Inhomogeneous distribution of Alzheimer pathology along the isocortical relief. Are cortical convolutions an Achilles heel of evolution?

Alzheimer's disease (AD) is neuropathologically characterized by neuritic plaques and neurofibrillary tangles. Progression of both plaques and tangles throughout the brain follows a hierarchical distribution which is defined by intrinsic cytoarchitectonic features and extrinsic connectivity patterns. What has less well been studied is how cortical convolutions influence the distribution of AD pathology. Here, the distribution of both plaques and tangles within subsulcal gyral components (fundi) to components forming their top regions at the subarachnoidal brain surface (crowns) by stereological methods in seven different cortical areas was systematically compared. Further, principle differences in cytoarchitectonic organization of cortical crowns and fundi that might provide the background for regionally selective vulnerability were attempted to identify. It was shown that both plaques and tangles were more prominent in sulcal fundi than gyri crowns. The differential distribution of pathology along convolutions corresponds to subgyral differences in the vascular network, GFAP-positive astrocytes and intracortical and subcortical connectivity. While the precise mechanisms accounting for these differences remain open, the presence of systematic inhomogeneities in the distribution of AD pathology along cortical convolutions indicates that the phylogenetic shaping of the cortex is associated with features that render the human brain vulnerable to AD pathology.

Wavelet analysis of skin blood flow in dermatosurgery using primary closure with tension.

Primary closure in dermatologic surgery is state of the art in small lesions at the head, but also in larger lesions at the trunk or the extremities. Microcirculatory effects on the skin blood flow near to the wound edges affected by primary closure. Forty three patients were investigated. Before and after surgery, skin blood flow was measured using Laser Doppler Fluxmetry (LDF). During primary closure, tension in the suture was measured and the tension on the wound edges was calculated. Times series were analyzed using continuous wavelet analyses, before, after 2 h and 24 h after surgery. After three months, the cosmetic results were requested. Median horizontal diameter was 22 mm (quartiles 20/48 mm), median vertical diameter was 44 mm (quartiles 26/60 mm). Mean string force was 12.0 SD 10.2 N. During the whole course of investigation, we found no change of microcirculatory parameters such as mean LDF or any scaling level following wavelet analysis caused by primary closure. Average of the cosmetic result was 1.8. It is a relative small number of patients and the defects are located in different areas. Skin blood flow and the microcirculatory pattern is not affected in the area by the tension on wound edges and provides therefore a fast healing process without any vegetatively induced complications even if the string force is high. In dermatosurgery, wounds can be closed directly without changing the microcirculatory pattern in the direct area of the wound margins.

Wavelet analysis of Laser Doppler Flux time series of tumor and inflammatory associated neoangiogenesis. Differences in rhythmical behavior.

We use continuous wavelet analysis (WA) of Laser Doppler Flux (LDF) time series measured in basal cell carcinomas (BCC) and plaque psoriasis (PP) in order to investigate the rhythmical behavior of blood flow in tumor or inflammatory associated neoangiogenesis.A total of 68 patients with primary BCCs and 40 patients with PP were included in the study. LDF time series were separated in four scaling levels corresponding to the influences of sympathetic activity (SL1), myogenic activity in the vessel wall (SL2), respiration (SL3) and heart beat (SL4).In BCC, SL1 decreased compared to healthy skin. In all other scaling levels, we found a statistically significant increase of the SLs compared to healthy skin. These increases were not found in PP.Rhythmical behavior of blood flow in malignant tumors is totally different from that in regions with inflammation. In BCCs, thermoregulatory processes, ascribed to sympathetic activity, decrease statistically significant. In contrast, inflammatory processes in PP do not substantially change sympathetic activity. WA of tumor perfusion could open a new noninvasive monitor system for controlling tumor therapy.

Wavelet analysis of skin perfusion in healthy volunteers.

OBJECTIVE: Rhythmical changes in microvascular perfusion of the skin depend on various influences, which appear continuously but not in a predictable manner. For identifying and quantifying different physiological influences the authors used wavelet transformation, analyzing continuously and simultaneously measured data. METHODS: A total of 34 healthy volunteers were included in the study. At the dorsum of the left hand, skin perfusion was measured by laser Doppler fluxmetry (LDF) and skin temperature was measured. Simultaneously, the electrocardiogram and the respiration were recorded. The recorded time series were analyzed with wavelet transformation and scale correlation (S-correlation). RESULTS: Semilinear analysis with wavelet transformation allowed a visualization of temporal changes in LDF frequency and amplitude in a color-coded quasi three-dimensional diagram. The authors found that tissue perfusion over an observation period of 327.68 s is governed by 6 closely connected, overlying waves with different degrees of freedom. The major determinants are low frequencies in LDF, which correlates with changes in skin temperature, responsible for 68.5% of the influence. Surprisingly, though indispensable for blood flow, respiration and heartbeat contributed to less then 2.5% of the rhythmic changes. CONCLUSIONS: When wavelet transformation is used in analyzing LDF time series, the different rhythms of cutaneous blood flow are made visible and quantifiable and can be assigned to different physiological origins. The application of this novel analysis method allows identifying mechanisms regulating skin perfusion, which will greatly facilitate the diagnosis of a variety of important vascular diseases, such as chronic venous insufficiency, diabetes, or neurotrophic disorders.

