A positive feedback loop between HER2 and ADAM12 in human head and neck cancer cells increases migration and invasion.

Increased activation of epidermal growth factor receptor (EGFR) family members such as HER2/Erbb2 can result in more aggressive disease, resistance to chemotherapy and reduced survival of head and neck squamous cell carcinoma (HNSCC) patients. In order to identify mechanisms through which these receptor tyrosine kinases accelerate tumor progression, the regulation of metalloprotease expression by EGFR family members was investigated in 11 squamous cell carcinoma (SCC) cell lines. HER2 expression was significantly correlated with ADAM12 (A Disintegrin And Metalloprotease 12) expression in these cell lines and was co-expressed in human head and neck cancers. Inhibition of HER2 or EGFR decreased ADAM12 transcripts whereas HER2 transfection upregulated ADAM12 expression. To understand the molecular mechanisms underlying HER2 regulation of ADAM12, we investigated the signaling pathways directing ADAM12 production in SCC cells. Inhibition of phosphatidyl inositol-3-kinase or mammalian target of rapamycin decreased ADAM12 transcripts in HER2-expressing SCC cells, whereas transfection with AKT increased ADAM12 mRNA. Experiments utilizing ADAM12 transfection or siRNA targeting of ADAM12 revealed that the protease increased both the migration and invasiveness of oral SCC cells. Surprisingly, ADAM12 also increased HER2 message, protein levels and activity through an Ets1-dependent mechanism. Collectively, these results reveal a novel positive activation loop between ADAM12 and HER2 that may contribute to HNSCC progression.

In dementia with Lewy bodies, Braak stage determines phenotype, not Lewy body distribution.

We used an autopsy series to determine whether the newest dementia with Lewy bodies (DLB) consensus pathologic classification correlates with premortem diagnosis of DLB. Neocortical sections from a total of 95 cases with Lewy bodies were stained with alpha-synuclein antibodies. We assigned cases according to the DLB consensus' categories and found a significant association with the premortem clinical diagnosis of DLB. Clinical diagnosis of DLB, however, depended on the presence of low Alzheimer disease pathology (by Braak staging) rather than on Lewy body distribution.

The shifting patterns of HIV encephalitis neuropathology.

HIV infected macrophages infiltrate the nervous system early in the progression of HIV infection, leading to a complex set of neuropathological alterations including HIV encephalitis (HIVE), leukoencephalopathy and vacuolar myelopathy that in turn result in neurodegeneration of selective cellular populations and pathways involved in regulating cognitive and motor functioning. Rapid progress in the development of highly active antiretroviral therapy (HAART) has changed the patterns of HIV related neuropathology and neurological manifestations in the past 10 years. The prevalence of opportunistic infections and central nervous system (CNS) neoplasms has decreased, and some groups have proposed that the frequency of chronic forms of HIVE have been rising as the HAART-treated HIV population ages. Accordingly, clinical manifestations have shifted from severe dementia forms to more subtle minor cognitive impairment, leading to the suggestion of a classification of HIV associated neurological conditions into an inactive form, a chronic variety, and a 'transformed' variant. From a neuropathological point of view these variants might correspond to: a) aggressive forms with severe HIVE and white matter injury, b) extensive perivascular lymphocytic infiltration, c) 'burnt-out' forms of HIVE and d) aging-associated amyloid accumulation with Alzheimer's-like neuropathology. Factors contributing to the emergence of these variants of HIVE include the development of viral resistance, immune reconstitution, anti-retroviral drug toxicity and co-morbid factors (e.g., methamphetamine, HCV). More detailed characterization of these proposed variants of HIVE is important in order to better understand the pathogenesis of HIV-associated neurological damage and to design more effective treatments to protect the nervous system.

Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium.

The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in approximately 50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

Anosmia is very common in the Lewy body variant of Alzheimer's disease.

