Familial Alzheimer disease: decreases in CSF Abeta42 levels precede cognitive decline.

CSF amyloid beta-peptide 42 (Abeta42) levels in presymptomatic subjects with pathogenic mutations in the PS1 gene are significantly lower than in an age-matched control group. Consequently, in these subjects, there is a window of opportunity estimated as at least 4 to 12 years to evaluate the ability of any putative prophylactic therapy to decrease, arrest, or reverse abnormalities in Abeta42 metabolism many years before clinical symptoms of Alzheimer disease are otherwise likely to occur.

Distinguishable effects of presenilin-1 and APP717 mutations on amyloid plaque deposition.

Both APP and PS-1 are causal genes for early-onset familial Alzheimer's disease (AD) and their mutation effects on cerebral Abeta deposition in the senile plaques were examined in human brains of 29 familial AD (23 PS-1, 6 APP) cases and 14 sporadic AD cases in terms of Abeta40 and Abeta42. Abeta isoform data were evaluated using repeated measures analysis of variance which adjusted for within-subject measurement variation and confounding effects of individual APP and PS-1 mutations, age at onset, duration of illness and APOE genotype. We observed that mutations in both APP and PS-1 were associated with a significant increase of Abeta42 in plaques as been documented previously. In comparison to sporadic AD cases, both APP717 and PS-1 mutation cases had an increased density (measured as the number of plaques/mm(2)) and area (%) of Abeta42 plaques. However, we found an unexpected differential effect of PS-1 but not APP717 mutation cases. At least some of PS-1 but not APP717 mutation cases had the significant increase of density and area of Abeta40-plaques as compared to sporadic AD independently of APOE genotype. Our results suggest that PS-1 mutations affect cerebral accumulation of Abeta burden in a different fashion from APP717 mutations in their familial AD brains.

Striate cortex increases contrast gain of macaque LGN neurons.

Recurrent projections comprise a universal feature of cerebral organization. Here, we show that the corticofugal projections from the striate cortex (VI) to the lateral geniculate nucleus (LGN) robustly and multiplicatively enhance the responses of parvocellular neurons, stimulated by gratings restricted to the classical receptive field and modulated in luminance, by over two-fold in a contrast-independent manner at all but the lowest contrasts. In the equiluminant plane, wherein stimuli are modulated in chromaticity with luminance held constant, such enhancement is strongly contrast dependent. These projections also robustly enhance the responses of magnocellular neurons but contrast independently only at high contrasts. Thus, these results have broad functional significance at both network and neuronal levels by providing the experimental basis and quantitative constraints for a wide range of models on recurrent projections and the control of contrast gain.

Familial Alzheimer's disease: site of mutation influences clinical phenotype.

Alzheimer's disease (AD) is caused by multiple genetic and/or environmental etiologies. Because differences in the genetically determined pathogenesis may cause differences in the phenotype, we examined age at onset and age at death in 90 subjects with dominantly inherited AD due to different mutations (amyloid precursor protein, presenilin-1, and presenilin-2 genes). We found that among patients with dominantly inherited AD, genetic factors influence both age at onset and age at death.

Postmenopausal hormone therapy and cognitive function in healthy older women.

OBJECTIVE: Accumulating biologic evidence suggests that estrogen is related to cognitive function. Several epidemiologic investigations have reported that hormone therapy may reduce the risk of Alzheimer's disease. However, fewer studies have examined the relation of postmenopausal hormone use to general cognitive function in nondemented older women. Thus, we examined the association of hormone therapy to performance on four cognitive tests among healthy participants of the Nurses' Health Study. DESIGN: Cohort study. SETTING: The Nurses' Health Study, an ongoing prospective cohort study begun in 1976. PARTICIPANTS: From the Nurses' Health Study, 2138 women aged 70-78 years. MEASUREMENTS: From 1995-1999 we administered four cognitive tests (Telephone Interview for Cognitive Status (TICS), immediate and delayed recall of the East Boston Memory Test (EBMT), and verbal fluency) by telephone. Hormone use was ascertained from biennial questionnaires beginning in 1976. Linear and logistic regression models were used to calculate multivariate-adjusted differences in scores and relative risks of a low score for never users compared to current and past hormone users. RESULTS: After adjustment for confounders, neither current nor long-term hormone users demonstrated better performance on an overall measure of cognition (TICS), or on three tests of verbal memory (immediate and delayed recall of the EBMT, immediate recall of the TICS 10-word list) than never users. On the test of verbal fluency, current hormone users scored significantly better than never users (linear regression estimate of the difference in score = 0.78 points, 95% confidence interval (CI) 0.19-0.38, P = .01 for any current use; and 0.91 points, 95% CI 0.28-1.54, P = .005 for > or = 5 years current use). Current hormone users also had a 30% decrease (RR = 0.70, 95% CI 0.45-1.09) in their risk of a low score on the test of verbal fluency. These results were similar for women taking estrogen alone and estrogen combined with a progestin. CONCLUSIONS: Verbal fluency may be enhanced among women taking postmenopausal hormones, however, there is little support for better overall cognitive function in hormone users than nonusers.

