Biomedical subjects

L A Hansen

Publications and source records attributed to L A Hansen.

At least 73 records · Page 4Linked to original sources

PubMed1996

Genetic studies in Alzheimer's disease with an NACP/alpha-synuclein polymorphism.

The non-Abeta component of Alzheimer's disease amyloid (NAC) is copurified with amyloid from the brain tissue of Alzheimer's disease victims and is immunohistochemically localized to amyloid fibrils. NAC is a hydrophobic peptide fragment from the NAC precursor protein (NACP/alpha-synuclein) that is localized to presynaptic terminals. We used a polymorphic dinucleotide repeat sequence in a genomic clone of NACP for genetic association and linkage studies. Screening of Alzheimer's disease families failed to establish linkage between NACP and Alzheimer's disease. Nevertheless, one of the NACP polymorphisms (NACP allele 2) was shown to have significant association with healthy elderly control individuals with apolipoprotein E risk. This may indicate a possible protective function of the allele.

Aged↗

PubMed1996

Neuropsychological deficits associated with diffuse Lewy body disease.

Diffuse Lewy body disease (DLBD), in its pure form, is a neuropathologic condition in demented patients that is characterized by subcortical and diffusely distributed neocortical Lewy bodies with little or no concomitant Alzheimer's disease (AD) pathology. Clinically, DLBD patients initially present with dementia of insidious onset and subsequently develop mild extrapyramidal motor dysfunction. The present study retrospectively examined the neuropsychological test performance of five patients with DLBD and compared their performance to that of equally demented patients with neuropathologically confirmed "pure" AD. The results showed that the DLBD patients were globally demented with deficits in memory, attention, language, psychomotor performance, and "executive" functions, and a strikingly severe deficit in visuospatial and visuoconstructive abilities. The visuoconstructive and psychomotor impairments of the DLBD patients were significantly worse than those of the AD patients, whereas the memory performance of the AD patients was worse than that of the DLBD patients. These results indicate that DLBD without concomitant AD pathology can produce a global dementia with aspects of both cortical and subcortical dysfunction and suggests that Lewy body pathology contributes importantly to the clinical manifestation of the Lewy body variant of AD.

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PubMed1996

Association of tumor development with increased cellular proliferation and transgene overexpression, but not c-Ha-ras mutations, in v-Ha-ras transgenic Tg.AC mice.

The transgenic mouse line Tg.AC carries a v-Ha-ras gene fused to a fetal (zeta) globin promoter and uniquely responds to chemical carcinogens and tumor promoters by the induction of epidermal papillomas. Although the transgene was not constitutively expressed in non-tumor-bearing tissues, expression was induced by exposure to selected chemicals. Tg.AC transgenic mice on the FVB/N background developed occasional spontaneous tumors, including odontomas, squamous cell carcinoma of the salivary gland, leukemias and a rare ovarian yolk sac carcinoma. Both spontaneous and induced tumors are associated with expression of the transgene and, as determined by in situ hybridization, transgene expression is localized to proliferative areas of the tumors. Sequence analysis of the endogenous c-Ha-ras gene in both induced and spontaneous tumors revealed no mutations in codons 12, 59 or 61. These results suggest that expression of the v-Ha-ras transgene induces proliferation of specific cells in diverse tissues which then acquire neoplastic properties.

Animals↗

PubMed1996

Neocortical lewy body counts correlate with dementia in the Lewy body variant of Alzheimer's disease.

Patients with the Lewy body variant (LBV) of Alzheimer's disease (AD) meet diagnostic criteria for AD but have a lighter burden of plaque and tangle AD pathology despite comparable dementia. We quantified neocortical Lewy bodies (LB) in LBV patients (n = 14) using anti-ubiquitin polyclonal antibody, selecting for quantification those neocortical regions with the highest densities of LB. Neocortical neurofibrillary tangles (NFT) and neuritic plaques were evaluated with thioflavin- S. A group of classical AD patients (n = 12), matched for disease duration, was also studied. For most of these cases, entorhinal neurofibrillary pathology had previously been assessed by applying a modification of the Braak and Braak AD staging protocol. Although LBV and AD groups had similar mental test scores when last evaluated prior to death, lower neocortical NFT and plaque counts and lower modified Braak stages were observed in LBV. Neocortical NFT counts correlated with impaired neuropsychological test performance in AD but not in LBV. Plaque counts did not correlate with mental status in either group. Lewy body concentrations in four neocortical areas correlated significantly with dementia severity in LBV. The association of AD lesions in the neocortex with dementia in LBV was comparatively weaker than that observed for LB concentrations. These findings suggest that neocortical LB combined with entorhinal NFT or subcortical Parkinson's disease-type pathology may equalize the degree of dementia seen in LBV with that encountered in classical AD.