BACKGROUND: Olfactory abnormalities are reported in Alzheimer's disease and Parkinson's disease. Anosmia appears to be common in dementia with Lewy bodies but not in pure Alzheimer's disease. OBJECTIVE: To determine whether anosmia improves discrimination between the Lewy body variant (LBV) of Alzheimer's disease and "pure" Alzheimer's disease. METHODS: 106 cases of necropsy confirmed pure Alzheimer's disease (n = 89) or LBV (n = 17) were reviewed. All had received butanol odour threshold testing. Anosmia was defined as a score < or = 1.0 on a 0-9 point scale. Logistic regression analysis was used to model potential predictors (for example, parkinsonism, smoking, hallucinations) of neuropathological diagnosis and anosmia. RESULTS: LBV cases had an increased prevalence of anosmia (65%) compared with Alzheimer's disease (23%; odds ratio (OR) = 6.3, p = 0.00045), or normal elderly people (6.7%). Within the dementia cases, the negative predictive value (92%) and specificity (78%) of anosmia were both good; sensitivity for detecting LBV was 65%, but the positive predictive value (PPV) was only 35%. Logistic regression models showed anosmia (OR = 5.4, p = 0.005) and visual hallucinations (OR = 7.3, p = 0.007) were strong independent predictors of Lewy body pathology. When anosmia was added as a core feature to consensus diagnostic criteria for probable Lewy body dementia, five additional cases of LBV were detected (29% increased sensitivity), but with four additional false positives (1% increased discrimination, 4% decreased specificity, 33% decreased PPV). CONCLUSIONS: Anosmia is very common in LBV. Adding anosmia as a core feature improved sensitivity for detecting LBV, but did not improve discrimination between Alzheimer's disease and LBV owing to a concomitant increase in false positives.

Smoking affects the phenotype of Alzheimer disease.

Because epidemiologic and in vitro evidence conflict, the authors studied the association between smoking and Alzheimer disease (AD) in 46 never, 47 former, and 15 active smokers with AD followed to autopsy. Disease parameters were examined by smoking status and amount smoked in bivariate tests and in multivariate models controlling for age, sex, education, and APOE status. Smoking status was not associated with cognitive or neuropathologic measures. However, active smokers were significantly younger at death and higher levels of smoking were associated with shorter disease duration.

Impact of APOE genotype on neuropathologic and neurochemical markers of Alzheimer disease.

BACKGROUND: The APOE epsilon4 allele has emerged as a major genetic factor for Alzheimer disease (AD), and its presence has been associated with an increase in beta-amyloid senile plaques (SPs) and neuritic plaques (NPs). Whether it affects neurofibrillary tangle (NFT) accumulation or cholinergic losses in AD remains controversial. In contrast, the epsilon2 allele has been reported to decrease the risk for AD. However, its effect on neuropathologic and neurochemical markers of disease is unclear. OBJECTIVE: To investigate the relationship between APOE genotype and both pathologic severity and cholinergic dysfunction in AD. METHODS: In an autopsy series of 296 patients with AD, APOE genotype was determined in blood or postmortem brain tissue. NPs and NFTs were counted in the midfrontal (MF), inferior parietal (IP), and superior temporal (ST) cortices and the hippocampus. Choline acetyltransferase (ChAT) activity was assessed in the MF, IP, and ST cortices. RESULTS: Compared with patients with no epsilon4 alleles, epsilon4 carriers (patients with either one or two epsilon4 alleles) did not differ significantly with regard to any pathologic or neurochemical measures, except for increased ST NPs. However, when cases were stratified into three groups according to the number of epsilon4 alleles, patients with two epsilon4 alleles had significantly more NPs and NFTs in all neocortical regions than those with either one or no epsilon4 alleles. The association of the epsilon4/4 genotype with neocortical pathologic severity remained significant even after adjusting for age at onset or age at death. In contrast, there were no significant group differences with regard to neocortical ChAT activity. When pathologic and neurochemical measures were compared between patients with the epsilon2 allele and those without, a strong relationship emerged between the epsilon2 allele and decreased NPs in all neocortical regions. CONCLUSIONS: The epsilon4 allele does not predict cholinergic decline in AD. Although the presence of a single epsilon4 allele appears to have no effect, the presence of two epsilon4 alleles is an important determinant of both NP and NFT accumulation. A putative protective role for the epsilon2 allele in AD may be mediated by reduced plaque burden.

