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Sensory capacities like smell, taste, hearing, vision decline with aging, but increasing evidence show that sensory dysfunctions are one of the early signs diagnosing the conversion from physiological to pathological brain state. Smell loss represents the best characterized sense in clinical practice and is considered as one of the first preclinical signs of Alzheimer’s and Parkinson’s disease, occurring a decade or more before the onset of cognitive and motor symptoms. Despite the numerous scientific reports and the adoption in clinical practice, the etiology of sensory damage as prodromal of dementia remains largely unexplored and more studies are needed to resolve the mechanisms underlying sensory network dysfunction. Although both cognitive and sensory domains are progressively affected, loss of sensory experience in early stages plays a major role in reducing the autonomy of demented people in their daily tasks or even possibly contributing to their cognitive decline. Interestingly, the chemosensory circuitry is devoid of a blood brain barrier, representing a vulnerable port of entry for neurotoxic species that can spread to the brain. Furthermore, the exposure of the olfactory system to the external environment make it more susceptible to mechanical injury and trauma, which can cause degenerative neuroinflammation. In this review, we will summarize several findings about chemosensory impairment signing the conversion from healthy to pathological brain aging and we will try to connect those observations to the promising research linking environmental influences to sporadic dementia. The scientific body of knowledge will support the use of chemosensory diagnostics in the presymptomatic stages of AD and other biomarkers with the scope of finding treatment strategies before the onset of the disease.

White matter hyperintensities (WMHs) are frequently seen on brain magnetic resonance imaging scans of older people. Usually interpreted clinically as a surrogate for cerebral small vessel disease, WMHs are associated with increased likelihood of cognitive impairment and dementia (including Alzheimer's disease [AD]). WMHs are also seen in cognitively healthy people. In this collaboration of academic, clinical, and pharmaceutical industry perspectives, we identify outstanding questions about WMHs and their relation to cognition, dementia, and AD. What molecular and cellular changes underlie WMHs? What are the neuropathological correlates of WMHs? To what extent are demyelination and inflammation present? Is it helpful to subdivide into periventricular and subcortical WMHs? What do WMHs signify in people diagnosed with AD? What are the risk factors for developing WMHs? What preventive and therapeutic strategies target WMHs? Answering these questions will improve prevention and treatment of WMHs and dementia.

Background Notch1 signaling is a cellular cascade with a fundamental role from brain development to adult brain function. Reduction in Notch1 affects synaptic plasticity, memory and olfaction. On the other hand, Notch1 overactivation after brain injury is detrimental for neuronal survival. Some familial Alzheimer’s disease (FAD) mutations in Presenilins can affect Notch1 processing/activation. Others report that Notch1 is overexpressed in sporadic Alzheimer’s disease (AD). These works indicate that imbalances in Notch1 may be implicated in AD pathophysiology. In this study, we addressed whether Notch1 alteration can be considered a hallmark of AD. Results Immunohistochemical analysis of Notch1 on cortical and hippocampal tissue from post-mortem patients indicates an accumulation of Notch1 in plaque-like structures in the brain parenchyma of subjects with sporadic AD. Further analysis shows that displaced Notch1 is associated with fibrillary tangles/plaques. Biochemical validation confirms an accumulation of Notch1 in cytosolic brain fractions. This increase in protein is not accompanied with a raise in the Notch1 targets Hes1 and Hey1. Examination of the cerebrospinal fluid (CSF) indicates that the full length and truncations of the Notch1 protein are reduced in AD patients hinting at an accumulation in the brain parenchyma. Conclusions Our research indicates that Notch1 is significantly displaced and accumulated in fibrillary structures in the susceptible hippocampal and cortical regions of sporadic AD patients. The dominant deposition of Notch1 in the brain parenchyma and its general signal reduction in neurons is consistent in all the AD patients analyzed and suggests that Notch1 may potentially be considered a novel hallmark of AD. Electronic supplementary material The online version of this article (doi:10.1186/s40478-016-0327-2) contains supplementary material, which is available to authorized users.

Genomic studies suggest an association of circadian clock genes with bipolar disorder (BD) and lithium response in humans. Therefore, we tested mice mutant in various clock genes before and after lithium treatment in the forced swim test (FST), a rodent behavioral test used for evaluation of depressive-like states. We find that expression of circadian clock components, including Per2, Cry1 and Rev-erbα, is affected by lithium treatment, and thus, these clock components may contribute to the beneficial effects of lithium therapy. In particular, we observed that Cry1 is important at specific times of the day to transmit lithium-mediated effects. Interestingly, the pathways involving Per2 and Cry1, which regulate the behavior in the FST and the response to lithium, are distinct as evidenced by the phosphorylation of GSK3β after lithium treatment and the modulation of dopamine levels in the striatum. Furthermore, we observed the co-existence of depressive and mania-like symptoms in Cry1 knock-out mice, which resembles the so-called mixed state seen in BD patients. Taken together our results strengthen the concept that a defective circadian timing system may impact directly or indirectly on mood-related behaviors.

Notch1 signaling is a cellular cascade with a fundamental role from brain development to adult brain function. Reduction in Notch1 affects synaptic plasticity, memory and olfaction. On the other hand, Notch1 overactivation after brain injury is detrimental for neuronal survival. Some familial Alzheimer's disease (FAD) mutations in Presenilins can affect Notch1 processing/activation. Others report that Notch1 is overexpressed in sporadic Alzheimer's disease (AD). These works indicate that imbalances in Notch1 may be implicated in AD pathophysiology. In this study, we addressed whether Notch1 alteration can be considered a hallmark of AD.Immunohistochemical analysis of Notch1 on cortical and hippocampal tissue from post-mortem patients indicates an accumulation of Notch1 in plaque-like structures in the brain parenchyma of subjects with sporadic AD. Further analysis shows that displaced Notch1 is associated with fibrillary tangles/plaques. Biochemical validation confirms an accumulation of Notch1 in cytosolic brain fractions. This increase in protein is not accompanied with a raise in the Notch1 targets Hes1 and Hey1. Examination of the cerebrospinal fluid (CSF) indicates that the full length and truncations of the Notch1 protein are reduced in AD patients hinting at an accumulation in the brain parenchyma.Our research indicates that Notch1 is significantly displaced and accumulated in fibrillary structures in the susceptible hippocampal and cortical regions of sporadic AD patients. The dominant deposition of Notch1 in the brain parenchyma and its general signal reduction in neurons is consistent in all the AD patients analyzed and suggests that Notch1 may potentially be considered a novel hallmark of AD.