David G. Munoz

Corticobasal degeneration and progressive supranuclear palsy share a common tau haplotype

Objective: To analyze the association of polymorphisms in the tau gene with pathologically confirmed corticobasal degeneration (CBD). Background: The authors previously described an extended tau haplotype (H1) that covers the human tau gene and is associated with the development of progressive supranuclear palsy (PSP). The authors now extend this analysis to CBD, a neurodegenerative condition with clinical and neuropathologic similarities to PSP. Like PSP, CBD is associated with accumulation of aggregates containing the 4-repeat isoforms of tau. Because of difficulty in diagnosis of CBD, the authors only analyzed cases with pathologically confirmed CBD. Methods: The authors collected 57 unrelated, neuropathologically confirmed cases of CBD. Tau sequencing in these cases failed to show the presence of pathogenic mutations. Polymorphisms that spanned the tau gene were analyzed in all CBD cases and controls. Results: Analyzing tau polymorphisms in CBD cases showed that the frequency of H1 and H1/H1 was significantly increased when analyzing all cases and when separating by country of origin. H1 frequency in all CBD cases was 0.921, compared with a control frequency of 0.766 (X2 = 9.1, p = 0.00255 [1df], OR 3.56 [8.43 > CI 95% > 1.53]). The H1/H1 frequency was also significantly higher at 0.842 compared with 0.596 in age-matched controls (X2 = 17.42, p = 0.00016, 2df), OR 3.61 [7.05 > CI 95% > 1.85]). Conclusions: The CBD tau association described here suggests that PSP and CBD share a similar cause, although the pathogenic mechanism behind the two diseases leads to a different clinical and pathologic phenotype.

Vascular factors in cognitive impairment--where are we now?

Medicine advances by swaying between extremes. Thirty years ago, “atherosclerosis” was almost synonymous with dementia, now “Alzheimer’s disease” is. However, a minority of investigators have noted vascular components of Alzheimer’s disease, and they got together at the first conference on the cerebrovascular pathology of Alzheimer’s disease in 1996 to explore these systematically.1 Since then, their efforts have had some resonance, but much remains to be sorted out before we can tackle the upcoming epidemic of cognitive impairment.

Corticobasal degeneration shares a common genetic background with progressive supranuclear palsy

Corticobasal degeneration is a sporadic form of tauopathy, involving the cerebral cortex and extrapyramidal motor system. A series of affected subjects was genotyped for a set of genetic markers along the tau protein gene. A specific haplotype is significantly overrepresented in patients versus controls. This haplotype is the same already reported in association with progressive supranuclear palsy. These data show that corticobasal degeneration and progressive supranuclear palsy, in addition to several clinical, pathological, and molecular features, may have the same genetic background. Ann Neurol 2000;47:374–377

Role of microglia in senile plaque formation

To assess the role of microglial cells in senile plaque (SP) formation, we examined the density and distribution of microglia in the temporal neocortex of three groups of nondemented individuals, chosen to represent sequential stages of SP formation (no SP, n = 14; diffuse plaques (DP) only, n = 12; both DP and neuritic plaques (NP), n = 14) and patients with Alzheimers disease (AD, n = 11). The mean density of microglia was significantly greater in the AD group. In nondemented individuals, the presence of NP but not DP was associated with an increased number of microglial cells. Most NP (91%) were focally associated with microglial cells. DP less commonly contained microglia, however, individuals with some NP had microglia within a greater proportion of their DP (47%) than did those with only DP (19%). These findings suggest that: (a) microglia are not involved in the formation of DP; (b) the presence of NP is associated with both an overall increase in microglia and the focal aggregation of cells around NP; (c) microglia may be locally involved in the conversion of DP into NP. This final point represents the most significant aspect of this study, providing the first quantitative evidence to support a specific role for microglia in the formation of NP from DP.

Familial frontotemporal dementia with ubiquitin-positive, tau-negative inclusions

Objective: To describe the clinical features, neuropathology, and genetic studies in a family with autosomal dominant frontotemporal dementia (FTD). Background: Clinical Pick’s disease, or FTD with parkinsonism, has been described in several families linked to chromosome 17 (FTDP-17). Most of these have shown tau protein mutations. The clinical and pathologic variations in these families resemble the spectrum of sporadic FTD or “Pick complex.” Methods: Clinical and behavioral analysis of the affected members with extensive histochemical and neuropathologic description of three cases, genetic analysis of three clinically affected members and seven at risk members to assess linkage to chromosome 17, and sequencing of the tau gene in two patients were performed. Results: The clinical pattern shows a highly stereotypic disinhibition dementia with late extrapyramidal features, progressive mutism, and terminal dysphagia in three generations of affected individuals. Neuropathology showed frontotemporal atrophy, and microscopically tau- and synuclein-negative and ubiquitin-positive neuronal inclusions, in the background of superficial cortical spongiosis, neuronal loss, and gliosis. Tau expression was restricted to oligodendroglia. All exons and surrounding introns of the tau gene were sequenced, and no mutation or disease-related polymorphisms were detected in either of two affected pedigree members. Conclusion: This family with autosomal dominant frontotemporal dementia (FTD) shows no tau expression in neurons. The ubiquitin-positive, tau-negative inclusions have been described before in FTD with and without motor neuron disease, but not in a familial form. The clinical and some pathologic features are similar to those of several of the families included in descriptions of FTD with parkinsonism linked to chromosome 17, but the linkage to tau has been excluded. The defect in this family, however, could be functionally related to tau mutations.

