Phase transformation behaviour of hydroxyapatite foams subject to heat treatment.

This study examined the relationship between sintering and phase transformation behaviour in hydroxyapatite (HA). Pellets and replicated foams were sintered at five different temperatures ranging from 1350 degrees C to 1550 degrees C. Hydroxyapatite remained as the major phase in all the samples studied. In the pellets, sintering took place prior to the phase transformation which occurs primarily at the surface. This created damage that extended into the interior of the pellet above 1400 degrees C. In contrast, the foams transformed at lower temperatures due to the higher surface area. This did not create damage in the foam. The differences in the foams and the pellets are discussed in terms of sintering and phase transformation behaviour.

Complement activation in very early Alzheimer disease.

The activation of the classical complement (C)-system in early-stage Alzheimer disease (AD) and nondemented aging was examined with immunohistochemistry in subjects assessed by the Clinical Dementia Rating (CDR). Activation (staining for C3 and C4 fragments) was found in all brains with amyloid deposits, including all nondemented (CDR 0) cases, with either small numbers of diffuse plaques or with sufficient plaques and tangles to indicate preclinical AD. Staining for C3 and C4 increased in parallel with plaque density in very mild to severe clinical AD. A subset of very mild AD (CDR 0.5) cases also showed C1q (on plaques) and C5b-9 (on neuritic plaques and tangles), whereas these C-fragments were consistently found in severe AD (CDR 3). Mirror section (split-face) analysis showed that C1q, C3, and apoJ (clusterin) occurred on the same plaques. However, C-system regulators CD59, CR1, DAF, and MCP were not detected on plaques or tangles at any stage, indicating that C-activation related to AD is incompletely controlled.

Preclinical detection of Alzheimer's disease: hippocampal shape and volume predict dementia onset in the elderly.

Structural deformity of the hippocampus is characteristic of individuals with very mild and mild forms of dementia of the Alzheimer type (DAT). The purpose of this study was to determine whether a similar deformity of the hippocampus can predict the onset of dementia in nondemented elders. Using high dimensional diffeomorphic transformations of a neuroanatomical template, hippocampal volumes and surfaces were defined in 49 nondemented elders; the hippocampal surface was subsequently partitioned into three zones (i.e., lateral, superior and inferior-medial), which were proximal to the underlying CA1 subfield, CA2-4 subfields plus dentate gyrus, and subiculum, respectively. Annual clinical assessments using the Clinical Dementia Rating scale (CDR), where CDR 0 indicates no dementia and CDR 0.5 indicates very mild dementia, were then performed for a mean of 4.9 years (range 0.9-7.1 years) to monitor subjects who converted from CDR 0 to CDR 0.5. Inward variation of the lateral zone and left hippocampal volume significantly predicted conversion to CDR 0.5 in separate Cox proportional hazards models. When hippocampal surface variation and volume were included in a single model, inward variation of the lateral zone of the left hippocampal surface was selected as the only significant predictor of conversion. The pattern of hippocampal surface deformation observed in nondemented subjects who later converted to CDR 0.5 was similar to the pattern of hippocampal surface deformation previously observed to discriminate subjects with very mild DAT and nondemented subjects. These results suggest that inward deformation of the left hippocampal surface in a zone corresponding to the CA1 subfield is an early predictor of the onset of DAT in nondemented elderly subjects.

The pathology of the substantia nigra in Alzheimer disease with extrapyramidal signs.