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PubMed1996

In vivo microperfusion of the ductuli efferentes testis of the rat: flow dependence of fluid reabsorption.

Individual ducts from the initial zone of the efferent ducts of the rat were microperfused in vivo using a double cannulation procedure, which allowed the recovery of perfused fluids for analysis and determination of the rate of fluid reabsorption from the perfused duct. The ducts were perfused at rates from 0.025 to 0.4 microliters min-1 with either Krebs-Ringer bicarbonate (KRB) solution or the native rete testis fluid (nRTF) that perfuses the ducts in situ. Reabsorption of KRB solution increased linearly with a perfusion rate of between 0.025 and 0.1 microliter min-1 (from 17.4 +/- 1.5 to 34.3 +/- 3.2 nl (10 mm duct)-1 min-1), then increased no further. Reabsorption of nRTF increased linearly between 0.025 and 0.2 microliters min-1 (from 17.7 +/- 1.5 to 61.4 +/- 13.5 nl (10 mm duct)-1 min-1) and then declined. The reabsorption rate from nRTF perfusates was significantly higher than from KRB perfusates. As a proportion of the luminal perfusate, reabsorption declined from 73.0 +/- 6.0 to 7.4 +/- 3.0% (10 mm duct)-1 for KRB solution and from 73.1 +/- 6.0 to 4.1 +/- 1.3% (10 mm duct)-1 for nRTF. There was no significant change in the concentration of either Na+ or Cl- in KRB solution or nRTF during perfusion through the efferent ducts, indicating that the reabsorption of these ions was isomolar. However, the reabsorption of K+ from nRTF occurred at a greater rate than that of water, and the initial [K+] declined from 17.2 +/- 0.4 mM in nRTF perfusates to 5.7 +/- 0.5 mM in collectates (perfusion rate, 0.1 microliter min-1) to achieve equilibrium with blood plasma (4.7 +/- 0.4 mM). The osmotic pressure of both KRB and nRTF perfusates equilibrated with blood plasma, indicating a high permeability of the epithelium to water. The results of this study provide further evidence that fluid reabsorption in the efferent ducts is isosmotic, or close to isosmotic, and have shown that, as in the homologous proximal kidney tubule, reabsorption is dependent on luminal flow rate. In contrast to the proximal tubule, however, reabsorption in the efferent ducts is not maintained as a constant proportion of the perfusion load. It is concluded that microperfusion in vivo provides a useful technique for studying fluid reabsorption in the efferent ducts of the rat.

Absorption↗

PubMed1996

The apolipoprotein E epsilon 4 allele is associated with increased neuritic plaques and cerebral amyloid angiopathy in Alzheimer's disease and Lewy body variant.

OBJECTIVE: To determine the relationship between apolipoprotein E (apoE) genotype and neuropathologic lesions in Alzheimer's disease (AD) and Lewy body variant (LBV). DESIGN: Retrospective genetic-neuropathologic study of AD and LBV cases. The main neuropathologic outcome measures were modeled as a function of apoE genotype, neuropathologic diagnosis, and gender. Age at death and duration of symptom effects were controlled for by ANCOVA. PATIENTS: One hundred twenty-seven cases with neuropathologically diagnosed AD (n = 84) or LBV (n = 43). MAIN OUTCOME MEASURES: Quantitative scores of neuritic plaques (NPs), neurofibrillary tangles (NFTs), cerebral amyloid angiopathy (CAA) severity, and CAA prevalence were averaged across four brain regions: midfrontal, inferior parietal, superior temporal, and hippocampal. RESULTS: The apoE epsilon 4 allele was associated with increased NPs within both AD and LBV. The epsilon 4 allele was associated with an increased frequency of CAA in the AD and LBV groups combined groups combined and in and in LBV alone. While CAA severity and NETs were increased in the epsilon 4/4 homozygous case when AD and LBV were combined, there were no significant effects within AD or LBV alone. CONCLUSIONS: The apoE epsilon 4 allele is strongly associated with increased NPs, but not neocortical NFTs, in both AD and LBV.

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PubMed1996

Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop.

