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Replies to post #173604 on Anavex Life Sciences Corp (AVXL)
4. Discussion
To the best of our knowledge, the present study is the first to describe AD-related changes in KCs, also taking into account MCI patients. According to our results, the KC reduction does not seem associated with the MCI condition. On the other hand, the amount of SWS discriminates HCs from both clinical groups. While no differences have been observed between MCI and HC groups, KC density was positively related with MMSE scores, which represent a measure of the degree of cognitive decline.
Our previous study [43] showed a large decrease of frontal spontaneous KC density in AD patients compared with HCs. This fall of KCs does not appear in the MCI group, not even after dividing it into two subgroups (SD and MD). In line with converging evidence, SD and MD may represent two phases along a continuum between normal aging and AD [66,67], so a progressive reduction of KCs between these phases would be expected. On the contrary, the present data suggest that the fall of KCs seems to have a tardy onset, appearing only in a full-blown phase of the disease. A possible explanation for the absence of KC density alteration in MCI patients is that the brain damage responsible for the KC density reduction emerges only in diagnosed AD. Alternatively, such brain alterations could be already present in MCI patients, but they are not severe enough to induce a significant KC density decrease.
At the same time, these data co-exist with two findings that discriminate HCs from both clinical groups: the amount of SWS and of fast sleep spindles, the other EEG hallmark of stage-2 NREM sleep. With respect to the former, the current study and the study by Gorgoni et al. [44] substantially show a higher percentage of SWS in HCs compared to MCI and AD patients, without any difference between the clinical groups. On the other hand, parietal fast sleep spindles density decreases in both MCI and AD patients compared to HCs, while it does not differ between MCI and AD groups [44]. Hence, it seems that both KC and spindle density, as well as the amount of SWS, decrease in AD patients compared to controls, but the lessening occurs at different stages of disease (earlier for sleep spindles and SWS). The time lag between these phenomena may reflect different pathological mechanisms underlying alterations in AD of KCs on the one hand, and of spindles and SWS on the other. This temporal dissociation could potentially shed light on the AD-MCI neural substrates’ degenerative process.
The spindle generation mainly involves the interaction between GABAergic inhibitory neurons of the thalamic reticular nucleus and thalamocortical networks [68,69,70,71,72]. At the same time, the pivotal role of the thalamocortical neurons for the generation of delta activity, which mainly characterizes SWS, has been widely demonstrated [70,73,74].
On the other hand, converging evidence in animals and humans points to a cortical origin and propagation of KCs [17,18,19,20], while the thalamus seems to have only a secondary role in mediating the cortically generated KCs [18,21]. Concurrently, several findings point to a sequential deterioration process in different brain areas in AD [67,75,76]: grey matter atrophy, characterizing AD and MCI, mainly implicates bilateral medial temporal lobe (MTL) (parahippocampus gyrus, amygdala, hippocampus, entorhinal cortex, uncus), posterious cingulate cortex, precuneus and thalamus, while more extensive cortical regions (including the frontal, temporal, parietal and insular areas) and subcortical areas seem to be altered only in AD [77]. Moreover, according to the evidence of the time course of neuropathological alterations of neurofibrillary tangles in AD [78] and MCI [79], the neuronal changes seem to start from the locus coeruleus and the dorsal raphe nucleus [80,81], and to spread at first through the MTL and afterwards, and only at the moment of the full diagnosis of AD, to the frontal, parietal and temporal cortical areas and more subcortical regions [77].
The temporal dissociation between the fall of KCs, and sleep spindles and SWS, then, could be explained by the fact that, in the progression of AD, the cortical areas implied in the KC generation mechanism may undergo a deterioration in a later phase of the degenerative process compared to the thalamic and cortico-thalamic pathways implicated in sleep spindles and delta activity production. As a consequence, in MCI patients, the frontal cortex is probably still intact enough to be able to produce KCs.
Even if this explanation remains speculative, the present findings seem to be coherent with the possible, extensively reported in literature, time course of the disease, which characterizes the deterioration of different brain areas in the progression of AD.
Finally, the absence of significant differences between the three groups in the WASO and SEI does not confirm some previous findings [3,4]. This unexpected result should likely be interpreted as a consequence of our strict exclusion criteria relative to the presence of sleep disorders.
An important limitation of the present study is linked to the issue of the diagnosis of MCI. According to the National Institute on Aging and Alzheimer’s Association’s workgroup [82], impairment in episodic memory is most commonly seen in MCI patients who subsequently progress to a diagnosis of AD. However, the cognitive evaluation on which the diagnosis is based is not able to determine if the primary cause of the symptoms are degenerative or not (for example, they could be vascular, depressive, traumatic, due to medical comorbidities or mixed disease), and thus it is not able to determine if the MCI condition is due to AD or to other underlying causes. Moreover, our study does not report data about the main well-known biomarkers of AD, such as ß-amyloid and tau neurofibrillary tangles, that could have provided fundamental hints about MCI etiology. Probably, different neural substrates could determine different outcomes in terms of sleep changes and, in particular, relative to the drop in KCs. For this reason, we are carrying out a follow-up study in order to be able to select only the MCI subjects who convert to AD. Removing from the analysis the MCI subjects whose symptoms are due to other pathological conditions may potentially shed light on the likelihood of the relationship between the fall of KCs and, specifically, the pathology of AD.
As a final point we have to specify that, although we excluded from the sample subjects with a diagnosis of obstructive sleep apnoea syndrome (OSAS) or with more than five events with oxygen saturation <90% per hour of sleep, the absence of a standard Obstructive Sleep Apnea (OSA) evaluation should be considered a further limitation, as participants could have had hypopneas unrevealed by the oximetry measurement.