BACKGROUND: Extrapyramidal signs (EPS) are common in Alzheimer disease (AD) and increase in prevalence as AD advances. The neuropathologic substrate responsible for EPS in AD remains to be fully characterized. METHODS: Subjects had a clinical diagnosis of AD confirmed by neuropathologic examination. EPS during life were documented by clinical methods assessing bradykinesia, cogwheel rigidity, rest tremor, and parkinsonian gait. Subjects with EPS and previous neuroleptic exposure were excluded. Twenty-eight subjects were in the EPS group and 104 subjects were without EPS. Neuron loss, alpha-synuclein (ASYN)-labeled pathology, and tau-labeled pathology in the substantia nigra were measured using semiquantitative techniques such that higher scores represented increased pathologic burden. RESULTS: Presence of nigral ASYN-labeled pathology was more common (50 vs 28.9%; p < 0.05) in the EPS group than in those without EPS. There was more nigral neuron loss in the EPS group (1.50 vs 1.11 in no-EPS group; p < 0.05). Tau-labeled burden was not different by group comparisons; however, EPS onset at later stages of dementia severity was associated with increased tau-labeled pathology (Kendall tau-B = 0.48, p < 0.01) and this association remained after controlling for dementia severity at death. Additionally, moderate to severe tau burden was more common in the subgroup with "pure AD" (definite AD without other neuropathology) with EPS (81.8%) than cases without EPS (49.0%; p < 0.05). Four subjects with EPS (14.3%) had little to no significant nigral pathologic changes. CONCLUSIONS: Clinically detected extrapyramidal signs (EPS) in Alzheimer disease (AD) are associated with substantia nigra pathology including alpha-synuclein aggregation, hyperphosphorylated tau accumulation, and neuron loss that may account for the increasing prevalence of EPS as AD progresses. In some cases, limited nigral pathology suggests extranigral factors in the clinical symptoms of EPS.

Progressive posterior cortical dysfunction: a clinicopathologic series.

BACKGROUND: Atypical presentations of neurodegenerative dementing disorders include the syndrome of progressive posterior cortical dysfunction (PPCD) involving selective higher order visuospatial deficits. The neuropathologic correlates of PPCD remain poorly defined. METHODS: This is a retrospective case series of 27 individuals (14 men, 13 women) diagnosed clinically with PPCD. Participants were either enrolled in the Alzheimer's Disease Research Center (ADRC) or referred to the memory diagnostic center of an urban academic medical center. Clinical evaluations included physical and neurologic examinations, the Clinical Dementia Rating (CDR), and psychometric measures. Neuropathologic examinations were completed in 21 individuals with PPCD. Psychometric measures from 65 individuals with mild dementia of the Alzheimer type (DAT) enrolled in the ADRC were used for comparison. RESULTS: Neuropathologic etiologies of PPCD were Alzheimer disease (AD) (n = 13), AD plus Parkinson disease (n = 1), AD-Lewy body variant (n = 2), dementia with Lewy bodies plus progressive subcortical gliosis of Neumann (n = 1), corticobasal degeneration (n = 2), and prion-associated diseases: Creutzfeldt-Jakob disease (n = 1) and fatal familial insomnia (n = 1). Confirming the clinical impression, psychometric profiles for individuals with PPCD differed from those of people with DAT alone and revealed disproportionate deficits on measures of visuospatial ability. CONCLUSIONS: AD was the most frequent cause of PPCD in this series, although non-Alzheimer's dementing disorders also should be considered.

Specificity and potential mechanism of sulfatide deficiency in Alzheimer's disease: an electrospray ionization mass spectrometric study.

Recently, we have demonstrated that sulfatide content was substantially depleted in post-mortem brain samples from subjects with very mild Alzheimer's disease (AD) relative to age-matched controls. However, it is unknown if the observed sulfatide deficiency is AD-specific and what mechanism(s) lead to this depletion. By exploiting the advantages of electrospray ionization mass spectrometry techniques, we examined the specificity and a potential mechanism of sulfatide deficiency in AD in the study. In contrast to the sulfatide depletion observed in AD, it was found that the sulfatide content in post-mortem brain samples from subjects with Parkinson's disease and dementia with Lewy bodies was either higher than or comparable to that observed from controls, respectively, suggesting that sulfatide deficiency is likely specific to AD. Examination of lipid alterations in cultured embryonic rat brain oligodendrocytes treated with amyloid-beta peptide demonstrated that there was no alteration in sulfatide content up to a 24-hr interval after amyloid-beta addition/treatment. However, there were significant decreases in plasmenylethanolamine and increases in sphingomyelin content in the same study. These findings suggest that sulfatide deficiency in AD is unlikely mediated directly by amyloid-beta peptide accumulation. Thus, these results illustrate the specificity of sulfatide deficiency in AD and exclude amyloid-beta accumulation as a factor directly contributing to sulfatide deficiency in AD.

