Contributed by H. Brent Clark, M.D., Ph.D.
The neuropathological bases of dementia have become better understood during the past several decades. Despite a common misconception that all dementia is secondary to Alzheimer’s disease, there are a number of other pathological forms of dementia. A shared feature of these disorders is the abnormal accumulation of proteins within cells of the nervous system. This article reviews the neuropathology and possible etiologies of the three most common neurodegenerative dementias: Alzheimer’s disease, frontotemporal dementia, and dementia with Lewy bodies. These conditions typically are sporadic, but study of rarer inherited forms has led to insights into their etiologies.
The most common type of dementia, Alzheimer’s disease (AD), typically presents as problems with memory, including difficulties with spatial memory and memory formation. As the disease progresses, patients experience a global loss of cognitive function. The disease is characterized by the presence of neurofibrillary tangles, cytoplasmic accumulations of an inappropriately phosphorylated form of a protein called tau. The second histological hallmark is the presence of senile plaques, extracellular accumulations of a peptide called A-beta, often in an amyloid configuration, that is intermingled with abnormally dilated neuronal processes (Figure A). Neurofibrillary tangles and neuronal loss first occur in the mesial temporal lobes, areas of the brain associated with memory formation, which explains the early clinical features. The role of the plaques and tangles in the pathophysiology of the disease is not clear, and there is no strong correlation between severity of dementia and severity of plaque deposition. The spread of tangles beyond the mesial temporal zones as the disease progresses correlates better with cognitive disability, but other pathological changes—such as somatic and dendritic atrophy, synaptic loss, and neuronal death—also are critical elements of the pathology.
Our growing understanding of genetic mutations associated with AD has led to a better understanding of its etiology. Three autosomal dominant mutations causative for AD have been identified. One occurs in the gene for the amyloid precursor protein (APP), which is the larger protein from which the A-beta peptide, a 40-42 amino acid segment, is cleaved. The most common mutation is in presenilin-1, a protein involved in the processing of APP, which is a function shared by the other known target for mutation, presenilin-2. Another genetic factor, a variant in apolipoprotein E, the epsilon 4 allele, while not causative, increases the risk for AD by as much as twelvefold if present in the homozygous state. Its role in the pathogenesis of AD may relate to its effect on processing of A-beta.
It appears that APP and A-beta have a critical role in the initiation of the disease process. The A-beta in senile plaques often takes the conformational form of amyloid, but because the amyloid burden does not correlate well with degree of dementia, many investigators believe that monomers or oligomeric aggregates of this peptide are toxic to neurons and may be a major pathogenetic factor.
Other contributory factors to the pathogenesis of AD include microglial activation. A form of neuroinflammation, microglial activation once was thought to be only a secondary reaction to neurodegeneration, but is now considered a likely contributor to pathogenesis. These inflammatory changes may be accompanied by oxidative stress and mitochondrial dysfunction. Concomitant cerebrovascular disease of any type increases the risk of dementia, even with lower burdens of tangles and plaques. Diabetes mellitus also increases the risk of AD. The greatest risk factor, however, is age, with AD’s prevalence reaching nearly 50% among those ages 85 and older.
A rarer form of dementia, frontotemporal dementia (FTD), was in the past commonly known as Pick’s disease, a term now restricted to a distinctive subtype of FTD. Until the past two decades, FTD was identified solely by the distribution of atrophy in the frontal and temporal lobes, with the rest of the brain less affected. Clinical manifestations of FTD are more variable than in AD and appear in two basic patterns. The “behavioral” pattern, often initially mistaken for signs of psychiatric disease, is characterized by disinhibition, loss of social graces, apathy, and deficits of executive functions, with memory and visualspatial functions spared in the early stages. The “primary progressive aphasia” pattern includes variable problems with semantic memory, expressive aphasia, or slow nonfluent speech and poor comprehension.