Granular elasticity: general considerations and the stress dip in sand piles.

Granular materials are predominantly plastic, incrementally nonlinear, preparation-dependent, and anisotropic under shear. Nevertheless, their static stress distribution is well accounted for, in the whole range up to the point of failure, by a judiciously tailored isotropic nonanalytic elasticity theory termed granular elasticity. The first purpose of this paper is to carefully expound this view. Then granular elasticity is employed to consider the stress distribution in two-dimensional sand piles (or sand wedges). Starting from a uniform density, the pressure at the bottom of the pile is found to show a single central peak. It turns into a pressure dip, if some density inhomogeneity, with the center being less compact, is assumed. These two pressure distributions are remarkably similar to recent measurements, made in piles obtained, respectively, by rainlike pouring and funneling. In an accompanying paper, the stress distributions in silos and under point loads, calculated using the same method, are also found to agree with experiments.

Granular elasticity: stress distributions in silos and under point loads.

An elastic-strain-stress relation, the result of granular elasticity as introduced in the preceding paper, is employed here to calculate the stress distribution (a) in cylindrical silos and (b) under point loads assuming uniform density. In silos, the ratio k{J} between the horizontal and vertical stress is found to be constant (as conjectured by Janssen) and given as k{J}=1-sin phi (with phi the Coulomb yield angle), in agreement with a construction industry standard usually referred to as the Jaky formula. Next, the stress distribution at the bottom of a granular layer exposed to a point force at its top is calculated. The results include both vertical and oblique point forces, which agree well with simulations and experiments using rainlike preparation. Moreover, the stress distribution of a sheared granular layer exposed to the same point force is calculated and again found in agreement with given data.

Wavelet analysis of cutaneous blood flow in melanocytic skin lesions.

Laser Doppler flowmetry (LDF) is frequently used to study the microcirculation. Usually LDF time series are analyzed by conventional linear methods, mainly Fourier analysis. The aim of this study was to observe dynamic blood perfusion of the skin in malignant and benign melanocytic skin lesions. Wavelet transformation was performed on each LDF time series in order to calculate a vasomotion field. First, the differences in vasomotion between healthy and pigmented skin were evaluated visually on six different time scales of the vasomotion field. In order to quantify the findings, vasomotion scale variance (VSV) was calculated for each scale plane of the vasomotion field. These VSV were compared using contrast DeltaVSV to determine the difference between healthy skin and a pigmented skin lesion in the same patient. After the measurements, the skin lesions were excised and examined histologically. We found that wavelet analysis of LDF time series is a specific, sensitive method for the in vivo identification of malignant melanoma. It is a non-invasive procedure and takes minimal time to be carried out.

Constitutive expression of p21H-ras(Val12) in pyramidal neurons results in reorganization of mouse neocortical afferents.

The effect of constitutive expression of p21H-ras(Val12) in pyramidal neurons upon the establishment of afferent input has been investigated in the primary somatosensory cortex of transgenic mice. In these animals, relevant transgene expression is confined to cortical pyramidal neurons and starts postnatally at a period when neuronal morphogenesis has been largely completed. We have shown recently that overexpression of p21H-ras(Val12) in these cells results in considerable enlargement of their size and consequently in expansion of the cortex. In the present study we demonstrate that the density of terminals representing intra- or interhemispheric afferents within cortical layers II/III, however, is only slightly decreased. The density of thalamocortical boutons within layer IV is even higher and the number of afferent contacts to transgenic pyramidal neurons is significantly increased compared to the wild-type. The number of catecholaminergic and cholinergic terminals is augmented proportionally to cortical size or even overproportionally, respectively. Along intercortical and striatal fibers arising from p21H-ras(Val12)-expressing pyramidal neurons, frequency of varicosities is significantly increased, but remains unchanged on cortical cholinergic and catecholaminergic axons originating from "nontransgenic" neurons. Additionally, a higher number of multiple synaptic bodies are found in transgenic mice, suggesting subtle effects on synaptic plasticity. It is concluded that the enlargement of pyramidal neurons due to transgenic expression of p21H-ras(Val12) is paralleled by significant changes in the quantity and pattern of afferent connections. Moreover, expression of p21H-ras(Val12) in pyramidal cells induces an enhanced establishment of efferent boutons.