Familial dementia with Lewy bodies: clinicopathologic analysis of two kindreds.

Familial cases of dementia with Lewy bodies (DLB) are rare. The authors describe two small kindreds with familial DLB: one with pure DLB meeting consensus criteria for DLB and one with coexistent AD pathology that did not fulfill DLB criteria. The authors call attention to the diverse features of DLB and suggest that current clinical criteria may not detect all cases. Familial DLB is clinically heterogeneous and occurs with or without coexistent AD, suggesting the relevance of LB pathology for the developing dementia.

Neuron number in the entorhinal cortex and CA1 in preclinical Alzheimer disease.

OBJECTIVES: To determine whether nondemented subjects with pathological evidence of preclinical Alzheimer disease (AD) demonstrate neuronal loss in the entorhinal cortex and hippocampus, and whether the onset of cognitive deficits in AD coincides with the onset of neuronal degeneration. METHODS: Preclinical AD cases have been defined by the absence of cognitive decline but with neuropathological evidence of AD. The hippocampus and entorhinal cortex were examined in 13 nondemented cases (Clinical Dementia Rating [CDR] 0) with healthy brains, 4 cases with preclinical AD, 8 cases with very mild symptomatic AD (CDR 0.5), and 4 cases with severe AD (CDR 3, hippocampus only). The volume and number of neurons were determined stereologically in 2 areas that are vulnerable to AD--the entorhinal cortex (as a whole and layer II alone) and hippocampal field CA1. RESULTS: There was no significant decrease in neuron number or volume with age in the healthy nondemented group and little or none between the healthy and preclinical AD groups. Substantial decreases were found in the very mild AD group in neuron number (35% in the entorhinal cortex, 50% in layer II, and 46% in CA1) and volume (28% in the entorhinal cortex, 21% in layer II, and 29% in CA1). Greater decrements were observed in CA1 in the severe AD group. CONCLUSIONS: There is little or no neuronal loss in aging or preclinical AD but substantial loss in very mild AD. The findings indicate that AD results in clinical deficits only when it produces significant neuronal loss.

Plasmalogen deficiency in early Alzheimer's disease subjects and in animal models: molecular characterization using electrospray ionization mass spectrometry.

To explore the hypothesis that alterations in ethanolamine plasmalogen may be directly related to the severity of dementia in Alzheimer's disease (AD), we performed a systematic examination of plasmalogen content in cellular membranes of gray and white matter from different regions of human subjects with a spectrum of AD clinical dementia ratings (CDR) using electrospray ionization mass spectrometry (ESI/MS). The results demonstrate: (1) a dramatic decrease in plasmalogen content (up to 40 mol% of total plasmalogen) in white matter at a very early stage of AD (i.e. CDR 0.5); (2) a correlation of the deficiency in gray matter plasmalogen content with the AD CDR (i.e. approximately 10 mol% of deficiency at CDR 0.5 (very mild dementia) to approximately 30 mol% of deficiency at CDR 3 (severe dementia); (3) an absence of alterations of plasmalogen content and molecular species in cerebellar gray matter at any CDR despite dramatic alterations of plasmalogen content in cerebellar white matter. Alterations of ethanolamine plasmalogen content in two mouse models of AD, APP(V717F) and APPsw, were also examined by ESI/MS. A plasmalogen deficiency was present (up to 10 mol% of total plasmalogen at the age of 18 months) in cerebral cortices, but was absent in cerebella from both animal models. These results suggest plasmalogen deficiency may play an important role in the AD pathogenesis, particularly in the white matter, and suggest that altered plasmalogen content may contribute to neurodegeneration, synapse loss and synaptic dysfunction in AD.