The importance of neuritic plaques and tangles to the development and evolution of AD.

OBJECTIVE: To determine the relation of neuritic plaques (NPs) and neurofibrillary tangles (NFTs) to the development and evolution of Alzheimer disease (AD). METHODS: An autopsy series of 102 patients with dementia and pathologically confirmed AD and 29 normal control subjects (NCs) was studied. AD cases were stratified according to their last Mini-Mental State Examination (MMSE) before death as mild, moderate, severe, or very severe. NPs and NFTs were enumerated in the midfrontal (MF), inferior parietal (IP), superior temporal (ST), hippocampal (Hip), or entorhinal cortices using thioflavin-S preparations. RESULTS: Most (87%) of the NCs had allocortical NFTs, whereas only a minority (37%) displayed neocortical NPs, and even fewer (19%) showed Hip NPs. In contrast, none of the NCs exhibited neocortical NFTs, except one case with a single ST tangle. However, neocortical NFTs were not detected in even 10% of the patients with AD and, in particular, were absent in nearly 50% of those with mild disease at death. Thus, their sensitivity as a marker of AD was lower than that of NPs, which, conversely, were found in all patients with AD. Comparing NCs and patients with mild AD, significant differences were found for numbers of NPs only. Across the AD groups, in contrast, although NP and NFT density increased with dementia severity, significant differences consistently emerged for NFTs alone. CONCLUSIONS: Deterioration in Alzheimer disease appears to be driven by neuritic plaques and neurofibrillary tangles at different stages of the disease. The significant increase in neuritic plaques, but not neurofibrillary tangles, in patients with even mild Alzheimer disease at death compared with normal control subjects suggests that only neuritic plaques are associated with the earliest symptoms of Alzheimer disease.

Alzheimer disease without neocortical neurofibrillary tangles: "a second look".

OBJECTIVE: To compare the clinical and pathologic features of plaque only Alzheimer disease (POAD) with plaque and tangle Alzheimer disease (PTAD). METHODS: An autopsy series of 16 patients with POAD and 32 subjects with PTAD on whom extensive antemortem neuropsychological testing was available. Plaques, tangles, and cerebral amyloid angiopathy were examined in the neocortex and hippocampus using thioflavin S staining. In addition, immunocytochemical analysis with AT8 for phosphorylated tau was performed. Midfrontal (MF) synaptic density, MF choline acetyltransferase (ChAT) activity, and apolipoprotein E genotyping were also assessed. RESULTS: Initial neuropsychological test scores and rates of cognitive decline on the Mini-Mental State Examination and Blessed Information-Memory-Concentration were similar between the two groups. However, compared to PTAD, POAD patients tended to deteriorate more slowly on the Mattis Dementia Rating Scale. Furthermore, they were somewhat less impaired on all these measures at last examination. There was an older age at onset and death, and a trend toward a shorter disease duration, in POAD compared to PTAD patients. POAD subjects, by definition, had no neocortical neurofibrillary tangles (NFT) (Braak stages IV or less). In addition, they also had fewer hippocampal NFT, fewer neuritic plaques, and higher mean MF ChAT activity than PTAD subjects. On the other hand, the two groups did not differ significantly in brain weight or MF synaptic density. Although lacking overt tangle formation, the POAD group displayed abnormal phosphorylated tau immunoreactivity in neocortical pyramidal neurons. CONCLUSIONS: Dementing syndromes virtually indistinguishable from each other can, and do, develop in the presence or absence of neocortical NFT. Patients without neocortical NFT are, on average, older at disease onset and death, and show a trend toward a shorter disease duration with somewhat slower deterioration. Although neocortical NFT per se are not obligatory for the development of clinical dementia, more subtle neocortical cytoskeletal tau pathology may contribute to cognitive decline in these subjects.

