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neurodegenerative diseases

Wednesday 16 July 2003

Definition: Neurodegenerative diseases are diseases of gray matter characterized principally by the progressive loss of neurons with associated secondary changes in white matter tracts.

Two other general characteristics bring them together as a group:
- First, the pattern of neuronal loss is selective, affecting one or more groups of neurons while leaving others intact.
- Second, the diseases arise without any clear inciting event in patients without previous neurologic deficits.

The neuropathologic findings observed in the degenerative diseases differ greatly; in some, there are intracellular abnormalities with some degree of specificity (e.g., Lewy bodies, neurofibrillary tangles), while in others, there is only loss of the affected neurons.

It is convenient to group the degenerative diseases according to the anatomic regions of the CNS that are primarily affected.

Some degenerative diseases have prominent involvement of the cerebral cortex, such as Alzheimer disease; others are more restricted to subcortical areas and may present with movement disorders such as tremors and dyskinesias. As genetic and molecular studies of these diseases have progressed, there has been recognition of shared features across many of the disorders.

A common theme among the neurodegenerative disorders is the development of protein aggregates that are resistant to normal cellular mechanisms of degradation through the ubiquitin-proteasome system. These aggregates can be recognized histologically as inclusions, which often form the diagnostic hallmarks of these different diseases. The basis for aggregation varies across diseases.

For example, it may be directly related to an intrinsic feature of a mutated protein (e.g., expanded polyglutamine repeat in Huntington disease), a feature of a peptide derived from a larger precursor protein (e.g., Aβ in Alzheimer disease), or an unexplained alteration of a normal cellular protein (e.g., α-synuclein in sporadic Parkinson disease).

The aggregated proteins are generally cytotoxic, but the mechanisms by which protein aggregation is linked to cell death may be different in these various diseases.

The major cortical degenerative disease is Alzheimer disease, and its principal clinical manifestation is dementia, that is, progressive loss of cognitive function independent of the state of attention.

There are many other causes of dementia, including the various forms of frontotemporal dementia, vascular disease (multi-infarct dementia), dementia with Lewy bodies (considered later in the context of Parkinson disease, the other Lewy body disorder), Creutzfeldt-Jakob disease, and neurosyphilis (both considered earlier).

These diseases also involve subcortical structures, but many of the clinical symptoms are related to the changes in the cerebral cortex. Regardless of etiology, dementia is not part of normal aging and always represents a pathologic process.

Types

- cortical degenerative diseases

Abnormal processing of neuronal proteins

Virtually all neurodegenerative disorders involve abnormal processing of neuronal proteins.

The aberrant mechanism can entail a misfolding of proteins, altered post-translational modification of newly synthesized proteins, abnormal proteolytic cleavage, anomalous gene splicing, improper expression, or diminished clearance of degraded protein.

Misprocessed proteins often accumulate because the cellular mechanisms for removing them are ineffective.

The particular protein that is improperly processed determines the malfunction of distinct sets of neurons and thus the clinical manifestations of the disease.

Protein aggregates

A common theme among the neurodegenerative disorders is the development of protein aggregates that are resistant to normal cellular mechanisms of degradation through the ubiquitin-proteasome system.

These aggregates can be recognized histologically as inclusions, which often form the diagnostic hallmarks of these different diseases. The basis for aggregation varies across diseases.

For example, it may be directly related to an intrinsic feature of a mutated protein (e.g., expanded polyglutamine repeat in Huntington disease), a feature of a peptide derived from a larger precursor protein (e.g., Aβ in Alzheimer disease), or an unexplained alteration of a normal cellular protein (e.g., α-synuclein in sporadic Parkinson disease).

The aggregated proteins are generally cytotoxic, but the mechanisms by which protein aggregation is linked to cell death may be different in these various diseases.

Cortical degenerative diseases

The major cortical degenerative disease is Alzheimer disease, and its principal clinical manifestation is dementia, that is, progressive loss of cognitive function independent of the state of attention.

There are many other causes of dementia, including the various forms of frontotemporal dementia, vascular disease (multi-infarct dementia), dementia with Lewy bodies (considered later in the context of Parkinson disease, the other Lewy body disorder), Creutzfeldt-Jakob disease, and neurosyphilis (both considered earlier).

These diseases also involve subcortical structures, but many of the clinical symptoms are related to the changes in the cerebral cortex. Regardless of etiology, dementia is not part of normal aging and always represents a pathologic process.

Frontotemporal dementia (FTD) and Alzheimer disease (AD)

FTD and AD are primary degenerative dementias, meaning that a gradual loss of neurons is responsible for the progressive brain dysfunction.

Within the group of presenile dementias (onset <65 years of age), FTD is the second most common form of neurodegenerative dementia after AD.

Clinically, Alzheimer disease (AD) is primarily a disease of memory and cognition caused by a more genereralized brain atrophy, starting in the medial temporal lobe.

The hallmarks of frontotemporal dementia (FTD) are behavior and/or language dysfunction caused by a more focal degeneration mainly affecting the frontal and temporal brain regions.

Nevertheless and despite the existence of usefud clinical diagnostic criteria for both disorders, the distinction between presenile AD and FTD can be difficult, especially in presenile cases, which often have an atypical presentation.

In particular, the inherited forms of FTD have an extremely broad phenotype ranging from typical FTD to cases where parkinsonism, amyotrophy or AD-like memory impairment are the major disabling features.

In addition, focal variants of AD, where memory loss is not a prominent early feature, are relatively common in a presenile setting and can mimic FTD.

Because deposition of tau protein aggregates in affected brain regions is a common feature in AD and tau-positive FTD, it is likely that both disorders share a common pathogenetic mechanism.

Anomalies of lipid metabolism

Several neurodegenerative disorders are associated with a pathological lipid metabolism.

Disease Affected lipids Enzymatic defects
Faber’s disease ceramide acid ceramidase
Niemann-Pick Disease sphingomyelin sphingomyelinase
Krabbe disease galactosylceramide, galactosylsphingosine galactosylceramidase Gaucher disease glucosylceramide, glucosylsphingosine glucosylceramidase Fabry disease digalactosylceramide *-galactosidase A
Tay-Sachs disease GM ganglioside β-hexosaminidase A Sandhoff disease GM ganglioside β-hexosaminidase A and B
Metachoromatic leukodystrophy sulfatide arylsulfatase A (sulfatidase)
Multiple sulfatase deficiency sulfatide arylsulfatase A, B, C
Sulfatidase-activator deficiency (sap-B deficiency) sulfatide, globotriaosylceramide, digalactosylceramide, GM3 ganglioside sulfatidase activator (SAP-1, SAP-B)
SAP-2 deficiency glucosylceramide SAP-2 (SAP-C)
SAP-precursor deficiency all glycolipids with short sugarchains, e.g. Cer, GlcCer, LacCer, GalCer, DigalCer, sulfatide SAP precursor SAP-A, -B, -C, -D
GM1-gangliosidosis GM1 ganglioside GM1 ganglioside, β-galactosidase GM2-gangliosidosis (B1 variant) GM2 ganglioside β-hexosaminidase A
GM2-gangliosidosis (AB variant) GM2 ganglioside β-hexosaminidase A

Types

- sporadic neurodegenerative diseases
- inherited neurodegenerative diseases

Molecular classification

- APP-associated diseases
- MAPT-associated (tauopathies)
- PSENs-associated diseases

See also

- abnormal protein aggregation
- microtubule-associated protein tau
- taupathies
- paraneoplastic neurological degenerations

References

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