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I.R.F. / Aging news / Diseases / 01112201

Alzheimer-type Lesions in Huntington's Disease
Posted on: November 22, 2002

Huntington's disease (HD), a neurodegenerative disorder with autosomal dominant inheritance, is clinically characterized by choreic movements, psychiatric manifestations, and dementia, leading to death in 10 to 20 years. HD is caused by a genetic CAG repeat defect in the coding region of the IT 15 gene on chromosome 4pl6.3, a locus which encodes a protein designed huntingtin. In this coding region, the CAG trinucleotide repeat normally comprises 10 to 36 CAG, but exceeds 37 in patients with HD. Neuropathologically, HD is characterized by diffuse cerebral atrophy and atrophy of the caudate nucleus and, less, of the putamen due to preferential loss of the medium spiny GABAergic type II neurons of the striatum and, at later stages of the disease, of pyramidal neurons of layers III, V and VI of the cerebral cortex. Other cerebral structures including the nucleus accumbens, pallidum. ventrolatcral thalamus, subthalamic nucleus, and substantia nigra may also be involved in a lesser extent and at a later stage in the disease. The intensity and extent of the striatal lesions correlating with the severity of the genetic defect and the clinical picture have been classified into 5 grades from absent changes to severe striatal atrophy. Recent studies suggest that the expression or processing of the mutated huntingtin in perikarya and nerve endings differs from that of the normal forms in these neuronal compartments leading to neuronal death, but the mechanisms of gene action causing a distinctive pattern of HD degeneration are not yet fully understood. Recently, transgenic mice with the human HD CAG mutation have been developed that exhibit a progressive neurological phenotype with features of HD. These mice develop neuronal intranuclear inclusions containing huntingtin and ubiquitin, prior to developing a neurological phenotype. In vitro studies demonstrated that proteolytic cleavage of a glutathione S-transferase-huntingtin fusion protein led to protein aggregates similar to scrappy prions and Aβ fibrils of AD. These fibrils were present only when the polyglutamine expansions were in the pathogenic range. Ultrastructural studies of transgenic mice with the HD mutation revealed similar structures in neurons. The demonstration of a high incidence of huntingtin- and ubiquitin-immunoreactive (IR) neuronal intranuclear inclusions in the cortex and striatum of juvenile onset HD brains with much rarer occurrence in adult HD patients and of ubiquitinated dystrophic neurites in many cortical areas suggests possible primary cortical pathology in HD. Such dystrophic neurites that appear to resemble ubiquinated "Lewy" neurites in Lewy body dementia and Parkinson's disease, are believed to be caused by impaired axonal transport and conversion of removal of membranous structures. Both ubiquitin and p-amyloid precursor protein-(APP) have been found in dystrophic neurites in a wide variety of diseases. While ubiquitin plays a major role in the degradation of abnormal proteins, APP is a membrane protein that in neurons undergoes fast axonal transport. Together with ubiquitin, it may indicate intense proteolytic activity in HD and related disorders that may be caused by aberrant deposition of protein aggregates in the brain leading to neuronal dysfunction.

While the movement disorders in HD correlate with striatal neuron loss causing increased glutamatergic stimulation of the cortex, the morphological substrate for the cognitive and behavioral decline in HD is controversial. It has been variously related to diffuse cortex neuron loss in frontal and deep entorhinal cortex causing disorders of the striato-prefrontal and limbic loops, or to disruption of cortical circuitries by dystrophic neurites. However, scientists, in 37% of brains of demented HD patients aged 27 to 93 years, found Alzheimer type lesions with amyloid deposition in subjects older than 54 years, suggesting that concomitant Alzheimer disease (AD) may be more prevalent in HD than previously recognized. Comparing a cohort of HD cases with and without AD, half of the patients with HD + AD being older than 77 years, scientists observed that neostriatal amyloid burden and neuritic plaques were more obvious in the AD only than in the HD-AD group, which could be secondary to HD-associated neostriatal atrophy. The HD gene had no detectable influence on the phenotype of AD. The present study compares the prevalence and intensity of Alzheimer type lesions in a small consecutive cohort of HD patients with age- and sex-matched controls.

