The deposition of insoluble -amyloid protein fibrils is probably the central event in the pathogenesis of Alzheimer's disease. Cerebrospinal fluid inhibits this fibril formation, likely by the intervention of one or several proteins binding to soluble -amyloid protein. In vitro, transthyretin (TTR), a CSF protein, impedes amyloid fibrillogenesis. Lowered concentrations of CSFTTR could therefore be associated with Alzheimer's disease. Concentrations of TTR in CSF samples from 149 consecutive patients were assayed, using a kinetic nephelemetric method. These concentrations were correlated positively with age, but were significantly lower in patients with Alzheimer's disease. These data raise the possibility that amyloid fibril formation could be promoted in patients with late onset Alzheimer's disease by the lack of suYcient concentrations of TTR.

No abstract

Anomalies of the cerebrospinal fluid flow rate and composition that have been reported in patients suffering from Alzheimer's disease (AD) could be related to alterations of the choroid plexuses (CD). Here we report a photonic and electron morphometric study in which we compared the height of CP epithelial cells and the thickness of their basement membrane on post-mortem samples from AD patients, age-matched controls and two newborns. Ageing appeared associated with epithelial atrophy and basement membrane thickening, but these features were significantly accentuated in AD. These data suggest that a dramatic alteration of the secretion and filtration could be involved in the multiparametric pathogenesis of late-onset AD.

BackgroundPhase-contrast magnetic resonance imaging (PC-MRI) enables quantification of cerebrospinal fluid (CSF) flow and total cerebral blood (tCBF) flow and may be of value for the etiological diagnosis of neurodegenerative diseases. This investigation aimed to study CSF flow and intracerebral vascular flow in patients with Alzheimer's disease (AD) and patients with amnesic mild cognitive impairment (a-MCI) and to compare the results with patients with idiopathic normal pressure hydrocephalus (NPH) and with healthy elderly volunteers (HEV).MethodsTen a-MCI and 9 mild AD patients were identified in a comprehensive neurological and neuropsychological assessment. They underwent brain MRI; PC-MRI pulse sequence was performed with the following parameters: two views per segment; flip angle: 25° for vascular flow and 20° for CSF flow; field-of-view (FOV): 14 × 14 mm²; matrix: 256 × 128; slice thickness: 5 mm; with one excitation for exams on the 3 T machine, and 2 excitations for the 1.5 T machine exams. Velocity (encoding) sensitization was set to 80 cm/s for the vessels at the cervical level, 10 or 20 cm/s for the aqueduct and 5 cm/s for the cervical subarachnoid space (SAS). Dynamic flow images were analyzed with in-house processing software. The patients' results were compared with those obtained for HEVs (n = 12), and for NPH patients (n = 13), using multivariate analysis.ResultsArterial tCBF and the calculated pulsatility index were significantly greater in a-MCI patients than in HEVs. In contrast, vascular parameters were lower in NPH patients. Cervical CSF flow analysis yielded similar values for all four populations. Aqueductal CSF stroke volumes (in μl per cardiac cycle) were similar in HEVs (34 ± 17) and AD patients (39 ± 18). In contrast, the aqueductal CSF was hyperdynamic in a-MCI patients (73 ± 33) and even more so in NPH patients (167 ± 89).ConclusionOur preliminary data show that a-MCI patients present with high systolic arterial peak flows, which are associated with higher mean total cerebral arterial flows. Aqueductal CSF oscillations are within normal range in AD and higher than normal in NPH. This study provides an original dynamic vision of cerebral neurodegenerative diseases, consistent with the vascular theory for AD, and supporting primary flow disturbances different from those observed in NPH.

According to the amyloid theory, the appearance of amyloid-β (Aβ) deposits represents a pivotal event in late onset Alzheimer's disease (LOAD). Physiologically, Aβ42 monomers are cleaned by capillary resorption, enzymatic catabolism, and cerebrospinal fluid (CSF) transport. Factors that promote the oligomerization of Aβ42 must be specified. In vitro, these monomers spontaneously form neurotoxic oligomers whose rate increases with time suggesting that the stasis of CSF favors the oligomerization. In animals, experimental hydrocephalus generates CSF stasis followed by the appearance of amyloid deposits. In normal pressure hydrocephalus, amyloid deposits are common, especially in elderly patients, and the turnover decline has the same order of magnitude as in AD. In this disease, the effects of CSF stasis are potentiated by the decline in the ability of CSF to inhibit the formation of oligomers. CSF originates from choroid plexus (CP). In LOAD, the functions of secretion, synthesis, and transport of CP are impaired and this is related to morphological modifications. These impairments favor the decrease of CSF turnover, the diminished levels of transthyretin, a sequestering protein synthesized by CP, and the oligomerization of Aβ42. They are potentiated by a reduced enzymatic catabolism and a decreased capillary reabsorption of Aβ42, both alterations being related to age.