Complementary distribution of vesicular glutamate transporters 1 and 2 in the nucleus accumbens of rat: Relationship to calretinin-containing extrinsic innervation and calbindin-immunoreactive neurons.

The caudomedial shell of the rat nucleus accumbens exhibits inhomogeneous distribution patterns of the vesicular glutamate transporters 1 (VGLUT1) and 2 (VGLUT2). This paper focuses on the question of whether patterns of VGLUT1 and VGLUT2 correspond to cytoarchitectonically and cytochemically defined subterritories of the caudomedial shell region. VGLUT2 was shown to be coexpressed with calretinin in the dense axonal plexus known to emanate from the paraventricular thalamic nucleus. In regions termed corridors, which are spared by this paraventricular thalamic innervation, axonal terminals were found to be clustered and VGLUT1-immunoreactive. It is assumed that these fibers originate in the prelimbic cortex and/or in the parvicellular basal amygdaloid nucleus known to project to accumbal shell components. Our findings confirm the existence of two well-separated neuronal circuits in the caudomedial shell that are dominated by two different excitatory input systems originating from either thalamic, cortical, or cortex-like amygdaloid sources. The large lateral corridors-which resemble the accumbal core not only in respect to their VGLUT1 immunolabeling but also concerning their content of calbindin-positive cells-may represent a component of the anatomically weakly defined accumbal shore region.

Rabbit forebrain cholinergic system: morphological characterization of nuclei and distribution of cholinergic terminals in the cerebral cortex and hippocampus.

Although the rabbit brain, in particular the basal forebrain cholinergic system, has become a common model for neuropathological changes associated with Alzheimer's disease, detailed neuroanatomical studies on the morphological organization of basal forebrain cholinergic nuclei and on their output pathways are still awaited. Therefore, we performed quantitative choline acetyltransferase (ChAT) immunocytochemistry to localize major cholinergic nuclei and to determine the number of respective cholinergic neurons in the rabbit forebrain. The density of ChAT-immunoreactive terminals in layer V of distinct neocortical territories and in hippocampal subfields was also measured. Another cholinergic marker, the low-affinity neurotrophin receptor (p75(NTR)), was also employed to identify subsets of cholinergic neurons. Double-immunofluorescence labeling of ChAT and p75(NTR), calbindin D-28k (CB), parvalbumin, calretinin, neuronal nitric oxide synthase (nNOS), tyrosine hydroxylase, or substance P was used to elucidate the neuroanatomical borders of cholinergic nuclei and to analyze the neurochemical complexity of cholinergic cell populations. Cholinergic projection neurons with heterogeneous densities were found in the medial septum, vertical and horizontal diagonal bands of Broca, ventral pallidum, and magnocellular nucleus basalis (MBN)/substantia innominata (SI) complex; cholinergic interneurons were observed in the caudate nucleus, putamen, accumbens nucleus, and olfactory tubercule, whereas the globus pallidus was devoid of cholinergic nerve cells. Cholinergic interneurons were frequently present in the hippocampus and to a lesser extent in cerebral cortex. Cholinergic projection neurons, except those localized in SI, abundantly expressed p75(NTR), and a subset of cholinergic neurons in posterior MBN was immunoreactive for CB and nNOS. A strict laminar distribution pattern of cholinergic terminals was recorded both in the cerebral cortex and in CA1-CA3 and dentate gyrus of the hippocampus. In summary, the structural organization and chemoarchitecture of rabbit basal forebrain may be considered as a transition between that of rodents and that of primates.

Perineuronal nets of extracellular matrix around hippocampal interneurons resist destruction by activated microglia in trimethyltin-treated rats.

The destruction of the extracellular matrix by inflammatory processes may induce neuronal dysfunction and accelerate neurodegeneration. We describe that chondroitin sulphate proteoglycan-immunoreactive perineuronal nets and the enwrapped interneurons persisted 2 weeks after trimethyltin intoxication of rats (TMT, 8 mg/kg, i.p.) in all regions of the severely affected hippocampus and dentate gyrus, whereas the diffuse immunoreactivity around the CA2 pyramidal cells was reduced. Fluoro-Jade staining of degenerating neurons and staining of microglia by Griffonia simplicifolia agglutinin showed that net-associated neurons survived in the vicinity of damaged pyramidal cells and that perineuronal nets were not removed by activated microglia. We conclude that the extracellular matrix of perineuronal nets resists destruction after TMT treatment in the inflamed neural tissue. A permanent reconstitution of matrix components may be one of the factors that may support the viability of distinct types of neurons during neurodegenerative diseases.

Immunocytochemical evidence for the striatal nature of the rat lateral part of interstitial nucleus of the posterior limb of the anterior commissure (IPAC).