Recent neuropathologic autopsy studies found that 15 to 25% of elderly demented patients have Lewy bodies (LB) in their brainstem and cortex, and in hospital series this may constitute the most common pathologic subgroup after pure Alzheimer's disease (AD). The Consortium on Dementia with Lewy bodies met to establish consensus guidelines for the clinical diagnosis of dementia with Lewy bodies (DLB) and to establish a common framework for the assessment and characterization of pathologic lesions at autopsy. The importance of accurate antemortem diagnosis of DLB includes a characteristic and often rapidly progressive clinical syndrome, a need for particular caution with neuroleptic medication, and the possibility that DLB patients may be particularly responsive to cholinesterase inhibitors. We identified progressive disabling mental impairment progressing to dementia as the central feature of DLB. Attentional impairments and disproportionate problem solving and visuospatial difficulties are often early and prominent. Fluctuation in cognitive function, persistent well-formed visual hallucinations, and spontaneous motor features of parkinsonism are core features with diagnostic significance in discriminating DLB from AD and other dementias. Appropriate clinical methods for eliciting these key symptoms are described. Brainstem or cortical LB are the only features considered essential for a pathologic diagnosis of DLB, although Lewy-related neurites, Alzheimer pathology, and spongiform change may also be seen. We identified optimal staining methods for each of these and devised a protocol for the evaluation of cortical LB frequency based on a brain sampling procedure consistent with CERAD. This allows cases to be classified into brainstem predominant, limbic (transitional), and neocortical subtypes, using a simple scoring system based on the relative distribution of semiquantitative LB counts. Alzheimer pathology is also frequently present in DLB, usually as diffuse or neuritic plaques, neocortical neurofibrillary tangles being much less common. The precise nosological relationship between DLB and AD remains uncertain, as does that between DLB and patients with Parkinson's disease who subsequently develop neuropsychiatric features. Finally, we recommend procedures for the selective sampling and storage of frozen tissue for a variety of neurochemical assays, which together with developments in molecular genetics, should assist future refinements of diagnosis and classification.

Dementia↗

PubMed1995

Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype.

Gene targeting was used to create a null allele at the epidermal growth factor receptor locus (Egfr). The phenotype was dependent on genetic background. EGFR deficiency on a CF-1 background resulted in peri-implantation death due to degeneration of the inner cell mass. On a 129/Sv background, homozygous mutants died at mid-gestation due to placental defects; on a CD-1 background, the mutants lived for up to 3 weeks and showed abnormalities in skin, kidney, brain, liver, and gastrointestinal tract. The multiple abnormalities associated with EGFR deficiency indicate that the receptor is involved in a wide range of cellular activities.

Abnormalities, Multiple↗

PubMed1995

Fragmentation of the neuronal cytoskeleton in the Lewy body variant of Alzheimer's disease.

We studied neuronal alterations in the Lewy body variant of Alzheimer's disease (LBV) with a monoclonal antibody (SMI32) against non-phosphorylated neurofilament proteins, and compared them with the alterations found in pure Alzheimer's disease (AD). A characteristic granular and fragmented appearance of SMI32-immunolabeled pyramidal neurons in layers 3 and 5 of the neocortex occurred in 78% of the LBV cases and was not found in the pure AD cases. Lewy bodies (LBs) in pyramidal neurons in layers 5 and 6 immunoreacted with SMI32 in 44% of the LBV cases. These alterations may be associated with the cognitive deficits found in LBV and are suggestive of an underlying, widespread pathology that includes both disruption of the neurofilamentous cytoskeleton and formation of LBs.

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PubMed1995

Cerebral infarction in Alzheimer's disease is associated with severe amyloid angiopathy and hypertension.

