White matter alterations in Alzheimer's disease without concomitant pathologies.

AIMS: Most individuals with AD neuropathological changes have co-morbidities which have an impact on the integrity of the WM. This study analyses oligodendrocyte and myelin markers in the frontal WM in a series of AD cases without clinical or pathological co-morbidities. METHODS: From a consecutive autopsy series, 206 cases had neuropathological changes of AD; among them, only 33 were AD without co-morbidities. WM alterations were first evaluated in coronal sections of the frontal lobe in every case. Then, RT-qPCR and immunohistochemistry were carried out in the frontal WM of AD cases without co-morbidities to analyse the expression of selected oligodendrocyte and myelin markers. RESULTS: WM demyelination was more marked in AD with co-morbidities when compared with AD cases without co-morbidities. Regarding the later, mRNA expression levels of MBP, PLP1, CNP, MAG, MAL, MOG and MOBP were preserved at stages I-II/0-A when compared with middle-aged (MA) individuals, but significantly decreased at stages III-IV/0-C. This was accompanied by reduced expression of NG2 and PDGFRA mRNA, reduced numbers of NG2-, Olig2- and HDAC2-immunoreactive cells and reduced glucose transporter immunoreactivity. Partial recovery of some of these markers occurred at stages V-VI/B-C. CONCLUSIONS: The present observations demonstrate that co-morbidities have an impact on WM integrity in the elderly and in AD, and that early alterations in oligodendrocytes and transcription of genes linked to myelin proteins in WM occur in AD cases without co-morbidities. These are followed by partial recovery attempts at advanced stages. These observations suggest that oligodendrocytopathy is part of AD.

Locus coeruleus at asymptomatic early and middle Braak stages of neurofibrillary tangle pathology.

AIMS: The present study analyses molecular characteristics of the locus coeruleus (LC) and projections to the amygdala and hippocampus at asymptomatic early and middle Braak stages of neurofibrillary tangle (NFT) pathology. METHODS: Immunohistochemistry, whole-transcriptome arrays and RT-qPCR in LC and western blotting in hippocampus and amygdala in a cohort of asymptomatic individuals at stages I-IV of NFT pathology were used. RESULTS: NFTs in the LC increased in parallel with colocalized expression of tau kinases, increased neuroketal adducts and decreased superoxide dismutase 1 in neurons with hyperphosphorylated tau and decreased voltage-dependent anion channel in neurons containing truncated tau were found. These were accompanied by increased microglia and AIF1, CD68, PTGS2, IL1ß, IL6 and TNF-α gene expression. Whole-transcriptome arrays revealed upregulation of genes coding for proteins associated with heat shock protein binding and genes associated with ATP metabolism and downregulation of genes coding for DNA-binding proteins and members of the small nucleolar RNAs family, at stage IV when compared with stage I. Tyrosine hydroxylase (TH) immunoreactivity was preserved in neurons of the LC, but decreased TH and increased α2A adrenergic receptor protein levels were found in the hippocampus and the amygdala. CONCLUSIONS: Complex alteration of several metabolic pathways occurs in the LC accompanying NFT formation at early and middle asymptomatic stages of NFT pathology. Dopaminergic/noradrenergic denervation and increased expression of α2A adrenergic receptor in the hippocampus and amygdala occur at first stage of NFT pathology, suggesting compensatory activation in the face of decreased adrenergic input occurring before clinical evidence of cognitive impairment and depression.

Amyloid and tau pathology of familial Alzheimer's disease APP/PS1 mouse model in a senescence phenotype background (SAMP8).

The amyloid precursor protein/presenilin 1 (APP/PS1) mouse model of Alzheimer's disease (AD) has provided robust neuropathological hallmarks of familial AD-like pattern at early ages, whereas senescence-accelerated mouse prone 8 (SAMP8) has a remarkable early senescence phenotype with pathological similarities to AD. The aim of this study was the investigation and characterization of cognitive and neuropathological AD markers in a novel mouse model that combines the characteristics of the APP/PS1 transgenic mouse model with a senescence-accelerated background of SAMP8 mice. Initially, significant differences were found regarding amyloid plaque formation and cognitive abnormalities. Bearing these facts in mind, we determined a general characterization of the main AD brain molecular markers, such as alterations in amyloid pathway, neuroinflammation, and hyperphosphorylation of tau in these mice along their lifetimes. Results from this analysis revealed that APP/PS1 in SAMP8 background mice showed alterations in the pathways studied in comparison with SAMP8 and APP/PS1, demonstrating that a senescence-accelerated background exacerbated the amyloid pathology and maintained the cognitive dysfunction present in APP/PS1 mice. Changes in tau pathology, including the activity of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3 ß (GSK3ß), differs, but not in a parallel manner, with amyloid disturbances.

[A neuropsychological and functional brain imaging study of visuo-imitative apraxia]. / Exploration neuropsychologique et par imagerie fonctionnelle cérébrale d'une apraxie visuo-imitative.

We describe the case of a 58-years-old right-handed women suffering from an occipital-parietal lesion. The administration of a cognitively based assessment tool for limb praxis (Batterie d'Evaluation des Praxies, B.E.P., Peigneux and Van der Linden, 1998) demonstrated bilateral visuo-imitative apraxia. Gesture production was mainly characterised by spatial, errors, and imitation of meaningful gestures was worse than their pantomime on verbal command. Moreover, the imitation of meaningless gestures and their reproduction on a manikin were worse than imitation of their matched meaningful gestures. In a cognitive perspective, adapted from the Rothi et al. (1997) and Goldenberg (1995) contributions to our understanding of limb praxis, this configuration of performance suggests deficits occurring at multiple levels. On one hand, it suggests either access difficulties or alteration of the output praxicon, i.e., the lexicon for visuo-kinesthetic engrams of meaningful gestures. On the other hand, the simultaneous deficit for meaningless gesture reproduction on the subject's own body and on a manikin favors an alteration of the structural descriptions of the human body (i.e., human body knowledge), underlying the mental transposition processes occurring between the visual analysis of a meaningless gestural configuration and its effective reproduction on oneself or on a manikin, thus contradicting the classic view of a direct pathway linking visual analysis and motor planning in meaningless gesture imitation. Finally, due to the output praxicon deficit, imitation of meaningful gestures is partly processed in the same way as meaningless gestures (also impaired in this case), leading to an interference effect between both degraded memory-based and visually-transposed traces, which account for imitation of meaningful gestures being worse than their pantomime on verbal command. We also assess regional cerebral metabolism using positron emission tomography (PET). Comparison with 41 healthy subjects (SPM96) demonstrated a statistically significant hypometabolism in the left intraparietal sulcus and superior parietal lobule, and in the right dorsal prestriate cortex. These results, together with a review of the other studies of visuo-imitative apraxia, suggest that the left intraparietal sulcus may be associated with access or integration of information from the output praxicon. The left superior parietal and the right dorsal prestriate deficits functionally impaired a bilateral dorsal network implied in the mental transformations of the body, thus suggesting that these mental transformations are underlined by knowledge of the human body, which may subsequently explain the deficit for the reproduction of meaningless and meaningful configurations.