Objective: Melanopsin retinal ganglion cells (mRGCs) are photoreceptors driving circadian photoentrainment, and circadian dysfunction characterizes Alzheimer disease (AD). We investigated mRGCs in AD, hypothesizing that they contribute to circadian dysfunction.Methods: We assessed retinal nerve fiber layer (RNFL) thickness by optical coherence tomography (OCT) in 21 mild‐moderate AD patients, and in a subgroup of 16 we evaluated rest–activity circadian rhythm by actigraphy. We studied postmortem mRGCs by immunohistochemistry in retinas, and axons in optic nerve cross‐sections of 14 neuropathologically confirmed AD patients. We coimmunostained for retinal amyloid β (Aβ) deposition and melanopsin to locate mRGCs. All AD cohorts were compared with age‐matched controls.Results: We demonstrated an age‐related optic neuropathy in AD by OCT, with a significant reduction of RNFL thickness (p = 0.038), more evident in the superior quadrant (p = 0.006). Axonal loss was confirmed in postmortem AD optic nerves. Abnormal circadian function characterized only a subgroup of AD patients. Sleep efficiency was significantly reduced in AD patients (p = 0.001). We also found a significant loss of mRGCs in postmortem AD retinal specimens (p = 0.003) across all ages and abnormal mRGC dendritic morphology and size (p = 0.003). In flat‐mounted AD retinas, Aβ accumulation was remarkably evident inside and around mRGCs.Interpretation: We show variable degrees of rest–activity circadian dysfunction in AD patients. We also demonstrate age‐related loss of optic nerve axons and specifically mRGC loss and pathology in postmortem AD retinal specimens, associated with Aβ deposition. These results all support the concept that mRGC degeneration is a contributor to circadian rhythm dysfunction in AD. ANN NEUROL 2016;79:90–109

Objective: To give a comprehensive overview of the phenotypic and genetic spectrum of STXBP1 encephalopathy (STXBP1-E) by systematically reviewing newly diagnosed and previously reported patients. Methods: We recruited newly diagnosed patients with STXBP1 mutations through an international network of clinicians and geneticists. Furthermore, we performed a systematic literature search to review the phenotypes of all previously reported patients. Results: We describe the phenotypic features of 147 patients with STXBP1-E including 45 previously unreported patients with 33 novel STXBP1 mutations. All patients have intellectual disability (ID), which is mostly severe to profound (88%). Ninety-five percent of patients have epilepsy. While one-third of patients presented with Ohtahara syndrome (21%) or West syndrome (9.5%), the majority has a nonsyndromic early-onset epilepsy and encephalopathy (53%) with epileptic spasms or tonic seizures as main seizure type. We found no correlation between severity of seizures and severity of ID or between mutation type and seizure characteristics or cognitive outcome. Neurologic comorbidities including autistic features and movement disorders are frequent. We also report 2 previously unreported adult patients with prominent extrapyramidal features. Conclusion: De novo STXBP1 mutations are among the most frequent causes of epilepsy and encephalopathy. Most patients have severe to profound ID with little correlation among seizure onset, seizure severity, and the degree of ID. Accordingly, we hypothesize that seizure severity and ID present 2 independent dimensions of the STXBP1-E phenotype. STXBP1-E may be conceptualized as a complex neurodevelopmental disorder rather than a primary epileptic encephalopathy.

The observation of action done by others determines a desynchronization of the rhythms recorded from cortical central regions. Here, we examined whether the observation of different types of hand movements (target directed, non-target directed, cyclic and non-cyclic) elicits different EEG cortical temporal patterns. Video-clips of four types of hand movements were shown to right-handed healthy participants. Two were target directed (grasping and pointing) motor acts; two were non-target directed (supinating and clenching) movements. Grasping and supinating were performed once, while pointing and clenching twice (cyclic movements). High-density EEG was recorded and analyzed by means of wavelet transform, subdividing the time course in time bins of 200 ms. The observation of all presented movements produced a desynchronization of alpha and beta rhythms in central and parietal regions. The rhythms desynchronized as soon as the hand movement started, the nadir being reached around 700 ms after movement onset. At the end of the movement, a large power rebound occurred for all bands. Target and non-target directed movements produced an alpha band desynchronization in the central electrodes at the same time, but with a stronger desynchronization and a prolonged rebound for target directed motor acts. Most interestingly, there was a clear correlation between the velocity profile of the observed movements and beta band modulation. Our data show that the observation of motor acts determines a modulation of cortical rhythm analogous to that occurring during motor act execution. In particular, the cortical motor system closely follows the velocity of the observed movements. This finding provides strong evidence for the presence in humans of a mechanism (mirror mechanism) mapping action observation on action execution motor programs.