OBJECTIVE: To determine if severe cerebral amyloid angiopathy (AA) in patients with Alzheimer's disease (AD) is associated with an increased prevalence of cerebral infarction diagnosed at autopsy. Amyloid angiopathy is increasingly recognized as a cause of ischemic infarcts, as well as cerebral hemorrhages. However, the relationship of AA to cerebral infarction in patients with AD is uncertain. DESIGN: Retrospective clinicopathological study of autopsy-confirmed cases of AD. PATIENTS: One hundred forty-five deceased patients with AD confirmed at autopsy. MAIN OUTCOME MEASURES: Semiquantitative scores of AA severity were done in four brain regions: midfrontal, inferior parietal, superior temporal, and hippocampal. The finding of cerebral infarction at autopsy was modeled as a function of AA severity, hypertension, age at death, AD severity, and sex in chi 2 and multiple logistic regression analyses. RESULTS: Severe AA was significantly associated with cerebral infarction at autopsy in patients with AD (odds ratio [OR], 3.5; 95% confidence interval [CI], 1.4 to 8.9). None of the other independent variables in the multiple logistic regression analysis were significant predictors. While hypertension was equally common in the severe and mild AA subgroups, the combination of both severe AA and hypertension interacted to increase the risk of infarction (OR, 14.2; 95% CI, 3.2 to 63.4) beyond that observed with hypertension (OR, 1.1; 95% CI, 0.4 to 3.2) or severe AA (OR, 1.3; 95% CI, 0.3 to 5.3) alone. CONCLUSIONS: Severe AA is associated with an increased frequency of cerebral infarction in patients with AD. This appears to be largely due to an interaction between severe AA and hypertension that may produce multiplicative injuries on the vasculature. Further study with regard as to how AA may cause ischemia and its role in the neuropathologic and clinical progression of AD is needed.

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PubMed1995

Clinical validity of the Mattis Dementia Rating Scale in detecting Dementia of the Alzheimer type. A double cross-validation and application to a community-dwelling sample.

OBJECTIVE: To assess the clinical validity of the Dementia Rating Scale (DRS) in detecting patients with dementia of the Alzheimer type (DAT). BACKGROUND: The DRS is widely used to evaluate cognitive functioning in older adults. Adequate normative data are unavailable; studies addressing the clinical validity of the DRS are limited by small sample sizes. DESIGN AND METHODS: Administered the DRS to 254 outpatients with DAT and 105 healthy elderly subjects. Performed (1) multiple regressions of demographic factors on the DRS and its subscales; (2) derivation of optimal DRS cutoff scores using receiver operating characteristic curves; (3) double cross-validation with stepwise logistic regressions; and (4) application of results to a community-dwelling sample. RESULTS: Age- and education-adjusted DRS scores were computed. The optimal DRS cutoff score for DAT of 129 or less revealed a sensitivity of 98% and a specificity of 97%. The logistic regressions resulted in a combination of the Memory and Initiation/Perseveration subscales that correctly classified 98% of all subjects, 92% of a subsample of 76 patients with mild DAT, and 100% of the 51 patients with autopsy-confirmed DAT. The resultant equation was then applied to a community-dwelling sample (238 healthy elderly subjects and 44 patients with DAT): 91% of patients and 93% of normal subjects were correctly classified. Of an additional 77 individuals with questionable DAT, 43 were classified as demented and 34 were classified as nondemented. CONCLUSIONS: The DRS is a clinically valid psychometric test for the detection of DAT. The Memory and Initiation/Perseveration subscales are its best discriminative indexes for an abbreviated version.

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PubMed1995

The CYP2D6B mutant allele is overrepresented in the Lewy body variant of Alzheimer's disease.

Approximately one-fourth of neuropathologically confirmed cases of Alzheimer's disease (AD) also have brainstem and neocortical Lewy bodies, constituting a Lewy body variant of AD. Because Lewy bodies are a pathologic hallmark of Parkinson's disease (PD), this subpopulation of AD subjects may have the same risk factors as PD subjects. Analyses of the cytochrome P450 CYP2D6-debrisoquine 4-hydroxylase mutant B allele, a susceptibility gene for PD, revealed a higher representation of this allele in the Lewy body variant of AD than in pure AD or non-AD without Lewy bodies.

Alleles↗

PubMed1995

Cortical Lewy body-containing neurons are pyramidal cells: laser confocal imaging of double-immunolabeled sections with anti-ubiquitin and SMI32.

To characterize neurons containing cortical Lewy bodies (LBs), vibratome sections of the superior temporal cortex from eight patients with the LB variant of Alzheimer's disease (LBV) were double-immunolabeled with anti-ubiquitin (a marker of LBs) and anti-nonphosphorylated neurofilament (SMI32; a marker of pyramidal cells) or parvalbumin (PV; a marker of interneurons) and were viewed with a laser-scanning confocal microscope. Almost all (96.1%) the LB-containing neurons were positive for SMI32, but not for PV. Furthermore, the average numbers of SMI32-immunoreactive neurons in layers 3 and 5 were 63% and 77% of those in controls, respectively. PV-immunoreactive neurons showed a greater than 40% decrease. These findings indicate that cortical LB-containing neurons are pyramidal cells and suggest that in LBV, there may be some differences in the degenerative processes effecting pyramidal cells and interneurons.