Mild cognitive impairment represents early-stage Alzheimer disease.

BACKGROUND: Mild cognitive impairment (MCI) is considered to be a transitional stage between aging and Alzheimer disease (AD). OBJECTIVE: To determine whether MCI represents early-stage AD by examining its natural history and neuropathologic basis. DESIGN: A prospective clinical and psychometric study of community-living elderly volunteers, both nondemented and minimally cognitively impaired, followed up for up to 9.5 years. Neuropathologic examinations were performed on participants who had undergone autopsy. SETTING: An AD research center. PARTICIPANTS: All participants enrolled between July 1990 and June 1997 with Clinical Dementia Rating (CDR) scores of 0 (cognitively healthy; n = 177; mean age, 78.9 years) or 0.5 (equivalent to MCI; n = 277; mean age, 76.9 years). Based on the degree of clinical confidence that MCI represented dementia of the Alzheimer type (DAT), 3 subgroups of individuals with CDR scores of 0.5 were identified: CDR 0.5/DAT, CDR 0.5/incipient DAT, and CDR 0.5/uncertain dementia. MAIN OUTCOME MEASURE: Progression to the stage of CDR 1, which characterizes mild definite DAT. RESULTS: Survival analysis showed that 100% of CDR 0.5/DAT participants progressed to greater dementia severity over a 9.5-year period. At 5 years, rates of progression to a score of CDR 1 (or greater) for DAT were 60.5% (95% confidence interval [CI], 50.2%-70.8%) for the CDR 0.5/DAT group, 35.7% (95% CI, 21.0%-50.3%) for the CDR 0.5/incipient DAT group, 19.9% (95% CI, 8.0%-31.8%) for the CDR 0.5/uncertain dementia group, and 6.8% (95% CI, 2.2%-11.3%) for CDR 0/controls. Progression to greater dementia severity correlated with degree of cognitive impairment at baseline. Twenty-four of the 25 participants with scores of CDR 0.5 had a neuropathologic dementing disorder, which was AD in 21 (84%). CONCLUSIONS: Individuals currently characterized as having MCI progress steadily to greater stages of dementia severity at rates dependent on the level of cognitive impairment at entry and they almost always have the neuropathologic features of AD. We conclude that MCI generally represents early-stage AD.

Absence of cognitive impairment or decline in preclinical Alzheimer's disease.

OBJECTIVE: To determine whether clinically nondemented elderly individuals with pathologically confirmed preclinical AD are characterized by cognitive decline as measured by psychometric tests before death. METHODS: Psychometric performance was examined retrospectively in 14 individuals who were nondemented at time of death and grouped in accordance with their neuropathologic findings: 1) Healthy brain (n = 9) was characterized by the absence of senile plaques or by only patchy neocortical deposits of plaques; 2) preclinical AD (n = 5) was characterized by neuritic and diffuse plaques distributed throughout the neocortex. All individuals showed neurofibrillary pathologic change in medial temporal lobe structures. For comparison, we also evaluated 10 individuals who died in the earliest symptomatic stage of dementia of the Alzheimer type (DAT). All individuals had been assessed by clinical and psychometric measures during life. The psychometric measures yielded a standardized factor score that represented global cognitive performance. RESULTS: At the last assessment before death, individuals with very mild DAT were impaired on the factor score and on individual psychometric measures with respect to the nondemented individuals. Those nondemented individuals with preclinical AD did not differ in performance from those with healthy brains. For individuals with at least three psychometric assessments during life, there was no decline in performance for either those with healthy brains (n = 5) or preclinical AD (n = 3), although decline was evident for very mild DAT individuals (n = 5). CONCLUSIONS: Pathologically confirmed preclinical AD is not associated with cognitive impairment or decline, even on measures shown to be sensitive to very mild DAT.

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.

Early DAT is distinguished from aging by high-dimensional mapping of the hippocampus. Dementia of the Alzheimer type.