Background: Anteromedial temporal lobe regions, particularly the amygdala, participate in the recognition of emotions from facial expressions. The authors studied the ability of facial emotion recognition (ER) in subjects with symptomatic epilepsy, evaluating whether mesial temporal lobe damage is related to an impairment in the recognition of specific emotions and whether the onset of seizures in a critical period of life could prevent the development of ER. Methods: Groups included patients with temporal lobe epilepsy (TLE) with MRI evidence of mesial temporal sclerosis (MTS) (n = 33); patients with TLE with MRI evidence of temporal lobe lesions other than MTS (n = 30); and patients with extratemporal epilepsy (n = 33). Healthy volunteers (n = 50) served as controls. ER was tested by matching a facial expression with the name of one of the following basic emotions: happiness, sadness, fear, disgust, and anger. A face-matching task was used to control visuoperceptual abilities with face stimuli. Results: No subject showed deficits in the face-matching task. ER was impaired in patients with right MTS, especially for fearful faces. Patients presenting left MTS, right or left temporal lobe lesions other than MTS, or extratemporal seizure foci showed ER performances similar to controls. In all subjects with right TLE, the degree of emotion recognition impairment was related to age at first seizure (febrile or afebrile) and age at epilepsy onset. Conclusions: Early-onset right-sided mesial temporal lobe epilepsy is the key substrate determining a severe deficit in recognizing emotional facial expressions, especially fear.

Mitochondrial optic neuropathies, that is, Leber hereditary optic neuropathy and dominant optic atrophy, selectively affect retinal ganglion cells, causing visual loss with relatively preserved pupillary light reflex. The mammalian eye contains a light detection system based on a subset of retinal ganglion cells containing the photopigment melanopsin. These cells give origin to the retinohypothalamic tract and support the non-image-forming visual functions of the eye, which include the photoentrainment of circadian rhythms, light-induced suppression of melatonin secretion and pupillary light reflex. We studied the integrity of the retinohypothalamic tract in five patients with Leber hereditary optic neuropathy, in four with dominant optic atrophy and in nine controls by testing the light-induced suppression of nocturnal melatonin secretion. This response was maintained in optic neuropathy subjects as in controls, indicating that the retinohypothalamic tract is sufficiently preserved to drive light information detected by melanopsin retinal ganglion cells. We then investigated the histology of post-mortem eyes from two patients with Leber hereditary optic neuropathy and one case with dominant optic atrophy, compared with three age-matched controls. On these retinas, melanopsin retinal ganglion cells were characterized by immunohistochemistry and their number and distribution evaluated by a new protocol. In control retinas, we show that melanopsin retinal ganglion cells are lost with age and are more represented in the parafoveal region. In patients, we demonstrate a relative sparing of these cells compared with the massive loss of total retinal ganglion cells, even in the most affected areas of the retina. Our results demonstrate that melanopsin retinal ganglion cells resist neurodegeneration due to mitochondrial dysfunction and maintain non-image-forming functions of the eye in these visually impaired patients. We also show that in normal human retinas, these cells are more concentrated around the fovea and are lost with ageing. The current results provide a plausible explanation for the preservation of pupillary light reaction despite profound visual loss in patients with mitochondrial optic neuropathy, revealing the robustness of melanopsin retinal ganglion cells to a metabolic insult and opening the question of mechanisms that might protect these cells.