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PubMed1995

Suppression of hyperacute and passively transferred experimental autoimmune encephalomyelitis by the anti-oxidant, butylated hydroxyanisole.

Butylated hydroxyanisole (BHA) was used to treat hyperacute, ordinary passive, and hyperacute passive experimental autoimmune encephalomyelitis (EAE) in the Lewis rat. The anti-oxidant, delivered via mini-osmotic pumps, reduced the incidence, severity and mortality in hyperacute EAE and also reduced the incidence, severity and duration of disease in passively induced EAE and hyperacute passive EAE. In all cases, cellular infiltration by both mononuclear and polymorphonuclear leukocytes were significantly reduced in treated rats. BHA appears therefore to act at the effector stage of EAE, reducing cellular infiltration in the brain and spinal cord and minimising clinical signs without blocking sensitisation or activation. This was supported by the finding that spleen cells from BHA-treated donors immunised for hyperacute EAE transferred disease at least as well as cells recovered from untreated donors.

Administration, Oral↗

PubMed1995

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part X. Neuropathology confirmation of the clinical diagnosis of Alzheimer's disease.

This report summarizes the neuropathologic findings in the first 106 autopsies of CERAD (Consortium to Establish a Registry for Alzheimer's Disease) dementia patients diagnosed clinically as having Alzheimer's disease (AD). In 92 (87%) of the 106 cases, neuropathologists confirmed Alzheimer's disease (AD) as the primary dementing illness. Coexistent Parkinson's disease (PD) changes were present in 19 (21%) and vascular lesions of varying nature and size in 26 (28%) of these 92 AD cases. The 14 cases in which AD was not interpreted as the primary dementing illness can be divided into four major subgroups based on their neuropathology findings: PD and related pathology (n = 5), hippocampal sclerosis (n = 3), miscellaneous neurodegenerative and other disorders (n = 3), and no significant changes (n = 3). Despite the relatively high level of clinical diagnostic accuracy, further refinement of assessment batteries may facilitate distinction of non-AD dementias from AD.

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PubMed1995

Apolipoprotein E epsilon 4 allele frequency is not increased in progressive supranuclear palsy.

We examined apolipoprotein E (ApoE) immunoreactivity and allele frequency in 12 autopsied cases of progressive supranuclear palsy (PSP), a neurodegenerative disease characterized by diffuse neurofibrillary tangle (NFT) formation without beta-amyloid deposits. In spite of the ApoE immunoreactivity associated with NFTs, in PSP the ApoE allele frequency was comparable with that of age-matched normal controls. This suggests that in Alzheimer's disease the increased frequency of ApoE epsilon 4 does not influence neurofibrillary degeneration, but is probably linked to beta-amyloid deposition.

Alleles↗

PubMed1995

Pilocytic astrocytoma presenting as an extra-axial tumor in the cerebellopontine angle: case report.

Glial tumors in the cerebellopontine angle (CPA) are rare. Four histologically distinct types of glial tumors of the CPA have been described in the literature as ependymoma, medulloblastoma, mixed glial tumor, and fibrillary astrocytoma. This case report describes a pilocytic astrocytoma of the CPA. A 58-year-old man with a hearing loss had an extra-axial tumor in the left CPA that extended into the internal auditory canal. The characteristics of the tumor on magnetic resonance imaging scans differed from those of typical CPA tumors. It adhered avidly to the cochlear and vestibular nerves, which had to be sacrificed for gross total resection. Microscopic examination showed the typical features of an adult-type pilocytic astrocytoma.

Astrocytoma↗

PubMed1995

Making the diagnosis of mixed and non-Alzheimer's dementias.

Community pathologists are often called on to perform autopsies to confirm clinical diagnoses of Alzheimer's disease, by far the most common cause of dementia. Diagnostic criteria have been provided by the Consortium to Establish a Registry for Alzheimer's Disease. Beyond pure and simple Alzheimer's disease, a significant proportion of dementia brains will feature Alzheimer's disease mixed with Lewy bodies, historically associated with idiopathic Parkinson's disease, or combined with various manifestations of cerebrovascular disease. Less commonly, the pathologist will encounter Lewy body disease alone, pure cerebrovascular disease, Pick's disease, progressive supranuclear palsy, Creutzfeldt-Jakob disease, or dementia lacking distinctive histopathology. This article is intended to reacquaint pathologists with these disorders and to provide a practical step-by-step approach to making the diagnosis of these mixed and non-Alzheimer's dementias.

Alzheimer Disease↗