On the neural correlates of visual perception.

Neurological findings suggest that the human striate cortex (V1) is an indispensable component of a neural substratum subserving static achromatic form perception in its own right and not simply as a central distributor of retinally derived information to extrastriate visual areas. This view is further supported by physiological evidence in primates that the finest-grained conjoined representation of spatial detail and retinotopic localization that underlies phenomenal visual experience for local brightness discriminations is selectively represented at cortical levels by the activity of certain neurons in V1. However, at first glance, support for these ideas would appear to be undermined by incontrovertible neurological evidence (visual hemineglect and the simultanagnosias) and recent psychophysical results on 'crowding' that confirm that activation of neurons in V1 may, at times, be insufficient to generate a percept. Moreover, a recent proposal suggests that neural correlates of visual awareness must project directly to those in executive space, thus automatically excluding V1 from a related perceptual space because V1 lacks such direct projections. Both sets of concerns are, however, resolved within the context of adaptive resonance theories. Recursive loops, linking the dorsal lateral geniculate nucleus (LGN) through successive cortical visual areas to the temporal lobe by means of a series of ascending and descending pathways, provide a neuronal substratum at each level within a modular framework for mutually consistent descriptions of sensory data. At steady state, such networks obviate the necessity that neural correlates of visual experience project directly to those in executive space because a neural phenomenal perceptual space subserving form vision is continuously updated by information from an object recognition space equivalent to that destined to reach executive space. Within this framework, activity in V1 may engender percepts that accompany figure-ground segregations only when dynamic incongruities are resolved both within and between ascending and descending streams. Synchronous neuronal activity on a short timescale within and across cortical areas, proposed and sometimes observed as perceptual correlates, may also serve as a marker that a steady state has been achieved, which, in turn, may be a requirement for the longer time constants that accompany the emergence and stability of perceptual states compared to the faster dynamics of adapting networks and the still faster dynamics of individual action potentials. Finally, the same consensus of neuronal activity across ascending and descending pathways linking multiple cortical areas that in anatomic sequence subserve phenomenal visual experiences and object recognition may underlie the normal unity of conscious experience.

Lewy bodies contain altered alpha-synuclein in brains of many familial Alzheimer's disease patients with mutations in presenilin and amyloid precursor protein genes.

Missense mutations in the alpha-synuclein gene cause familial Parkinson's disease (PD), and alpha-synuclein is a major component of Lewy bodies (LBs) in sporadic PD, dementia with LBs (DLB), and the LB variant of Alzheimer's disease (AD). To determine whether alpha-synuclein is a component of LBs in familial AD (FAD) patients with known mutations in presenilin (n = 65) or amyloid precursor protein (n = 9) genes, studies were conducted with antibodies to alpha-, beta-, and gamma-synuclein. LBs were detected with alpha- but not beta- or gamma-synuclein antibodies in 22% of FAD brains, and alpha-synuclein-positive LBs were most numerous in amygdala where some LBs co-localized with tau-positive neurofibrillary tangles. As 12 (63%) of 19 FAD amygdala samples contained alpha-synuclein-positive LBs, these inclusions may be more common in FAD brains than previously reported. Furthermore, alpha-synuclein antibodies decorated LB filaments by immunoelectron microscopy, and Western blots revealed that the solubility of alpha-synuclein was reduced compared with control brains. The presence of alpha-synuclein-positive LBs was not associated with any specific FAD mutation. These studies suggest that insoluble alpha-synuclein aggregates into filaments that form LBs in many FAD patients, and we speculate that these inclusions may compromise the function and/or viability of affected neurons in the FAD brain.