Elevated S-adenosylhomocysteine in Alzheimer brain: influence on methyltransferases and cognitive function.

Hyperhomocysteinemia is common in Alzheimer's disease and is negatively correlated with cognitive function. Hyperhomocysteinemia can increase S-adenosylhomocysteine (SAH), a potent methyltransferase inhibitor. This study investigates the role of brain SAH in the cognitive and neurological disruption in Alzheimer's disease. SAH was significantly (26%) higher in prefrontal cortex of Alzheimer patients than normals. Brain homogenates from Alzheimer patients inhibited an exogenous methyltransferase 15% more than normal homogenates (P <.001). Brain SAH levels correlated (r=.508) with methyltransferase inhibition by brain homogenates. Methyltransferase inhibition by Alzheimer brain homogenates correlated inversely with cognitive function as determined by MMSE (r=-0.36). Phenylethanolamine N-methyltransferase (PNMT) and catechol O-methyltransferase (COMT) activities were more than 30% lower (P<0.001) in Alzheimer than normal brains. Brain PNMT activity correlated significantly with cognitive function (r=0.243), age of Alzheimer's onset (r=0.272), and choline acetyltransferase activity (r=0.333), but negatively with neurofibrillary tangles (r=-0.332). COMT activity also correlated significantly with cognitive function (r=0.324), age of disease onset (r=0.209), choline acetyltransferase activity (r=0.326), levels of synaptophysin (r=0.506), and negatively with tangles (r=-0.216 P=0.039). Elevated SAH in Alzheimer brain inhibits methyltransferases and is related to markers of disease progression and cognitive impairment.

Abeta1-42 promotes cholinergic sprouting in patients with AD and Lewy body variant of AD.

BACKGROUND: The neurodegenerative process in Alzheimer's disease (AD) and in the Lewy body variant of AD (LBV) patients is characterized by cholinergic dysfunction and deposition of amyloid beta-peptide (Abeta) 1-40 and 1-42; however, the differential effects of Abeta species on the cholinergic system are not completely clear. OBJECTIVE: To better understand the relationship between levels of Abeta1-40 and 1-42 on cholinergic deficits in AD and LBV patients. METHODS: Levels of choline acetyltransferase (ChAT) activity and ChAT immunoreactivity in the plaques in the frontal cortex of patients with AD and LBV were correlated with Abeta1-42 and 1-40 levels determined by ELISA and with neuropathologic and neurologic markers. RESULTS: Although the overall levels of ChAT activity were reduced in AD and LBV cases, there was a direct correlation with Abeta1-42 levels. Furthermore, patients with high Abeta1-42 levels had more abundant cholinergic dystrophic neurites in the plaques than cases with lower Abeta1-42. CONCLUSION: Abeta1-42 may also trigger cholinergic dysfunction by promoting aberrant neuritic sprouting.

Early and persistent alterations in prefrontal cortex MAO A and B in Alzheimer's disease.

Both monoamine oxidase (MAO) A and MAO B in the brain have been implicated in the etiology of Alzheimer's disease. MAO B is elevated in plaque-associated glia in Alzheimer brain. Elevations in MAO A in Alzheimer neurons have been linked to increases in neurotoxic metabolites and neuron loss. We investigated the relationship between cognitive function in Alzheimer patients and post-mortem prefrontal cortex MAO A and B activities. Prefrontal cortex tissue from 92 Alzheimer patients and 74 neurologically normal subjects was obtained at autopsy and analyzed for activities of MAO A and B by radioenzymatic methods. Mini Mental Status Exam was performed on Alzheimer patients within 1 year of death. Alzheimer brains were analyzed for Braak stage, tangles, plaques and choline acetyltransferase activity. Prefrontal cortex MAO B activity was significantly increased by 16% in Alzheimer patients versus normals, whereas MAO A activity was significantly decreased by 17% in these same patients. Neither MAO A nor MAO B activities correlated with cognitive function (MMSE score), choline acetyltransferase activity, plaques, neurofibrillary tangles, Braak stage, or age of disease onset in the Alzheimer patients. With increasing Alzheimer duration or increasing Braak stage, MMSE scores and choline acetyltransferase activity declined, but levels of MAO A and B in prefrontal cortex were unchanged. Patients in the upper quintile for MAO A or B activity did not differ significantly from those in the lowest quintile with respect to MMSE scores or age of Alzheimer disease onset. We conclude that the changes in MAO A and B in the prefrontal cortex occur very early in Alzheimer's disease and remain relatively constant as the disease progresses.