OBJECTIVE: To determine the feasibility of using high-dimensional brain mapping (HDBM) to assess the structure of the hippocampus in older human subjects, and to compare measurements of hippocampal volume and shape in subjects with early dementia of the Alzheimer type (DAT) and in healthy elderly and younger control subjects. BACKGROUND: HDBM represents the typical structures of the brain via the construction of templates and addresses their variability by probabilistic transformations applied to the templates. Local application of the transformations throughout the brain (i.e., high dimensionality) makes HDBM especially valuable for defining subtle deformities in brain structures such as the hippocampus. METHODS: MR scans were obtained in 18 subjects with very mild DAT, 18 healthy elderly subjects, and 15 healthy younger subjects. HDBM was used to obtain estimates of left and right hippocampal volume and eigenvectors that represented the principal dimensions of hippocampal shape differences among the subject groups. RESULTS: Hippocampal volume loss and shape deformities observed in subjects with DAT distinguished them from both elderly and younger control subjects. The pattern of hippocampal deformities in subjects with DAT was largely symmetric and suggested damage to the CA1 hippocampal subfield. Hippocampal shape changes were also observed in healthy elderly subjects, which distinguished them from healthy younger subjects. These shape changes occurred in a pattern distinct from the pattern seen in DAT and were not associated with substantial volume loss. CONCLUSIONS: Assessments of hippocampal volume and shape derived from HDBM may be useful in distinguishing early DAT from healthy aging.

Increased neocortical neurofibrillary tangle density in subjects with Alzheimer disease and psychosis.

BACKGROUND: Psychosis is common in patients with Alzheimer disease. While the relationship between psychosis and clinical variables has been examined frequently, few studies have examined the relationship between psychosis and the 2 major neuropathological hallmarks of Alzheimer disease: neurofibrillary tangles and senile plaques. We characterized the occurrence of psychosis in relation to dementia severity and determined if subjects with Alzheimer disease and psychosis had a greater neurofibrillary tangle or senile plaque burden than subjects with Alzheimer disease and no psychosis. METHODS: One hundred nine subjects with Alzheimer disease were followed longitudinally with semistructured assessments in order to assign a Clinical Dementia Rating and determine whether psychosis was present. After the subjects died, their brains were obtained for histological examination. Analysis of variance was used to compare the densities of neurofibrillary tangles, total senile plaques, and cored senile plaques in subjects with psychosis vs subjects without psychosis, in several neocortical regions, the hippocampus, and the entorhinal cortex. RESULTS: Psychosis occurred commonly in Alzheimer disease, affecting 63% of subjects. The frequency of psychosis increased with increasing dementia severity. More importantly, we found that subjects with psychosis had a 2.3-fold (95% confidence interval, 1.2-3.9) greater density of neocortical neurofibrillary tangles than did subjects without psychosis. The increase was independent of dementia severity. No similar relationship with psychosis was seen for total senile plaques or cored senile plaques. CONCLUSIONS: The increase in psychosis frequency that occurs with the progression of dementia severity and the independent association between psychosis and neurofibrillary tangle density suggest the possibility that some common underlying process or processes specific to Alzheimer disease may regulate both phenomena. Arch Gen Psychiatry. 2000;57:1165-1173.

Misleading results with the 14-3-3 assay for the diagnosis of Creutzfeldt-Jakob disease.

The definitive diagnosis of Creutzfeldt-Jakob disease (CJD) requires brain tissue analysis. A positive assay for the 14-3-3 protein in CSF has been suggested to be highly sensitive and specific in patients with CJD. The authors describe three patients for whom CSF 14-3-3 assays were falsely positive or falsely negative. Caution against overreliance on this putative biomarker is suggested in the diagnosis of CJD.

Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease.