Amyloid-beta-protein isoforms in brain of subjects with PS1-linked, beta APP-linked and sporadic Alzheimer disease.

To determine whether similar abnormalities of various soluble full-length and N-terminal truncated Abeta peptides occur in postmortem cerebral cortex of affected PS1 mutation carriers, we examined the amounts of two amyloid species ending at residue 40 or at residues 42(43) using sandwich ELISA systems. Our results indicate that PS1 mutations effect a dramatic accumulation in brain of the highly insoluble potentially neurotoxic long-tailed isoforms of the Abeta peptide such as Abeta1-42(43) and Abetax-42(43). This enhancing effect of PS1 mutation on Abetax-42(43) deposition was highly similar to that of a betaAPP mutation (Val717Ile) but the effects on Abetax-40 production were significantly different between these two causal genes. In contrast to previous studies of soluble Abeta in plasma and in supernatants from cultured fibroblasts of subjects with PS1 mutations, our studies also show that there is an increase in insoluble Abetax-40 peptides in brain of subjects with PS1 mutations.

Familial and sporadic Alzheimer's disease: neuropathology cannot exclude a final common pathway.

Whether all etiologic forms of Alzheimer's disease (AD) share a final common pathway is a major issue. We determined the severity and regional distribution of neuronal loss, amyloid plaques, neuritic plaques (NPs), and neurofibrillary tangles (NFTs), and calculated the ratio of neuronal loss to NPs and NFTs in brains of 19 familial AD (FAD) patients with linkage to chromosome 14, six AD patients with mutations of chromosome 21 (codon 717 of the beta-amyloid percursor protein gene), and 11 sporadic AD (SAD) patients. There was no difference in the pattern of distribution of the various pathologic features or in the ratio of neuronal loss to NPs or NFTs in any AD group. However, FAD groups could be distinguished from SAD by the greater severity and the lack of influence of apolipoprotein E genotype on pathology. These differences may reflect differences in age at onset rather than different etiopathologic mechanisms. The similarity of pathologic findings in the different AD groups provides evidence for a final common pathophysiologic pathway in AD.

Altered expression of transforming growth factor-beta in Alzheimer's disease.

We compared immunohistochemical expression of the transforming growth factor-betas (TGF-beta 1, TGF-beta 2, and TGF-beta 3) using brain tissue from patients with nondominantly inherited Alzheimer's disease (NDAD) (n = 9), autosomal dominantly inherited Alzheimer's disease with linkage to 14q24.3 (FAD-14) (n = 4), and cognitively normal controls (n = 10) to determine whether their pathologic changes are associated with an altered distribution of the TGF-betas. We found increased expression of TGF-beta 2 in large, tangle-bearing neurons with widespread staining of glia in NDAD and FAD-14 patients compared with control cases. This result was confirmed with sandwich ELISA assays of brain tissue, which showed TGF-beta 2 levels in AD and NDAD to average 3.2 times the average level of control cases. Despite proximity of TGF-beta 1 and TGF-beta 3 to the sites of susceptibility loci on chromosomes 19 and 14, we did not find that TGF-beta 1 and TGF-beta 3 were selectively altered in any AD subtypes. However, selective induction of TGF-beta 2 may occur in NDAD and FAD-14.

Familial Alzheimer's disease and cortical Lewy bodies: is there a genetic susceptibility factor?

The reason for the occurrence of Lewy body disease (LBD) in Alzheimer's disease (AD) patients is unknown. If brains from etiologically different AD groups differ in their tendency to develop cortical Lewy bodies, the concurrence of LBD in AD patients may be a manifestation of the AD process in specific AD subsets. To address this issue, we counted cortical Lewy bodies in AD patients with genetic abnormalities on chromosome 14 (n = 19), and chromosome 21 (n = 3), sporadic AD (n = 27), Down's syndrome (n = 1) and control (n = 26) patients. Cortical Lewy bodies were occasionally present in AD patients with long-duration disease in most of the above AD subgroups, but were not present in any of our age-matched control cases. We suggest that cortical Lewy body formation may be an intrinsic part of the late pathologic changes of AD regardless of etiology and that it is not specific to any of the AD subtypes studied.

Space-time spectra of complex cell filters in the macaque monkey: a comparison of results obtained with pseudowhite noise and grating stimuli.