The present study focuses on the basal forebrain region originally designated as fundus striati, but currently known as 'interstitial nucleus of the posterior limb of the anterior commissure' (IPAC). Using multiple immunofluorescence of the calcium-binding proteins parvalbumin and calbindin, the GABA(A) receptor alpha1-subunit, vasoactive intestinal polypeptide (VIP), met(5)-enkephalin (MENK) and glutamic acid decarboxylase (GAD), it was shown that VIP-immunostained axons, which are typical for major parts of the extended amygdala, densely innervate only the medial part of IPAC, while they are absent in the lateral part. On the other hand, large-sized GABAergic, parvalbumin- and GABA(A) receptor alpha1-subunit-immunoreactive neurons, which are densely covered by separate GAD- and MENK-immuno reactive terminals and a type of medium-sized alpha1-subunit-monolabelled cells, occur in the dorsal striatum and in the adjacent lateral part of IPAC as well. Large-sized neurons double labelled for parvalbumin and the GABA(A) receptor alpha1-subunit are also widely distributed in the neighbouring ventral pallidum. Neurons of this type are absent, however, in the medial part of IPAC and other extended amygdala subunits. Our findings confirm the recent suggestion of a morphofunctional dichotomy of IPAC (Comp. Neurol. 439 (2001) 104), as only the medial part reveals characteristics as typical for extended amygdala, while its lateral part exhibits cytochemical peculiarities of striatal tissue. Therefore, the term 'lateral part of IPAC' should be replaced by the term 'putaminal fundus (fundus putaminis)' according to recently published designations of corresponding striatal constituents (Atlas of the Human Brain, 2002, Academic Press, San Diego, CA; J. Chem. Neuroanat. 23 (2002) 75).

Functional recovery of cholinergic basal forebrain neurons under disease conditions: old problems, new solutions?

Recognition of the involvement of cholinergic neurons in the modulation of cognitive functions and their severe dysfunction in neurodegenerative disorders, such as Alzheimer's disease, initiated immense research efforts aimed at unveiling the anatomical organization and cellular characteristics of the basal forebrain (BFB) cholinergic system. Concomitant with our unfolding knowledge about the structural and functional complexity of the BFB cholinergic projection system, multiple pharmacological strategies were introduced to rescue cholinergic nerve cells from noxious attacks; however, a therapeutic breakthrough is still awaited. In this review, we collected recent findings that significantly contributed to our better understanding of cholinergic functions under disease conditions, and to the design of effective means to restore lost or damaged cholinergic functions. To this end, we first provide a brief survey of the neuroanatomical organization of BFB nuclei with emphasis on major evolutionary differences among mammalian species, in particular rodents and primates, and discuss limitations of the translation of experimental data to human therapeutic applications. Subsequently, we summarize the involvement of cholinergic dysfunction in the pathogenesis of severe neurological conditions, including stroke, traumatic brain injury, virus encephalitis and Alzheimer's disease, and emphasize the critical role of pro-inflammatory cytokines as common mediators of cholinergic neuronal damage. Moreover, we review leading functional concepts on the limited recovery of cholinergic neurons and their impaired plastic re-modeling, as well as on the hampered interplay of the ascending cholinergic and monoaminergic projection systems under neurodegenerative conditions. In addition, recent advances in the dynamic labeling of living cholinergic neurons by fluorochromated antibodies, referred to as in vivo labeling, and novel neuroimaging approaches as potential diagnostic tools of progressive cholinergic decline are surveyed. Finally, the potential of cell replacement strategies using embryonic and adult stem cells, and multipotent neural progenitors, as a means to recover damaged cholinergic functions, is discussed.

In vivo labeling of rabbit cholinergic basal forebrain neurons with fluorochromated antibodies.

Cholinergic basal forebrain neurons (CBFN) expressing the low-affinity neurotrophin receptor p75 (p75(NTR)) were previously selectively labeled in vivo with carbocyanine 3 (Cy3)-tagged anti-p75(NTR), but the applied 192IgG-conjugates recognized p75(NTR) only in rat. The antibody ME 20.4 raised against human p75(NTR) had been shown to cross-react with the receptor in monkey, raccoon, sheep, cat, dog, pig and rabbit. Hence, for in vivo labeling of rabbit CBFN in the present study, ME 20.4 was fluorochromated with Cy3-N-hydroxysuccinimide ester and purified Cy3-ME 20.4 was injected intracerebroventricularly. Two days post-injection, clusters of Cy3-ME 20.4 were found in CBFN displaying choline acetyltrans-ferase-immunoreactivity. Following photoconversion, electron microscopy revealed fluorochromated antibodies in secondary lysosomes. In conclusion, Cy3-ME 20.4 might become an appropriate marker for CBFN in live and fixed tissues of various mammalian species.