Apolipoprotein E (apoE) alleles determine the age-adjusted relative risk (epsilon4 > epsilon3) for Alzheimer's disease (AD). ApoE may affect AD pathogenesis by promoting deposition of the amyloid-beta (Abeta) peptide and its conversion to a fibrillar form. To determine the effect of apoE on Abeta deposition and AD pathology, we compared APP(V717F) transgenic (TG) mice expressing mouse, human, or no apoE (apoE(-/-)). A severe, plaque-associated neuritic dystrophy developed in APP(V717F) TG mice expressing mouse or human apoE. Though significant levels of Abeta deposition also occurred in APP(V717F) TG, apoE(-/-) mice, neuritic degeneration was virtually absent. Expression of apoE3 and apoE4 in APP(V717F) TG, apoE(-/-) mice resulted in fibrillar Abeta deposits and neuritic plaques by 15 months of age and substantially (>10-fold) more fibrillar deposits were observed in apoE4-expressing APP(V717F) TG mice. Our data demonstrate a critical and isoform-specific role for apoE in neuritic plaque formation, a pathological hallmark of AD.

White matter hyperintensities and gray matter lesions in physically healthy depressed subjects.

OBJECTIVE: Previous studies reported that depressed subjects had more white matter hyperintensities on magnetic resonance imaging scans than control subjects, but the subjects had cerebrovascular disease risk factors. This study used subjects with a history of recurrent major depression and matched comparison subjects, screened to exclude cerebrovascular disease risk factors, to determine whether depressed subjects had more white matter hyperintensities and other lesions. METHOD: A semiautomated volumetric computer program was used to compare numbers and volumes of white matter hyperintensities, basal ganglia lesions, and total lesions in 24 women with a history of recurrent major depression and 24 comparison subjects case-matched on age and education and group-matched on height. In addition, images were measured with the use of a validated categorical scale. All subjects were screened to exclude cerebrovascular disease risk factors. RESULTS: There were no significant differences in the total volumes or total numbers of lesions. However, multiple linear regression showed a significant correlation of age and depression with number of lesions; this was accounted for by a greater number of small lesions (diameter < or = 0.4 cm). CONCLUSIONS: These findings suggest that cerebrovascular disease risk factors most likely mediated the relationship between depression and white matter hyperintensities seen in previous studies. However, the independent effect of depression, as well as an age-by-depression interaction, for small lesions suggests a causal role of depression in certain types of white matter pathology irrespective of other cerebrovascular disease risk factors. The volumetric method used in this study may be more sensitive than other methods in determining lesion characteristics and correlations with clinical variables.

Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17.

Tau proteins aggregate as cytoplasmic inclusions in a number of neurodegenerative diseases, including Alzheimer's disease and hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Over 10 exonic and intronic mutations in the tau gene have been identified in about 20 FTDP-17 families. Analyses of soluble and insoluble tau proteins from brains of FTDP-17 patients indicated that different pathogenic mutations differentially altered distinct biochemical properties and stoichiometry of brain tau isoforms. Functional assays of recombinant tau proteins with different FTDP-17 missense mutations implicated all but one of these mutations in disease pathogenesis by reducing the ability of tau to bind microtubules and promote microtubule assembly.

Hereditary dysphasic disinhibition dementia: a frontotemporal dementia linked to 17q21-22.

OBJECTIVE: The clinical and pathologic features of hereditary dysphasic disinhibition dementia (HDDD) are described to determine whether it is a variant of known dementias. BACKGROUND: Several dementing disorders have clinical and pathologic similarities with AD, Pick's disease, and the "nonspecific" dementias. A detailed description of clinical and pathologic presentation will aid classification, but ultimately the discovery of causative gene(s) will define these disorders. METHODS: The authors performed a clinical assessment: gross and microscopic pathologic evaluation of brain tissue, genetic linkage studies, and sequence analyses. RESULTS: HDDD is an autosomal-dominant frontotemporal dementia with many similarities to Pick's disease. Salient clinical features are global dementia with disproportionate dysphasia and "frontotemporal" symptoms. A linkage between HDDD and 17q21-22 was shown, with a maximum lod score of 3.68 at zero recombination. CONCLUSIONS: Several dementias have been linked to the same region and have been termed frontotemporal dementia with parkinsonism linked to chromosome 17. These disorders may represent phenotypic variants arising from mutations within a common gene.