Neurodegenerative Disease Processes

Neurodegenerative disorders of the central nervous system (CNS) are characterized by the loss of specific populations of neural cells, the pattern and distribution of which shape the clinical presentation of the patient. This has led to the standard way in which these disorders are diagnosed: namely, the clinical phenotype of motor impairment (tremor, rigidity, and hypokinesia) in Parkinson disease (PD) with a loss of nigral dopaminergic neurons, amyotrophic lateral sclerosis (ALS) with the loss of motor neurons, and so on ( Table 92.1 ). These cellular losses are typically also defined by the accumulation of an abnormal protein that usually gives rise to an inclusion (e.g., α-synuclein–containing Lewy bodies (LBs) in PD or hyperphosphorylated tau neurofibrillary tangles in progressive supranuclear palsy [PSP]). This has led to calls to reclassify neurodegenerative disorders by the proteinopathy that characterizes them—α-synucleinopathies, tauopathies, etc. (see Table 92.1 ). Although this latter approach has much to merit it, especially when one comes to study disease pathogenesis, many clinicians would argue that they cannot see the pathology of cell inclusions (although this may change with the advent of new positron emission tomography [PET] ligands for these protein aggregates), only the clinical phenotype. Therefore most patients are still diagnosed using clinical criteria which predict a pathology and a therapeutic approach. In all cases this therapy serves to treat symptoms. There is an urgent unmet need to identify disease-modifying therapies for these disorders as the world’s population ages and we face a burgeoning burden of age-related neurodegenerative diseases.

In this chapter we discuss some of the mechanisms underlying the loss of cells in neurodegenerative disorders and how this may shape future therapies.

However, before discussing this in more detail, it is worth making a few general points about neurodegenerative disorders of the CNS:

• Similar clinical presentations can have different disease causes: for example, idiopathic PD can initially look just like the parkinsonian form of multiple system atrophy (MSA); many cases of what look like corticobasal degeneration (CBD) end up having a pathological diagnosis of PSP or Alzheimer disease (AD) ( ). This poses a challenge for the selection of patients for clinical trials who may not respond to a treatment because they do not have the target pathology (rather than the drug lacking efficacy).

• Similar pathological states can have different clinical presentations: for example, tauopathies presenting as PSP and CBD ( ) or c9orf72 presenting as frontotemporal dementia (FTD) or ALS (

• Many patients dying of specific diseases have a mixed pathology at postmortem, especially in the more elderly population (e.g., AD with amyloid plaques, tau tangles, along with vascular disease and α-synuclein deposition). Indeed there is even some suggestion that one pathology may trigger another: for example, AD in patients presenting initially with a cerebral amyloid angiopathy ( ) or tau driving additional degeneration alongside α-synuclein pathology ( ).

• All primary neurodegenerative disorders of the CNS have a glial response which may contribute to the disease state; for example, ALS may be driven by neurotoxic signals and/or abnormal glutamate handling by astrocytes ( ). In this respect, diseases that were once thought of as being more glial in nature—such as multiple sclerosis (MS)—are now being reclassified as neurodegenerative, given that this defines the disease in the secondary progressive phase after the initial inflammatory events ( ).

• All neurodegenerative disorders generate an immune/inflammatory/microglial response, which again may be an integral part of the disease process; for example, in Huntington disease (HD) there are changes in the circulating immune cells that experimentally alter the disease course of HD in transgenic animals (reviewed in ).

• It is also increasingly being recognized that traditional single disease entities may have different “disease subtypes” within them; for example, in PD there is evidence to show that some patients develop dementia earlier than others, which is driven by certain genetic variants in tau and the glucocerebrosidase (GBA) gene, as well as possibly inflammation ( ; ). As such, these diseases, despite superficially looking the same, may have different pathogenic pathways, or at least a similar pathogenic process with different kinetics. This disease heterogeneity is present across all neurodegenerative disorders and is an additional challenge for the design of clinical trials around disease modification.

• Over the past 25 years many Mendelian forms of classical neurodegenerative diseases of the CNS have been described (e.g., AD and PD). These monogenic forms of disease have been very helpful in identifying pathways of disease, especially through the generation of cell and animal models of disease ( ). However, while instructive, understanding the basis of these disorders does not necessarily mean that the same processes occur in the commoner sporadic forms of disease, although in some cases genes linked to familial forms of the disease have also emerged from a genome wide association study (GWAS) (e.g., LRRK2 in PD) ( ). For example, patients with Parkin mutations present with parkinsonism and have a pathology that affects protein degradation within the cell, but the few patients who have come to postmortem do not appear to have classical LB pathology, the hallmark of idiopathic PD ( ). As such, these patients do not have the same disease and thus the same fundamental disease process as that which underlies sporadic PD. In other words, many rare genetic forms of common sporadic disorders are instructive only up to a point.

• Finally it is currently recognized that many neurodegenerative disorders of the CNS may not have a pathology that is solely cell autonomous (i.e., driven only by an intrinsic problem within the neuron affected by the disease process). Rather, all disorders (even solely genetic disorders such as HD) have a noncell autonomous aspect to them that includes not only the glial/inflammatory component discussed earlier but also the possible spreading of pathogenic protein strains from one cell to another in a prion-like fashion (e.g., tauopathies, α-synuclein in PD, and certain forms of ALS) ( ).

It is important to remember these major points when one comes to try and understand the relative role of different pathogenic pathways in neurodegenerative disorders of the CNS, because it is all too easy to study one isolated pathway as the only pathway to cell loss in these conditions. The reality is that many pathways are involved and that there is a significant degree of overlap between seemingly different disorders. Therefore we will briefly summarize all the pathways linked to cellular dysfunction and death in these disorders, highlighting commonalities as well as differences and how this may ultimately impact on new therapeutic approaches for these disorders. In the end, it is likely that successful therapeutic strategies will target a number of these pathways together rather than focusing on one, because this has so far proven unsuccessful (e.g., ).