Study protocol on Alzheimer's disease and related disorders: focus on clinical and imaging predictive markers in co-existing lesions.

BACKGROUND: One of the crucial challenges for the future of therapeutic approaches to Alzheimer's disease (AD) is to target the main pathological processes responsible for disability and dependency. However, a progressive cognitive impairment occurring after the age of 70, the main population affected by dementia, is often related to mixed lesions of neurodegenerative and vascular origins. Whereas young patients are mostly affected by pure lesions, ageing favours the occurrence of co-lesions of AD, cerebrovascular disease (CVD) and Lewy body dementia (LBD). Most of clinical studies report on functional and clinical disabilities in patients with presumed pure pathologies. But, the weight of co-morbid processes involved in the transition from an independent functional status to disability in the elderly with co-lesions still remains to be elucidated. Neuropathological examination often performed at late stages cannot answer this question at mild or moderate stages of cognitive disorders. Brain MRI, Single Photon Emission Computed Tomography (SPECT) with DaTscan®, amyloid Positron Emission Tomography (PET) and CerebroSpinal Fluid (CSF) AD biomarkers routinely help in performing the diagnosis of underlying lesions. The combination of these measures seems to be of incremental value for the diagnosis of mixed profiles of AD, CVD and LBD. The aim is to determine the clinical, neuropsychological, neuroradiological and biological features the most predictive of cognitive, behavioral and functional impairment at 2 years in patients with co-existing lesions. METHODS: A multicentre and prospective cohort study with clinical, neuro-imaging and biological markers assessment will recruit 214 patients over 70 years old with a cognitive disorder of AD, cerebrovascular and Lewy body type or with coexisting lesions of two or three of these pathologies and fulfilling the diagnostic criteria for dementia at a mild to moderate stage. Patients will be followed every 6 months (clinical, neuropsychological and imaging examination and collection of cognitive, behavioural and functional impairment) for 24 months. DISCUSSION: This study aims at identifying the best combination of markers (clinical, neuropsychological, MRI, SPECT-DaTscan®, PET and CSF) to predict disability progression in elderly patients presenting coexisting patterns. TRIAL REGISTRATION: NCT02052947 .

[Effect of a non-pharmacological intervention, Voix d'Or(®), on behavior disturbances in Alzheimer disease and associated disorders]. / Effet d'une intervention non médicamenteuse, Voix d'Or(®), sur les troubles du comportement dans la maladie d'Alzheimer ou une maladie apparentée.

An innovative non-pharmacological intervention called Voix d'Or(®) (Golden Voice) was proposed in the Cognitive behavioral unit (CBU) of the Memory center at the Hospices civils in Lyon. Voix d'Or(®) offers eight sound activities disseminated via an audio device based on different approaches sociotherapeutic (music therapy, reminiscence, relaxation, reorientation in reality). The aim of this study was to test the effects of the Voix d'Or(®) program on behavioral and psychological symptoms of dementia (BPSD) in patients with Alzheimer's disease hospitalized in the CBU. Twenty four patients with agitation and/or apathy and/or anxiety and/or depression were included. Patients were randomly selected in the intervention group exposed to Voix d'Or versus a control group exposed to usual occupational activities. Patients were assessed before (T0) and after (T1) the intervention period. Several variables were measured: frequency and severity of behavioral disorders, anxiety, depression, agitation and apathy. A significant improvement of anxiety level between T0 and T1was observed in the group with Voix d'Or(®) compared to the control group. This study suggests that this non-pharmacological intervention may be beneficial on anxiety in patients with Alzheimer's disease.

Interhemispheric balance sets nostril differences in color-induced nasal thermal judgments.

