(1) Background: We proposed to review worldwide estimates of cognitive impairment prevalence and incidence in adults older than 50 years of age living in the community. (2) Methods: Systematic searches were performed in January 2019 using MEDLINE/PubMed. Articles were selected if they referred to cognitive impairment, prevalence, incidence, elders, and population or community-based studies. Analysis, aggregated by different methodologic features, was performed. (3) Results: Prevalence (80 studies) ranged between 5.1% and 41% with a median of 19.0% (25th percentile = 12.0%; 75th percentile = 24.90%). Incidence (11 studies) ranged from 22 to 76.8 per 1000 person-years with a median of 53.97 per 1000 person-years (25th percentile = 39.0; 75th percentile = 68.19). No statistically significant effects were found except for inclusion age. (4) Conclusion: We propose that the homogenization and clarification of the definition of what constitutes cognitive impairment are essential to refine the epidemiological understanding of this entity. The results of this review reinforce the importance of adherence to standardized cut-off scores for cognitive tests to promote study comparability.

Fanni Gergely, Geoffrey Woods and colleagues identify a disease-associated CEP63 mutation in a family with primary microcephaly. They further show that CEP63 and CEP152 interact and form a discrete ring around the proximal end of the parental centriole, implicating this complex in the regulation of centrosome number. Autosomal recessive primary microcephaly (MCPH) is characterized by a substantial reduction in prenatal human brain growth without alteration of the cerebral architecture and is caused by biallelic mutations in genes coding for a subset of centrosomal proteins1,2,3,4,5,6,7,8,9,10. Although at least three of these proteins have been implicated in centrosome duplication11, the nature of the centrosome dysfunction that underlies the neurodevelopmental defect in MCPH is unclear. Here we report a homozygous MCPH-causing mutation in human CEP63. CEP63 forms a complex with another MCPH protein, CEP152, a conserved centrosome duplication factor12,13,14,15. Together, these two proteins are essential for maintaining normal centrosome numbers in cells. Using super-resolution microscopy, we found that CEP63 and CEP152 co-localize in a discrete ring around the proximal end of the parental centriole, a pattern specifically disrupted in CEP63-deficient cells derived from patients with MCPH. This work suggests that the CEP152-CEP63 ring-like structure ensures normal neurodevelopment and that its impairment particularly affects human cerebral cortex growth.

Animals depend on a large variety of rewards but their brains have a limited dynamic coding range. When rewards are uncertain, neuronal coding needs to cover a wide range of possible rewards. However, when reward is likely to occur within a specific range, focusing the sensitivity on the predicted range would optimize the discrimination of small reward differences. One way to overcome the trade-off between wide coverage and optimal discrimination is to adapt reward sensitivity dynamically to the available rewards. We investigated how changes in reward distribution influenced the coding of reward in the orbitofrontal cortex. Animals performed an oculomotor task in which a fixation cue predicted the SD of the probability distribution of juice volumes, while the expected mean volume was kept constant. A subsequent cue specified the exact juice volume obtained for a correct saccade response. Population responses of orbitofrontal neurons that reflected the predicted juice volume showed adaptation to the reward distribution. Statistical tests on individual responses revealed that a quarter of value-coding neurons shifted the reward sensitivity slope significantly between two reward distributions, whereas the remaining neurons showed insignificant change or lack of adaptation. Adaptations became more prominent when reward distributions changed less frequently, indicating time constraints for assessing reward distributions and adjusting neuronal sensitivity. The observed neuronal adaptation would optimize discrimination and contribute to the efficient coding of a large variety of potential rewards by neurons with limited dynamic range.

We investigated three families whose offspring had extreme microcephaly at birth and profound mental retardation. Brain scans and postmortem data showed that affected individuals had brains less than 10% of expected size (≤10 standard deviation) and that in addition to a massive reduction in neuron production they displayed partially deficient cortical lamination (microlissencephaly). Other body systems were apparently unaffected and overall growth was normal. We found two distinct homozygous mutations of NDE1, c.83+1G>T (p.Ala29GlnfsX114) in a Turkish family and c.684_685del (p.Pro229TrpfsX85) in two families of Pakistani origin. Using patient cells, we found that c.83+1G>T led to the use of a novel splice site and to a frameshift after NDE1 exon 2. Transfection of tagged NDE1 constructs showed that the c.684_685del mutation resulted in a NDE1 that was unable to localize to the centrosome. By staining a patient-derived cell line that carried the c.83+1G>T mutation, we found that this endogeneously expressed mutated protein equally failed to localize to the centrosome. By examining human and mouse embryonic brains, we determined that NDE1 is highly expressed in neuroepithelial cells of the developing cerebral cortex, particularly at the centrosome. We show that NDE1 accumulates on the mitotic spindle of apical neural precursors in early neurogenesis. Thus, NDE1 deficiency causes both a severe failure of neurogenesis and a deficiency in cortical lamination. Our data further highlight the importance of the centrosome in multiple aspects of neurodevelopment.