Studies of the dominantly inherited forms of FTD have identified genetic mutations associated with FTD and increased our understanding of its pathogenesis. Mutations in the gene for tau, the same protein seen in neurofibrillary tangles, account for some cases of FTD. These patients accumulate abnormally phosphorylated tau in their brains, largely in glial cells. Pick’s disease, although a sporadic form, also is characterized by tau-containing neuronal inclusions (Pick bodies). More recently, studies of other FTD-kindreds have found mutations in the gene for progranulin, a protein involved in regulation of inflammation. Patients from these families have abnormal intranuclear neuronal aggregates of a protein called TDP-43, a RNA/DNA-binding protein normally involved in regulation of gene transcription. When brain tissue from patients with sporadic FTD has been examined for TDP-43 immunoreactivity, this nuclear protein has been found to be abnormally translocated from the nucleus to the cytoplasm of some neurons (Figure B). More recently, an additional mutation has been found in a gene on chromosome 9 (C9orf72). The mutation is an expansion of a hexanucleotide repeat, GGGGCC. One hypothesis is that messenger-RNA containing the expanded abnormal repeat sequesters certain transcriptional splicing factors and causes alterations in protein expression patterns. There also is evidence that a novel mechanism of protein translation across these expanded repeats results in the formation of dipeptide-repeat proteins that accumulate in cytoplasmic inclusions within neurons and could contribute to pathogenesis. Abnormalities of TDP-43 and mutations in C9orf72 also have been identified in many patients with amyotrophic lateral sclerosis (ALS), suggesting a link between that condition and FTD.
Dementia With Lewy Bodies
Lewy bodies, intracytoplasmic neuronal inclusions composed of the protein alpha-synuclein (Figure C), are associated with another form of dementia. They also are the characteristic finding in idiopathic Parkinson’s disease. Many patients with Parkinson’s disease develop cognitive problems, but in some patients the dementia precedes the onset of the movement disorder by at least one year. That presentation is termed dementia with Lewy bodies (DLB), but pathologically the two often are indistinguishable at end stage. The clinical features of DLB differ from AD in that memory loss is not the predominant presenting feature, although it may develop later. Deficits in executive function, attention, and visual-spatial abilities are often seen at onset. Visual hallucinations also are a characteristic feature, as is diurnal or day-to-day fluctuation in cognitive impairment. Even in patients who present initially with dementia, Parkinsonian features usually develop.
Involvement of the cerebral cortex and limbic areas tends to correlate with cognitive changes in both patients with Parkinson’s disease-related dementia and DLB. At autopsy, the characteristic pathological changes in patients with DLB are widespread, and it is difficult to determine whether dementia preceded or followed the onset of Parkinsonism. To further complicate matters, there is a significant crossover of AD-related pathology in patients with Parkinson’s disease and/or DLB.
A number of genetic mutations have been associated with DLB/Parkinson’s disease. Of interest, one of those mutations is in alpha-synuclein, the principal component of Lewy bodies. Other mutations are in proteins involved in protein and lipid metabolism, mitochondrial function, and immune mechanisms. Regardless of the underlying mechanism, DLB is characterized by an intraneuronal accumulation of alpha-synuclein, which particularly when in oligomeric forms, may be harmful. Lewy bodies could represent a compensatory attempt to sequester the toxic protein into less harmful large aggregates. A recent hypothesis proposes that the spread of the disease within the nervous system is mediated via trans-synaptic passage of abnormal conformational forms of alpha-synuclein in a manner similar to what is thought to occur in prion diseases, such as Creutzfeldt-Jakob disease.
Dr. H. Brent Clark is the director of neuropathology at the University of Minnesota Medical School and University of Minnesota Health and is a professor in the Departments of Laboratory Medicine and Pathology, Neurology, and Neurosurgery. He has had a longstanding interest in the pathology of neurodegenerative diseases, particularly the hereditary cerebellar ataxias.
Article appears in MetroDoctors. 2016;18(6):14-15. MetroDoctors is the journal of the Twin Cities Medical Society.
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