Jinzhou Tian

Histopathological changes underlying frontotemporal lobar degeneration with clinicopathological correlation

We have investigated the pathological correlates of dementia in the brains from a consecutive series of 70 patients dying with a clinical diagnosis of frontotemporal lobar degeneration (FTLD). Clinical misdiagnosis rate was low with only 3 patients (4%) failing to show pathological changes consistent with this diagnosis; 1 patient had Alzheimer’s disease and 2 had cerebrovascular disease (CVD). In the remaining 67 patients, the most common underlying histological cause was ubiquitin pathology with 24 (36%) cases so affected. In these, ubiquitin-positive inclusions were present in the cerebral cortex as small, rounded or crescent-shaped structures within the cytoplasm of neurones of layer II, together with coiled or curvilinear bodies within neurites, and in the hippocampus as small, solid and more spherical-shaped inclusion bodies within the cytoplasm of dentate gyrus granule cells. In one patient, “cat’s eye” or “lentiform” intranuclear ubiquitin inclusions were also present. The second most common histological type was dementia lacking distinctive histology (DLDH), in which neither tau nor ubiquitin inclusions were present, with 16 cases (24%) being affected. Pick-type histology was seen in 14 cases (21%) and tau histological changes associated with frontotemporal dementia (FTD) linked to chromosome 17 (FTDP-17) were present in 11 cases (16%). One case (1%) showed an unusual tau pathology that could not be allocated to any of the other tau groups. Only 1 case (1%) had neuronal intermediate filament inclusion dementia. No cases with ubiquitinated, valosin-containing protein-immunoreactive intranuclear inclusion bodies of the type seen in inclusion body myopathy with Paget’s disease of bone and frontotemporal dementia were seen. Clinicopathological correlation showed that any of these histological subtypes can be associated with FTD. However, for FTD with motor neurone disease (FTD+MND), semantic dementia or primary progressive aphasia (PA), the histological profile was either ubiquitin type or DLDH type; Pick-type histology was seen in only 1 case of PA. None of these latter three clinical subtypes was associated with a mutation in tau gene and FTDP-17 type of tau pathology. All cases of progressive apraxia were associated with Pick-type histology. Present data therefore indicate that, although ubiquitin pathology is the most common histological form associated with FTLD, this pathology is not tightly linked with, nor is pathologically diagnostic for, any particular clinical form of the disease, including FTD+MND.

An immunohistochemical study of cases of sporadic and inherited frontotemporal lobar degeneration using 3R- and 4R-specific tau monoclonal antibodies

The pathological distinctions between the various clinical and pathological manifestations of frontotemporal lobar degeneration (FTLD) remain unclear. Using monoclonal antibodies specific for 3- and 4-repeat isoforms of the microtubule associated protein, tau (3R- and 4R-tau), we have performed an immunohistochemical study of the tau pathology present in 14 cases of sporadic forms of FTLD, 12 cases with Pick bodies and two cases without and in 27 cases of familial FTLD associated with 12 different mutations in the tau gene (MAPT), five cases with Pick bodies and 22 cases without. In all 12 cases of sporadic FTLD where Pick bodies were present, these contained only 3R-tau isoforms. Clinically, ten of these cases had frontotemporal dementia and two had progressive apraxia. Only 3R-tau isoforms were present in Pick bodies in those patients with familial FTLD associated with L266V, Q336R, E342V, K369I or G389R MAPT mutations. Patients with familial FTLD associated with exon 10 N279K, N296H or +16 splice site mutations showed tau pathology characterised by neuronal neurofibrillary tangles (NFT) and glial cell tangles that contained only 4R-tau isoforms, as did the NFT in P301L MAPT mutation. With the R406W mutation, NFT contained both 3R- and 4R-tau isoforms. We also observed two patients with sporadic FTLD, but without Pick bodies, in whom the tau pathology comprised only of 4R-tau isoforms. We have therefore shown by immunohistochemistry that different specific tau isoform compositions underlie the various kinds of tau pathology present in sporadic and familial FTLD. The use of such tau isoform specific antibodies may refine pathological criteria underpinning FTLD.

Relationships between arteriosclerosis, cerebral amyloid angiopathy and myelin loss from cerebral cortical white matter in Alzheimer's disease