Influence of Alzheimer pathology on clinical diagnostic accuracy in dementia with Lewy bodies.

OBJECTIVE: To determine whether AD neurofibrillary pathology influences clinical diagnostic accuracy in dementia with Lewy bodies (DLB). BACKGROUND: Pathologic diagnosis of DLB mandates Lewy bodies but also allows for AD pathology in the form of plaques and tangles. Because clinical diagnostic accuracy of DLB remains low, the authors questioned whether the severity of AD pathology in the form of tangles might affect the clinician's ability to correctly diagnose DLB in life. DESIGN/METHODS: Ninety-eight subjects with autopsy-proven DLB who had been evaluated annually at the University of California San Diego AD Research Center were identified. The clinical diagnosis used was the last diagnosis before death. Pathologic diagnosis of DLB was made according to Consensus guidelines, and Braak staging was used to assess the degree of neurofibrillary AD pathology. The clinical characteristics of subjects with DLB with low vs high Braak stages were compared and the clinical diagnostic accuracy for subjects stratified according to Braak stage was determined. RESULTS: Only 27% of the subjects with DLB demonstrated both visual hallucinations and spontaneous extrapyramidal signs (EPS). The low Braak stage (0 to 2, n = 24) subjects had a higher frequency of visual hallucinations (65%) than did subjects with DLB with higher (3 to 6, n = 66) Braak stages (33%, p = 0.008), and showed a slightly greater but not significant degree of EPS. Although clinical diagnostic accuracy for DLB was relatively low (49%), it was higher for subjects with low (75%) compared to high (39%) Braak stages (p = 0.0039). CONCLUSIONS: The degree of concomitant AD tangle pathology has an important influence on the clinical characteristics and, therefore, the clinical diagnostic accuracy of DLB.

Cognitive profiles differ in autopsy-confirmed frontotemporal dementia and AD.

BACKGROUND: Frontotemporal dementia (FTD) is currently distinguished from AD primarily on the basis of behavioral features because studies of cognition have shown negligible or inconsistent differences. However, the poor discriminability of cognitive measures may relate to reliance on imprecise clinically diagnosed groups. Therefore, a retrospective examination of neuropsychological test performance in autopsy-confirmed patients is warranted. OBJECTIVE: To compare the pattern of cognitive deficits exhibited by patients with autopsy-confirmed FTD and AD. METHODS: The profiles of cognitive deficits exhibited by patients with neuropathologic diagnosis of FTD (n = 14) or AD (n = 28) were compared. The Mattis Dementia Rating Scale (MDRS), letter and category fluency tests, Wechsler Intelligence Scale for Children-Revised block design test, Boston naming test, and clock drawing test were administered. RESULTS: Multivariate analysis of covariance controlling for age, education, and level of dementia revealed that patients with FTD performed significantly worse than patients with AD on letter and category fluency tests but significantly better on the MDRS memory subscale, block design test, and clock drawing test. A logistic regression model, validated in an independent clinical sample, used letter fluency, MDRS memory, and block design scores to correctly classify 91% of AD patients and 77% of FTD patients. CONCLUSIONS: A double dissociation in the pattern of cognitive deficits exhibited by FTD and AD patients was demonstrated. The FTD patients were more impaired than AD patients on word generation tasks (i.e., verbal fluency) that are sensitive to frontal lobe dysfunction but less impaired on tests of memory and visuospatial abilities sensitive to dysfunction of medial temporal and parietal association cortices.

Cholinergic deficits in the brains of patients with parkinsonism-dementia complex of Guam.