Frontotemporal dementia with ubiquitinated cytoplasmic and intranuclear inclusions.

Abstract. Dementia of motor neuron disease type (DMND) is a variety of frontotemporal dementia (FTD) which is pathologically defined by characteristic neuronal ubiquitinated, tau- and synuclein-negative intracytoplasmic inclusions. Many cases with this pathology, however, do not have motor neuron disease. In the present study, we document the presence of ubiquitinated neuronal intranuclear inclusions in a sub-population of cases of neuropathologically verified DMND. Immunohistochemical localization of ubiquitin was performed on sections of post-mortem brain from 12 patients with DMND as well as from cases with other neurodegenerative diseases including amyotrophic lateral sclerosis, Parkinsons disease, dementia with Lewy bodies, corticobasal degeneration, progressive supranuclear palsy, and multiple system atrophy. All of the cases of DMND showed ubiquitinated, tau-negative intracytoplasmic inclusions in dentate granule cells and cortical neurons. Of these 12 cases of DMND, 3 also showed neuronal ubiquitinated intranuclear inclusions. In 1 of these cases, CAG repeat expansions in the genes known to harbor these mutations were excluded. Cases with intranuclear inclusions displayed striatal atrophy and reduced brain weight relative to non-inclusion-bearing cases. In addition, patients with intranuclear inclusions tended to have a younger age of onset, a prolonged duration of disease, absence of motor neuron symptoms, and a family history of dementia. Intranuclear inclusions were not identified in the control cases with other neurodegenerative diseases. Ubiquitinated neuronal intranuclear inclusions have not been reported previously in DMND. The presence of ubiquitinated intranuclear inclusions along with striatal atrophy in a subset of cases of DMND may signify the existence of a neuropathologically distinct subset of this unique form of FTD.

Rate of progression of cognitive decline in Alzheimer’s disease: effect of butyrylcholinesterase K gene variation

Objective: To determine whether individuals with Alzheimer’s disease (AD) and the K variant allele of butyrylcholinesterase have a slower rate of cognitive decline than those without the K variant allele of butyrylcholinesterase. Method: The cognitive status of 339 community based subjects with AD was assessed with the Mini Mental State Examination at baseline and yearly over a three year follow up period. The rates of cognitive decline of subjects with and without the K variant allele were compared. Result: Presence of the K allele was associated with a slower average rate of cognitive decline in subjects with severe AD. Conclusions: This finding is consistent with the suggestion that the K variant of butyrylcholinesterase has an important role in disease progression in AD, and this may have implications for treatment.

Prevalence and disease associations of argyrophilic grains of Braak

Braaks argyrophilic grains (BAG) are spindle-shaped structures originally described in patients with dementia. We have determined that the prevalence of BAGs in an unselected series of 300 consecutive autopsies of subjects over the age of 30 is 5.6%, or 11.7% if only subjects older than 65 are considered. All the 17 subjects identified were older than 68; 6 received other neuropathological diagnoses of degenerative disease and 11 did not. Only 2 of the latter had shown clinical evidence of mental impairment. Braaks argyrophilic grains were associated with ballooned neurons, superficial linear spongiosis, and gliosis of entorhinal cortex and amygdala. Subcortical neurofibrillary tangles were consistently found in patients with dementia, but not in other subjects. In a separate series studying the prevalence of BAG in neurodegenerative diseases, we found a strong, but not universal association with progressive supranuclear palsy, and to a lesser degree with the lobar atrophies (Picks disease and corticobasal ganglionic degeneration). Numerous BAG were present in occasional cases of diffuse Lewy body disease, multiple systems atrophy, and motor neuron disease. We conclude that rather than defining a single disease. BAG constitute lesions that accompany several degenerative diseases, but also occur in normal elderly subjects, and rarely in demented subjects without other major histological findings.

Cerebrovascular Pathology in Alzheimer's Disease: Cause, Effect or Epiphenomenon?

ABSTRACT: Cerebrovascular pathology abounds in Alzheimers disease. Changes in the endothelium, disruption of the blood‐brain barrier and amyloid deposition in the cerebral blood vessels are almost universal in advanced cases. Do these changes represent the cause, the effect, or the consequences of a common pathogenesis of Alzheimers disease? This volume addresses some of these issues by presenting new knowledge gained from a diversity of fields. Recognition of the mechanisms involved will open new possibilities for therapeutic trials.

Effects of astrocytes, insulin and insulin-like growth factor I on the survival of motoneurons in vitro

We isolated motoneurons from E15 dissociated mouse spinal cord by density centrifugation and planted them onto poly-ornithine-coated coverslips in a growth medium (DMEM/F12) supplemented with progesterone, transferrin, selenium, horse serum and muscle extract. Under these conditions only 28% of the motoneurons survived for 8 days. When living astrocytes on a separate coverslip were introduced into dishes containing motoneurons, there was a two-fold increase in neuronal survival. The addition of insulin and insulin-like growth factor I (IGF-I) to such cultures alone or together, still further increased motoneuron survival, but this did not happen in the absence of astrocytes. We conclude that (a) astrocytes exert a trophic role in the survival of spinal motoneurons, (b) the effect does not require physical contact of the cells, and (c) insulin and IGF-1 have neurotrophic activity for motoneurons, an effect possibly mediated by living astrocytes.