Pathological relationships between damage to the deep white matter of the cerebral cortex [as evidenced by myelin loss (ML)], cerebral amyloid angiopathy (CAA) and arteriosclerosis (ART) were investigated in the brains of 137 patients with autopsy‐confirmed Alzheimers disease (AD), in order to better understand the causes of white matter damage in AD, and the contribution of this to the pathogenesis of the disorder. All 137 patients had some degree of CAA in one or more brain regions although the occipital cortex was severely affected by CAA more frequently, and consequently mean CAA severity score was significantly greater, than other cortical regions. Eighty‐seven patients (63.5%) were affected by ML, with more patients showing ML from occipital cortex than from other cortical regions leading to a significantly higher mean ML severity score in this region. One hundred and twenty‐six patients (92%) were affected by ART, although the occipital cortex was not more frequently affected by ART than other cortical areas, the mean ART severity score in occipital cortex was nonetheless significantly greater than that of frontal and temporal cortex. Eighty‐seven patients showed both CAA and ML, although there was only a weak correlation between degree of CAA and extent of ML (P = 0.035). Forty‐seven patients showed ML and significant ART, 16 patients showed significant ART but no ML, 40 patients showed ML in the absence of significant ART and 34 patients showed neither significant ART nor ML. Overall, and for each of the four brain regions, the extent of ML correlated significantly (P < 0.001) with degree of ART. However, when only those 47 patients with ML and significant ART were considered, much stronger correlations between the extent of ML and the degree of ART were achieved both overall and within each of the four brain regions. The overall ART severity score (and overall scores for each pathological marker of ART) significantly correlated with that of CAA (P < 0.001). Pathological processes leading to white matter damage, in terms of ML at least, in AD are thus likely to be heterogeneous. Many patients suffer ML in association with ART, but in others ML cannot be explained by presence of ART or CAA. In such patients, autoregulatory changes in blood vessels might be responsible for ML. The association between the extent of CAA and ART suggests shared risk factors for each pathological change.

Mechanisms and effects of curcumin on spatial learning and memory improvement in APPswe/PS1dE9 mice

Evidence suggests that curcumin, the phytochemical agent in the spice turmeric, might be a potential therapy for Alzheimers disease (AD). Its antioxidant, anti‐inflammatory properties have been investigated extensively. Studies have also shown that curcumin can reduce amyloid pathology in AD. The underlying mechanism, however, is complex and is still being explored. In this study, we used the APPswe/PS1dE9 double transgenic mice, an AD model, to investigate the effects and mechanisms of curcumin in the prevention and treatment of AD. The water maze test indicated that curcumin can improve spatial learning and memory ability in mice. Immunohistochemical staining and Western blot analysis were used to test major proteins in β‐amyloid aggregation, β‐amyloid production, and β‐amyloid clearance. Data showed that, 3 months after administration, curcumin treatment reduced Aβ40, Aβ42, and aggregation of Aβ‐derived diffusible ligands in the mouse hippocampal CA1 area; reduced the expression of the γ‐secretase component presenilin‐2; and increased the expression of β‐amyloid‐degrading enzymes, including insulin‐degrading enzymes and neprilysin. This evidence suggests that curcumin, as a potential AD therapeutic method, can reduce β‐amyloid pathological aggregation, possibly through mechanisms that prevent its production by inhibiting presenilin‐2 and/or by accelerating its clearance by increasing degrading enzymes such as insulin‐degrading enzyme and neprilysin.

Relationships in Alzheimer's disease between the extent of Aβ deposition in cerebral blood vessel walls, as cerebral amyloid angiopathy, and the amount of cerebrovascular smooth muscle cells and collagen

The relationship between degree of cerebral amyloid angiopathy (CAA) and the amount of smooth muscle cells (SMCs) and deposition of collagen IV fibres (COL IV) was investigated in the frontal and occipital cortex of 70 patients with autopsy confirmed Alzheimers disease (AD). The extent of CAA was significantly greater in occipital than in frontal cortex, although SMC loss was greater in frontal than in occipital cortex. COL IV staining was significantly higher in occipital than in frontal cortex. The degree of SMC loss correlated with CAA, as Aβ40 but not as Aβ42 or total Aβ, in frontal cortex, but not in occipital cortex. Leptomeningeal arteries within occipital cortex showed significantly greater external diameter, greater wall thickness and greater luminal area than those in frontal cortex. The degree of CAA correlated with thickness of blood vessel wall and external diameter in frontal cortex, whereas extent of SMC loss correlated with thickness of blood vessel wall in occipital cortex. There were significant negative correlations between duration of disease and thickness of vessel wall, external diameter and luminal area. In patients with disease durations exceeding 10 years, external vessel diameter and thickness of the vessel wall were both halved compared with patients with durations less than 5 years; luminal area was reduced by about 75%. Blood vessels in AD undergo degenerative changes involving deposition of Aβ and COL IV with loss of SMC. SMC loss may relate to increasing Aβ deposition in early stages of disease, but this relationship may be lost with disease progression.