White noise stimuli were used to estimate second-order kernels for complex cells in cortical area V1 of the macaque monkey, and drifting grating stimuli were presented to the sample of neurons to obtain orientation and spatial-frequency tuning curves. Using these data, we quantified how well second-order kernels predict the normalized tuning of the average response of complex cells to drifting gratings. The estimated second-order kernel of each complex cell was transformed into an interaction function defined over all spatial and temporal lags without regard to absolute position or delay. The Fourier transform of each interaction function was then computed to obtain an interaction spectrum. For a cell that is well modeled by a second-order system, the cell's interaction spectrum is proportional to the tuning of its average spike rate to drifting gratings. This result was used to obtain spatial-frequency and orientation tuning predictions for each cell based on its second-order kernel. From the spatial-frequency and orientation tuning curves, we computed peaks and bandwidths, and an index for directional selectivity. We found that the predictions derived from second-order kernels provide an accurate description of the change in the average spike rate of complex cells to single drifting sine-wave gratings. These findings are consistent with a model for complex cells that has a quadratic spectral energy operator at its core but are inconsistent with a spectral amplitude model.

Cross-correlation analyses of nonlinear systems with spatiotemporal inputs.

Methods are presented for analyzing the low-order stimulus-response cross-correlation functions (or kernels) of visual neurons studied with spatiotemporal white noise. In particular, formulas are derived that relate the low-order kernels of a cell to its responses to single-drifting, double-drifting, and counterphase gratings. The harmonic response terms contributed by the low-order kernels include a mean response term, first- and second-harmonic terms, and sum- and difference-harmonic terms. Using the formulas in this paper, one can obtain kernel-based predictions for the spatiotemporal-frequency tuning of each harmonic. These kernel-based predictions can then be compared with harmonic tuning data obtained in experiments with real grating stimuli. The methods are illustrated using data recorded from one simple and one complex cell from the primary visual cortex of the monkey. The approach of transforming low-order kernels into predicted harmonic tuning functions provides a useful data reduction technique as well as providing insight into the interpretation of kernels.

Structural testing of multi-input linear-nonlinear cascade models for cells in macaque striate cortex.

Structural testing methods based on experimental white noise stimulus-response data were used to evaluate multi-input linear-nonlinear (LN) cascade models for simple and complex cells in macaque striate cortex. An LN structural test index, based on white noise stimulation, was developed and found to be suitable for classifying cells as simple vs complex. In particular, classification results based on the LN structural test index were similar to classification results based on a traditional modulation index derived from cell responses to drifting sinewave gratings. Judging from their structural test indices, complex cells deviated more strongly from LN behavior than did simple cells. Yet, even with simple cells, on average, only about 60% of the first- and second-order white noise stimulus-response relation was consistent with LN behavior. Just two of thirteen simple cells studied had an LN consistency level that exceeded 80%. Similar results were found in tests for consistency with an LNL model which includes an additional linear post-filter. We conclude that a conventional multi-input LN network model may be a useful approximation to the response behavior of some simple cells. However, even during steady state stimulus conditions, subcortical and/or cortical nonlinearities other than a static output nonlinearity play a very significant role in shaping the responses of most simple cells in the macaque striate cortex.

Interneuronal interaction between members of quadrature phase and anti-phase pairs in the cat's visual cortex.

Interactions between adjacent simple cells recorded simultaneously from the same microelectrode placement were studied by correlational analysis. The receptive fields of pairs of such cells exhibit either 90 degrees (quadrature phase) or 180 degrees (anti-phase) phase relationships. We now show that the majority of quadrature phase pair members do not receive common input from the immediately precedent stage along the visual pathway, nor do these cells interact with each other. The anti-phase pairs show relatively strong mutual inhibition. These results suggest that each of the physically adjacent phase-related simple cells receives excitatory input from a distinct group of pre-cortical cells, and that mutual inhibitions between members of anti-phase pairs are used to construct the inhibitory subzones of these cells. We propose a model which incorporates these new results and provides a parsimonious explanation for the construction of both quadrature phase and anti-phase pairs.

Spatial and temporal frequency selectivity of neurons in visual cortical area V3A of the macaque monkey.