Patients with parkinsonism-dementia complex (PDC) of Guam showed moderate loss of choline acetyl transferase activity in the midfrontal and inferior parietal cortex, and severe loss in the superior temporal cortex. This deficit was similar to that seen in Alzheimer's disease and less severe than Lewy body disease. Thus, cholinergic deficits in the neocortex might contribute to some of the cognitive alterations in PDC of Guam.

Correlation of nicotinic receptor binding with clinical and neuropathological changes in Alzheimer's disease and dementia with Lewy bodies.

We investigated the relationship between the loss of nicotinic acetylcholine receptors (nAChR) and the cognitive decline or neuropathological changes seen in Alzheimer's Disease (AD) and dementia with Lewy bodies (DLB). Midfrontal (MF) cortex of 31 AD, 24 DLB and 11 non-demented controls was examined. Total plaque (TP), neuritic plaque (NP) and neurofibrillary tangle (NFT) counts were obtained. NAChR binding was assayed using 3H-epibatidine [3H-EPI]. Last Blessed Information-Memory-Concentration scores (BIMC), Mini-Mental State Examination (MMSE), Mattis Dementia Rating Scale (DRS) scores were collected. There were no correlations between 3H-EPI binding and TP, NP, NFTs counts in either AD or DLB. Last BIMC, MMSE, DRS scores did not correlate with 3H-EPI binding in AD or DLB. Thus, decline in cognitive function does not correlate with loss of nAChR in DLB or AD at the end of life suggesting that later in these diseases, loss of nAChR binding is not a reliable marker of cognitive function in AD or DLB. Loss of nAChR activity does not appear to be related to plaques or NFTs in AD or DLB.

Altered expression of the synuclein family mRNA in Lewy body and Alzheimer's disease.

The main objective of this study was to determine if levels of alpha-, beta- and/or gamma-synuclein mRNAs are differentially affected in brains of Lewy body disease (LBD) and Alzheimer's disease (AD) patients, compared to controls. In control cases, highest levels of expression were observed in the neocortex and the lowest in basal ganglia and substantia nigra. beta-Synuclein was the most abundant message (75-80%), followed by gamma-synuclein (10-15%) and alpha-synuclein (8-10%). Analysis of the superior temporal cortex, a region selectively affected in LBD and AD, showed that compared to controls, levels of alpha-synuclein were increased in cases of diffuse LBD (DLBD), levels of beta-synuclein were decreased in AD and DLBD, and levels of gamma-synuclein were increased in AD cases. This study suggests that a critical balance among products of the synuclein gene is important to maintain normal brain function and that alterations in this balance might be associated with neurodegenerative disorders.

Conservation conflicts across Africa.

There is increasing evidence that areas of outstanding conservation importance may coincide with dense human settlement or impact. We tested the generality of these findings using 1 degree-resolution data for sub-Saharan Africa. We find that human population density is positively correlated with species richness of birds, mammals, snakes, and amphibians. This association holds for widespread, narrowly endemic, and threatened species and looks set to persist in the face of foreseeable population growth. Our results contradict earlier expectations of low conflict based on the idea that species richness decreases and human impact increases with primary productivity. We find that across Africa, both variables instead exhibit unimodal relationships with productivity. Modifying priority-setting to take account of human density shows that, at this scale, conflicts between conservation and development are not easily avoided, because many densely inhabited grid cells contain species found nowhere else.

Altered expression of synaptic proteins occurs early during progression of Alzheimer's disease.

The expression levels of three synaptic proteins (synaptophysin, synaptotagmin, and growth-associated protein 43 [GAP43]) in AD cases clinically classified by Clinical Dementia Rating (CDR) score were analyzed. Compared with control subjects (CDR = 0), mild (early) AD (CDR = 0.5 to 1) cases had a 25% loss of synaptophysin immunoreactivity. Levels of synaptotagmin and GAP43 were unchanged in mild AD, but cases with CDR of >1 had a progressive decrement in these synaptic proteins. Thus, synaptic injury in frontal cortex is an early event in AD.