Association study of the vascular endothelial growth factor gene with the risk of developing Alzheimer's disease

Numerous observations indicate that cerebrovascular dysfunction contributes to cognitive decline and neurodegeneration in AD. Converging evidence points to a pivotal role for vascular endothelial growth factor (VEGF) in neuronal protection, and the lack of activity of this in neurodegenerative disorders. The VEGF gene is located at 6p21.3, a site several studies have shown to have significant linkage with AD, and a functional polymorphism within the VEGF promoter may alter the risk of developing AD. We assessed the potential impact of this polymorphism on the risk of developing AD in a large French case-control population, and investigated its association with the severity of brain vascular lesions (arteriosclerosis, white matter loss and cerebral amyloid angiopathy) in several brain regions (frontal, temporal, parietal and occipital cortex) in AD. No association of the VEGF promoter polymorphism with the risk of developing AD was observed. No relationship between this polymorphism and vascular pathological changes in AD was detected. Our data indicate that although this polymorphism is functional, it does not confer greater risk for AD, nor modulate the extent of vascular pathology.

Negative association between amyloid plaques and cerebral amyloid angiopathy in Alzheimer's disease

Cerebral amyloid angiopathy (CAA) is an important, though still relatively neglected, aspect of the pathology of Alzheimers disease (AD), and both the source of amyloid beta protein (Abeta) in CAA, and its relationship to senile plaque (SP) Abeta, remain unclear. We have investigated the relationship between Abeta deposition in SP and CAA in four regions of brain from 69 patients with AD in order to gain insight into the pathogenetic mechanism(s) underlying these pathologies. CAA was present to some degree in all 69 patients, with the occipital cortex being affected more often and more severely than frontal, temporal and parietal cortices. By definition, SPs were present in all brain areas in all 69 patients, with greater uniformity of distribution than CAA, though the occipital cortex was less severely affected than the other brain regions. There was no significant (positive) correlation between CAA rating and that of SP for any one cortical region, but on combining data from all four regions there was a significant inverse correlation (P=0.037) between CAA and SP ratings. Such data suggest that the cellular sources and mechanisms leading to Abeta deposition as SP or CAA are likely to differ and may proceed independently of each other.

A polymorphism in the angiotensin 1-converting enzyme gene is associated with damage to cerebral cortical white matter in Alzheimer's disease

The impact of the insertion (I)/deletion (D) (I/D) polymorphism in the angiotensin 1-converting enzyme (ACE) gene on the extent of white matter myelin loss (ML) was investigated in four regions of the cerebral cortex in an autopsy-confirmed series of 93 patients with Alzheimers disease (AD). The possible influence of APO E epsilon4 allele acting in concert with ACE D allele was assessed. The extent of ML did not differ between D/D, I/D and I/I genotype groups when data from all four brain regions were combined. However, separate analysis showed that the frontal and temporal cortex tended to be affected more severely by ML in patients with D/D genotype compared to those with I/D and I/I genotypes. Stratification according to APO E epsilon4 allele revealed a greater overall ML in patients bearing at least one copy of ACE D allele and one APO E epsilon4 allele, especially in individuals homozygous for both. The APO E epsilon4 allele may therefore act synergistically in patients with AD (and other subjects) bearing ACE D/D genotype to increase the risk of ML, perhaps through transient ischaemic episodes consequent upon poor cardiac output associated with coronary atherosclerosis in patients with the APO E epsilon4 allele.

Is there a relation between APOE expression and brain amyloid load in Alzheimer's disease?

Background: It has been proposed that, independent of the ε4 allele, APOE promoter polymorphisms (−491 A/T and −219 G/T) may be risks factor for Alzheimer’s disease by modulating APOE expression. Objective: To measure the level of APOE expression in Alzheimer’s disease. Methods: Brains were obtained at necropsy from 114 patients with early and late onset sporadic Alzheimer’s disease in Greater Manchester (UK) during years 1986 to 2001. Total RNA was extracted from 84 brains. Purified lymphocytes were obtained from fresh blood from 16 probable Alzheimer cases from Lille (France). APOE and β-actin gene expression was determined by reverse transcriptase polymerase chain reaction in brain and lymphocytes. Results: An inverse correlation between APOE expression level and Aβ loads was observed. As previously described and extended to 114 cases here, an association between the −219 TT genotype and a higher level of parenchymal Aβ deposition was found, irrespective of APOE ε4 allele status. This effect was more pronounced in older individuals, whereas higher Aβ load appeared more closely related to ε4 in the younger age group (cut off point at the median age at death (72.5 years)). The −219 TT genotype was associated with a decrease in APOE expression. There was a 60% decrease in APOE expression in lymphocytes from probable Alzheimer cases v controls (p = 0.01). Conclusions: In the oldest individuals, reduced APOE expression, modulated in part by −219 G/T polymorphism, may influence risk and constitute a determinant Aβ load in Alzheimer’s disease.

Neurodegeneration in frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9orf72 is linked to TDP-43 pathology and not associated with aggregated forms of dipeptide repeat proteins

A hexanucleotide expansion in C9orf72 is the major genetic cause of inherited behavioural variant Frontotemporal dementia (bvFTD) and motor neurone disease (MND), although the pathological mechanism(s) underlying disease remains uncertain.