Response properties of neurons in V3A were studied at a retinal eccentricity of 2-4 deg. The distributions of spatial frequency bandwidths and orientation bandwidths were similar to those of neurons in V1. Peaks of spatial frequency tuning curves ranged from 0.35 to 8.0 c/deg with a mean of 1.75 c/deg. Most V3A cells showed lowpass or, less often, broad bandpass temporal frequency selectivity. The mean direction selectivity index was 0.41. The response properties of cells in V3A differed most from those in V1 with respect to the larger receptive field widths in V3A averaging about 4 deg, the consequent larger number of cycles of the preferred grating that fall within the receptive field, and the previously reported profound response suppression incurred when patches of the preferred grating are extended both within and beyond the classical receptive field. The response properties of cells in V3A differed most from those in V3 in that V3A neurons are much less selective to the speed and direction of stimulus motion than are neurons in V3. The overall response properties of cells in V3A are consistent with anatomical evidence that places this cortical area in the visual pathway from V3A to V4 and then to IT.

Responses of simple and complex cells to compound sine-wave gratings.

We have studied the responses of simple and complex cells in the primary visual cortex of the cat to rigidly drifting compound sine-wave gratings as a function of the phase offset between fundamental and harmonic frequencies that both fell within the passband of the cell. Simple cells show phase-dependent increases and decreases in peak and mean response which are predictable on the basis of a cell's line weighting function. However, the amplitudes and phases of the base and harmonic frequencies in the response are, in general, not well predicted by the relationships of these same components in the compound grating stimuli. These distortions are shown to be largely a consequence of the rectification that follows linear summation at the simple cell stage. Such distortions are, in principle, correctable when the responses of a second simple cell, as part of a 180 deg phase pair, are taken into account. Complex cells typically showed a strong nonlinear response component at the difference frequency of drifting compound gratings. This was sometimes accompanied by a linear response component at one, or both, of the separate stimulus frequencies. Information about the absolute phases of the frequency components of a compound grating is not preserved in the nonlinear response of complex cells; however, information about the local phase difference between the gratings is preserved. In effect, the nonlinear component of the complex cell response is proportional to the time-varying signal envelope that results from the mutual interference of stimulus frequencies that fall in the cell's spatial receptive field and frequency passband.

Diversity of complex cell responses to even- and odd-symmetric luminance profiles in the visual cortex of the cat.

We have tested the hypothesis that complex cell receptive fields are made up of subfields which, for a given cell, have either exclusively even or exclusively odd symmetry. To do this we have measured the response of complex cells in the visual cortex of the cat to members of pairs of spatially limited even-symmetric stimuli (single light and dark bars) and pairs of odd-symmetric stimuli ("light-dark" and "dark-light" double bars) successively drifting across their receptive fields. The strength of a cell's response was estimated by measuring the sum of all spikes produced by a stimulus. Some complex cells respond about equally to single light and dark bars; others respond appreciably more to either the light or dark bar. The central tendency of average response histograms was estimated by measuring the mean with respect to position across the width of the receptive field. Many complex cells show distinct spatial offsets between the mean for narrow single light and that for dark bars as well as between means to double bars of opposite phase. Combined offset plots were constructed with the spatial offsets between means for single light bars and single dark bars along the x axis and the offsets between means to double bars of opposite phase along the y axis. There is significant scatter in the combined offset points; some falling at the origin, some at significant distances from the origin along the axes, and others well within each of the four quadrants. These diverse localizations in the offset plots rule out the simple models of complex cell spatial substructure described above and, therefore, imply considerable heterogeneity within the population of complex cells.

Response suppression by extending sine-wave gratings within the receptive fields of neurons in visual cortical area V3A of the macaque monkey.

Even though there are many more cycles of the "optimal" grating extending across the receptive fields of cells in V3A than of cells in V1 and V2, the spatial frequency bandwidths in V3A are no narrower than in V1 or V2. Thus, the inputs to V3A cells are not combined in a phase coherent manner across the entire receptive field. Moreover, the defined receptive fields of cells in V3A are generally surrounded by suppressive regions which are, on average, much stronger than those found for neurons in V1 and V2. Even within the classical receptive field, most neurons in V3A respond far more vigorously to a limited patch of a few cycles of a grating at the preferred spatial frequency than to wider grating stimuli. This intra-receptive field suppression demonstrates a new level of response complexity, and suggests that V3A cells may antagonistically combine nonlinear mechanisms that themselves encode stimulus energy over a restricted region of space and spatial-frequency.