles had moderate specificity and sensitivity when differentiating between the mild cognitive impairment and AD dementia groups. In the study by Chen et al., success was found in implementing CuInS2/ZnS quantum dots functionalized with dopamine for the detection of tau protein. Results showed that the synthesized quantum dots had the ability to detect tau protein concentrations as low as 9.3 pM. Another study synthesized graphene oxide magnetic nanoparticles conjugated with tannin-capped silver nanoparticles to detect tau tangles. These nanoparticles were able to detect low tau concentrations of 5.74 fg/mL. Multi-walled carbon nanotubes were also found to detect significantly low tau concentrations of 15.0 nM in artificial cerebrospinal fluid and 7.8 nM in solution buffer. Another study showed that surface plasmon resonance systems synthesized with silica fibers had promising potential to detect total-tau protein levels as low as 2.4 pg/mL and phosphorylated-tau protein levels as low as 1.6 pg/mL. Specifically, these nanoparticulate systems effectively differentiated between healthy controls and AD patients and showed a 6-fold increase in total-tau levels and a 3-fold increase in phosphorylated-tau levels between AD patients and the healthy controls.
As shown by extensive studies, tau-targeting nanoparticles show promising potential to function as an effective AD diagnostic tool. However, before these nanoparticulate systems can be utilized on a widespread clinical scale, certain limitations such as efficiency, biosensor multiplexing, long-term biocompatibility and cost-effective manufacturing must be overcome. Overall, coupling nanoparticle-based diagnostics with conventional diagnostics could significantly enhance the efficacy of AD biosensors and offer improved AD diagnostic techniques.