Previous studies suggested a very low coexistence of HD and AD, although a small number of autopsy-confirmed combination instances have been reported. In a previous autopsy study of HD patients, 12 among 42 evaluable brains (28.5%) ‐ all over age 60 (mean 68) years ‐ revealed mild to moderate numbers of senile plaques and/or NFTs. In a recent review, scientists stated that there is no aberrant TAU immunoreactivily in HD, which is in sharp contrast to both Pick's disease and Alzheimer's disease. On the other hand, other ones in 34% of the brains of demented HD patients found Alzheimer-type lesions with amyloid deposits in subjects older than 54 years. Scientists reported neostriatal amyloid burden and neuritic plaques in elderly HD patients, 64% of whom had at least one ApoE e4 allele. Although the HD gene appears to have no influence on the phenotype of concomitant AD, the relationship between C-AG trinucleotide repeat and AD as well as the implication of amyloid-like intranuclear neuronal aggregates of expanded polyglutamines and of ubiquitinated dystrophic neurites for neuronal cell death in HD and related neurodegenerative disorders are far from being understood. However, since the frequency of the intranuclear inclusions in HD brain has recently been found to correlate with the length of the IT 15 CAG triplet repeat and these inclusions were detected only in affected cerebral regions. The presence of these inclusions containing protein aggregates may be related to the pathogenesis of glutamine repeat-linked neurodegeneration.

The present comparative study in a small autopsy cohort of HD and age-and sex-matched control brains showed that early AD-type lesions in either CA 1 hippocampal area or entorhinal cortex in moderately demented HD-subjects corresponding to Braak stages 0 to I may occur as early as at age 34 and 45 years, which is somewhat earlier as in a general population. This suggests that early Alzheimer-like lesions may contribute to cognitive impairment in HD. However, none of the HD patients nor of the controls showed neuritic Alzheimer-like lesions to suggest probable or definite AD according to current diagnostic criteria.

The sequence of the cytoskeletal neuronal changes in HD, at least in part, follows the progress of hyperphosphorylated TAU protein changes related to the formation of NFTs and NTs in the (trans)entorhinal cortex. However, it does not always follow the hierarchical model of neuropathological staging for the evolution of neuronbrillary pathology in normal aging and AD, proposed as follows: transentorhinal lamina pre-alpha (lamina principalis externa, lamina II). lamina pre-alpha of the entorhinal cortex, hippocampal area CA 1, lamina pri-α of eniorhinal cortex (lamina interna IV); association cortex together with lamina pre-β of the entorhinal cortex (lamina III), parastriate and striate cortex. The latter ones being never involved in the present cohort of HD patients, while almost all of the control brains of our sample followed this model of neuritic AD-related pathology, in HD brains, there were several order violations, since in some cases, particularly in younger patients, the earliest AT-8 positive neuronal lesions were seen in the CA 1 sector of hippocampus with preservation of the (trans)entorhinal cortex. The reasons for these order deviations are unknown, but similar independent development of NFTs in the entorhinal region and hippocampus have been reported in elderly people irrespective of their cognitive impairment.

Similar deviations in the distribution pattern of early AD-related lesions have been observed in argyrophilic grain disease (AGD), featured by the widespread occurrence of argyrophilic, TAU-inmmunoreactive structures referred to as argyrophilic grains that are preferentially located in the CA 1 hippocampus area and related limbic structures. AGD may or may not be associated with dementia; the grains occasionally are the only morphological substrate of progressive late onset dementia, or may be associated with neuritic AD lesions, mainly corresponding to Braak stages III and IV, or other neurodegenerative disorders, such as progressive supranuclear palsy, corticobasal degeneration, motor neuron disease or Pick's disease, but ‐ as in the present cohort ‐ have not been observed with HD. Extracellular amyloid deposits (senile plaques) usually showing a distribution pattern independent of neuritic or TAU-related Alzheimer-like pathology were seen in only 18% of our HD cohort, usually associated with neuritic Braak stages II and III, and occurred as early as age 42 years. This conforms with earlier data suggesting that initial Braak stages I and II usually develop in the absence of amyloid deposits. However, even in elderly HD patients, amyloid deposits were rather rare and less severe than in controls or in comparison to other HD series.

In conclusion, the presented data confirm the results of previous studies showing a rare coexistence of HD and AD, although early Alzheimer-like lesions, in particular non-neuritic TAU pathology with "pretangle" changes in limbic neurons, do occur in HD patients in rather young age. In our cohort as early as 34 years, which was about a decade earlier as in the control group. On the other hand, Alzheimer-related changes were comparatively mild even in elderly HD patients, usually being limited to the limbic system without progression to isocortical association areas, thus not allowing a diagnoses of HD-AD. This is in line with the results in an earlier autopsy sample of HD, although the coexistence of both neurodegenerative diseases in rare cases is well documented. While in the series of 64% of the HD-AD patients had at least one ApoE e4 allele, a known risk factor for AD. ApoE studies in our cohort were not performed. However, in general, ApoE geneotypes do not affect the age of onset of HD and the ApoE e4 allele frequency in HD docs not differ from that of controls. Hence, the reasons for the comparatively mild development of Alzheimer-type lesions in many HD brains and their contribution to cognitive decline in HD remain to be elucidated.

Source: K. A. Jellinger, Journal of Neural Transmission 1998
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