Terms describing preclinical states of AD (including both "asymptomatic at-risk state for AD" and "presymptomatic AD") refer to the long asymptomatic stage between the earliest pathogenic events/brain lesions of AD and the first appearance of specific cognitive changes.
The development of disease-modifying therapies for Alzheimer's disease is hampered by our lack of understanding of the early pathogenic mechanisms and the lack of early biomarkers and risk factors.
This subtle nigrostriatal synaptic vulnerability may reflect one of the earliest pathogenic processes in LRRK2-associated PD.
The ability to detect and monitor a neurodegenerative disease soon after its onset and to anticipate its future progression is a fundamental step towards uncovering early pathogenic mechanisms and developing targeted therapies.
Our data are consistent with evidence from other studies that point to NMJ alteration as an early pathogenic event and support the validity of the T70I zebrafish model (Fischer et al., 2004; Dupuis et al., 2009; Dupuis and Loeffler, 2009; Ramesh et al., 2010).
We show that failure of VMAT-containing synaptic vesicle release to nerve terminals is an early pathogenic manifestation, and the formation of neurofibrillary tangle-like pathology in the soma of DA neurons is a late-stage of tauopathy, providing pathological evidence for why MAPT may be a strong risk factor for idiopathic PD.
Together, these data suggest that changes in brain Aβ42 metabolism and amyloid formation are early pathogenic events in AD, and that significant disruptions in CSF tau metabolism likely occur after Aβ42 initially aggregates and increases as amyloid accumulates.
Thus, both JAK and SYK signaling pathways are involved in early pathogenic mechanisms of arthritis and simultaneous inhibition of both kinases results in greater efficacy.
In myeloma, overexpression of cyclin D members occurs in most cases, and is considered to be a common and early pathogenic event in the development of the disease.
These microtubule, actin cytoskeletal and molecular motor defects are early pathogenic events in our AD model and might lead to transport abnormalities and the accumulation of organelles (synaptic vesicles, autophagosomes, mitochondria, lysosomes) within axonal neurites promoting the dystrophic process.