Sniffing out of sight always the same colorless and odorless solution containing no thermal agents while viewing a bottle with colored water increases sensitivity of the left nostril/right hemisphere (RH) for warming sensations and sensitivity of the right nostril/left hemisphere (LH) for cooling sensations. It is likely that engagement in a temperature judgment task and the development of specific expectancies due to the presence of color cues alter and enhance processing in brain areas involved in thermosensory processing. The lateralized patterns thus intimate hemispheric specialization for thermosensory processing probably originating in reciprocal inhibition that confers balance between the hemispheres. If the inhibition-balance hypothesis were correct then the more the left nostril proves sensitive to warming the more the right nostril would prove sensitive to cooling. One hundred and ninety one healthy volunteers were tested here. The left nostril dominance for warming and the right dominance for cooling were replicated once more. The dominance of the left nostril for warming (left minus right nostril) correlated highly with the dominance of the left nostril to cooling (right minus left nostril) and the individual patterns of results were distributed along an axis starting from the expected left nostril/warming - right nostril/cooling pattern and ending at the opposite left nostril/cooling - right nostril/warming pattern. Furthermore, the point where the left nostril dominance for warming responses dropped and inverted perfectly coincided with the point where the right nostril dominance for cooling responses inverted too. Such a good continuum between the expected and the opposite patterns supports the inhibition-balance hypothesis. Finally, 66% of subjects exhibited the expected left-warming/right-cooling pattern suggesting, therefore, that, despite this continuum, there is a dominant lateral specialization for temperature processing.

A role for the insula in color-induced nasal thermal sensations.

This article is the first step towards understanding the mechanisms underlying the intriguing, recently discovered lateralized color-induced nasal thermal sensations. In the presence of color cues and complete absence of thermal stimulus, larger sensitivity of the left nostril/right hemisphere (RH) for warming sensations and larger right nostril/left hemisphere (LH) for cooling sensations were replicated several times. It was suggested that engagement in a temperature judgment task and the development of specific expectancies due to the presence of color cues could alter and enhance processing in brain areas involved in thermosensory processing, such as the middle/posterior insula. The lateralized patterns could thus intimate hemispheric specialization for thermosensory processing. However, such lateralization may be due to either exclusive specialization of each hemisphere or specialization-through-reciprocal inhibition between the hemispheres. The two hypotheses predict different results following a unilateral insular stroke. Here, we present the results of a sample of healthy volunteers and patient MB, a young woman suffering from unilateral left-side damage of the posterior insula, in a task involving color-induced nasal thermal judgment. The expected lateralized pattern was found in the performance of the controls. In line with our previous suggestions that the LH is more involved in the processing of cooling sensations, patient MB exhibited changes only in the judgment of cooling sensations. Her results also clearly support the specialization-through-reciprocal inhibition account since she exhibited decreased cooling judgments contralaterally but increased cooling judgments ipsilaterally. Accordingly, we conclude that (a) the lateralized patterns arise because of hemispheric specialization; (b) the LH is seemingly more involved in the processing of cooling sensations; (c) this specialization is underlain by reciprocal interhemispheric inhibition; and (d) even in the absence of thermal stimulus, the development of expectancies suffices to activate modality-specific brain areas involved in the current task in such a way that damage to these areas disturbs the corresponding specific processes.

Hot colors: the nature and specificity of color-induced nasal thermal sensations.

The nature of the recently discovered color-induced nasal thermal sensations was investigated in four Experiments. Subjects were required to fixate a bottle containing a red or green solution presented centrally (Exp1 and Exp4) or laterally (Exp2) and to sniff another bottle, always the same one, but which they were not allowed to see, containing 10 ml of a colorless, odorless and trigeminal-free solution. Each nostril was tested separately, and subjects were asked whether the sniffed solution induced warming or cooling sensations (plus an ambient sensation in Exp4) in the nasal cavity. The results of Experiments 1 and 2 confirmed the warming/left nostril-cooling/right nostril dissociation, suggesting the existence of different lateralized processes for thermal processing. However, Experiment 2 failed to demonstrate dominance of warming responses when subjects' eyes were directed to the left or cooling responses when they were directed to the right. Nor did gaze direction interact with the tested nostril. This suggests that the color-induced thermal sensations are specifically related to the nasal trigeminal system, rather than a general process related to general hemispheric activity. When the exposed bottles were colorless (Exp3), no lateralized patterns were observed, suggesting, in combination with the results of Experiments 1 and 2, that both color cues and nasal stimulations are necessary for lateralized patterns to arise. Rendering the temperature judgment even more difficult (Exp4), made the lateralized patterns shift towards the associated (i.e., ambient) responses. The results are discussed in a general framework which considers that, even in the absence of real thermal stimulus, preparing to process thermal stimuli in the nasal cavity may activate the underlying lateralized neural mechanisms, and that those mechanisms are reflected in the responses.