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It is established that chronic spirochetal infection can cause slowly progressive dementia, brain atrophy and amyloid deposition in late neurosyphilis. Recently it has been suggested that various types of spirochetes, in an analogous way to Treponema pallidum, could cause dementia and may be involved in the pathogenesis of Alzheimer's disease (AD). Here, we review all data available in the literature on the detection of spirochetes in AD and critically analyze the association and causal relationship between spirochetes and AD following established criteria of Koch and Hill. The results show a statistically significant association between spirochetes and AD (P = 1.5 × 10-17, OR = 20, 95% CI = 8-60, N = 247). When neutral techniques recognizing all types of spirochetes were used, or the highly prevalent periodontal pathogen Treponemas were analyzed, spirochetes were observed in the brain in more than 90% of AD cases. Borrelia burgdorferi was detected in the brain in 25.3% of AD cases analyzed and was 13 times more frequent in AD compared to controls. Periodontal pathogen Treponemas (T. pectinovorum, T. amylovorum, T. lecithinolyticum, T. maltophilum, T. medium, T. socranskii) and Borrelia burgdorferi were detected using species specific PCR and antibodies. Importantly, co-infection with several spirochetes occurs in AD. The pathological and biological hallmarks of AD were reproduced in vitro by exposure of mammalian cells to spirochetes. The analysis of reviewed data following Koch's and Hill's postulates shows a probable causal relationship between neurospirochetosis and AD. Persisting inflammation and amyloid deposition initiated and sustained by chronic spirochetal infection form together with the various hypotheses suggested to play a role in the pathogenesis of AD a comprehensive entity. As suggested by Hill, once the probability of a causal relationship is established prompt action is needed. Support and attention should be given to this field of AD research. Spirochetal infection occurs years or decades before the manifestation of dementia. As adequate antibiotic and anti-inflammatory therapies are available, as in syphilis, one might prevent and eradicate dementia.

Human area 17 is known to contain a single (the primary) visual area, whereas areas 18 and 19 are believed to contain multiple visual areas (defined as individual representations of the contralateral visual hemifield). This is known to be the case in monkeys, where several boundaries between visual areas are characterized by bands of callosal afferents and/or by changes in myeloarchitecture. We here describe the pattern of callosal afferents in (human) areas 17, 18, and 19 as well as their cortical architecture and we infer the position of some visual areas. Sections from occipital lobes of 6 human brains with unilateral occipital infarctions have been silver-impregnated for degenerating axons, thereby revealing callosal afferents to the intact occipital cortex. Their tangential distribution is discontinuous, even in cases with large lesions. A band of callosal afferents straddles the area 17/18 boundary, whereas the remainder of area 17 and a 15-45 mm wide stripe of area 18 adjacent to the callosal band along the 17/18 border are free of them. Patches of callosal afferents alternate with callosal-free regions more laterally in area 18 and in area 19. We conclude that, in man, a second visual area (analogue of V2) lies in area 18, horseshoe-shaped around area 17, and includes the inner part of the acallosal stripe adjacent to the callosal band along the 17/18 boundary. The outer part of this acallosal stripe belongs to a third visual area, which may contain dorsally the analogue of V3 and ventrally that of VP. Thus the lower parts of the second and third visual areas lie on the lingual gyrus, whereas the analogue of the macaque's fourth visual area probably lies on the fusiform gyrus. Although the proposed subdivision of the occipital cortex relies largely on the pattern of callosal afferents, some putative human visual areas appear to have distinct architectonic features. The analogue of V2 is rather heavily myelinated and its layer III contains large pyramidal neurons. Its upper part is not well delimited laterally since adjacent "V" has similar architecture. Its lower part, however, differs clearly from the adjacent "VP," which is lightly myelinated and lacks the large pyramids in layer III. The cortex lateral to "VP" is heavily myelinated and contains fairly large pyramids in layers III and V. The myeloarchitecture of the lateral part of the occipital cortex is not uniform; a very heavily myelinated region stands out in the lateral part of area 19, near the occipito-temporal junction.(ABSTRACT TRUNCATED AT 400 WORDS)

To date, there is no reasonable explanation as to why plaques and tangles simultaneously accumulate in Alzheimer's disease (AD). We demonstrate here by Western blotting and ELISA that a stable complex can form between tau and amyloid-␤ protein (A␤). This complex enhances tau phosphorylation by GSK3␤, but the phosphorylation then promotes dissociation of the complex. We have localized the sites of this interaction by using peptide membrane arrays. A␤ binds to multiple tau peptides, especially those in exons 7 and 9. This binding is sharply reduced or abolished by phosphorylation of specific serine and threonine residues. Conversely, tau binds to multiple A␤ peptides in the mid to C-terminal regions of A␤. This binding is also significantly decreased by GSK3␤ phosphorylation of tau. We used surface plasmon resonance to determine the binding affinity of A␤ for tau and found it to be in the low nanomolar range and almost 1,000-fold higher than tau for itself. In soluble extracts from AD and control brain tissue, we detected A␤ bound to tau in ELISAs. We also found by double immunostaining of AD brain tissue that phosphorylated tau and A␤ form separate insoluble complexes within the same neurons and their processes. We hypothesize that in AD, an initial step in the pathogenesis may be the intracellular binding of soluble A␤ to soluble nonphosphorylated tau, thus promoting tau phosphorylation and A␤ nucleation. Blocking the sites where A␤ initially binds to tau might arrest the simultaneous formation of plaques and tangles in AD.immunochemistry ͉ neurofibrillary tangles ͉ senile plaques ͉ surface plasmon resonance S o far, no reasonable interpretation has been advanced to explain the simultaneous appearance of senile plaques and neurofibrillary tangles (NFTs) in Alzheimer's disease (AD). Senile plaques develop extracellularly with the main component being aggregated amyloid-␤ protein (A␤), whereas NFTs develop intracellularly with the main component being aggregated forms of phosphorylated tau. The two aggregation processes appear to occur independently, because NFTs develop in neuronal cell bodies and senile plaques develop around their nerve endings. This observation has led to two schools of thought regarding AD causation. The tau hypothesis holds that the disease is driven by tangles resulting from an excess of tau phosphorylation or a deficiency of its dephosphorylation (1). The hypothesis does not explain plaques. The amyloid hypothesis holds that the disease is driven by excess production of A␤ (2, 3). This hypothesis does not explain NFTs. Nevertheless, the amyloid cascade hypothesis is dominant because mutations in amyloid precursor protein (APP), which enhance A␤ production, cause autosomal dominant AD but not other types of dementia (2). On the other hand, mutations in tau that promote tau aggregation produce autosomal dominant frontotemporal dementia but not AD (4, 5). As a result, the presumption is that excess A␤ is a major cause and an upstream event of AD tangle formation, but exactly how an A␤ excess ...