New diagnostic criteria for metopic ridges and trigonocephaly: a 3D geometric approach.

BACKGROUND: Trigonocephaly occurs due to the premature fusion of the metopic suture, leading to a triangular forehead and hypotelorism. This condition often requires surgical correction for morphological and functional indications. Metopic ridges also originate from premature metopic closure but are only associated with mid-frontal bulging; their surgical correction is rarely required. Differential diagnosis between these two conditions can be challenging, especially in minor trigonocephaly. METHODS: Two hundred seven scans of patients with trigonocephaly (90), metopic rigdes (27), and controls (90) were collected. Geometric morphometrics were used to quantify skull and orbital morphology as well as the interfrontal angle and the cephalic index. An innovative method was developed to automatically compute the frontal curvature along the metopic suture. Different machine-learning algorithms were tested to assess the predictive power of morphological data in terms of classification. RESULTS: We showed that control patients, trigonocephaly and metopic rigdes have distinctive skull and orbital shapes. The 3D frontal curvature enabled a clear discrimination between groups (sensitivity and specificity > 92%). Furthermore, we reached an accuracy of 100% in group discrimination when combining 6 univariate measures. CONCLUSION: Two diagnostic tools were proposed and demonstrated to be successful in assisting differential diagnosis for patients with trigonocephaly or metopic ridges. Further clinical assessments are required to validate the practical clinical relevance of these tools.

An Ultra-Rare Mixed Phenotype with Combined AP-4 and ERF Mutations: The First Report in a Pediatric Patient and a Literature Review.

The adaptor protein 4 (AP-4) constitutes a conserved hetero-tetrameric complex within the family of adaptor protein (AP) complex, crucial for the signal-mediated trafficking of integral membrane proteins. Mutations affecting all subunits of the AP-4 complex have been linked to autosomal-recessive cerebral palsy and a complex hereditary spastic paraparesis (HSP) phenotype. Our report details the case of a 14-year-old boy born to consanguineous parents, presenting psychomotor delay, severe intellectual disability, microcephaly, and trigonocephaly. Despite a history of febrile seizures, subsequent years were devoid of seizures, with normal EEG. Exome sequencing revealed pathogenic variants in both the AP4B1 and ERF genes. Significantly, the patient exhibited features associated with AP4B1 mutations, including distinctive traits such as cranial malformations. The ERF gene variant, linked to craniosynostosis, likely contributes to the observed trigonocephaly. This case represents the initial documentation of a concurrent mutation in the AP4B1 and ERF genes, underscoring the critical role of exome analysis in unraveling complex phenotypes. Understanding these complex genotypes offers valuable insights into broader syndromic conditions, facilitating comprehensive patient management.

Yoda1 opens the lymphatic path for craniosynostosis therapy.

The rediscovery of meningeal lymphatic vessels (MLVs) has sparked research interest in their function in numerous neurological pathologies. Craniosynostosis (CS) is caused by a premature fusion of cranial sutures during development. In this issue of the JCI, Matrongolo and colleagues show that Twist1-haploinsufficient mice that develop CS exhibit raised intracranial pressure, diminished cerebrospinal fluid (CSF) outflow, and impaired paravascular CSF-brain flow; all features that were associated with MLV defects and exacerbated pathology in mouse models of Alzheimer's disease. Activation of the mechanosensor Piezo1 with Yoda1 restored MLV function and CSF perfusion in CS models and in aged mice, opening an avenue for further development of therapeutics.

Atypical sagittal suture craniosynostosis: pathological considerations for early closure of the anterior part of the sagittal suture.

Sagittal suture synostosis is one of the most common craniosynostoses and is often diagnosed by characteristic narrow and long skull shape, scaphocephaly. However, some patients with sagittal suture synostosis do not present with typical scaphocephaly, making early diagnosis difficult. In this study, five cases of characteristic skull deformity showing a narrowing of the cranium posterior to the coronal suture on computed tomography (CT) are presented. The three older children presented with papilledema and intellectual disability and a closed sagittal suture on CT. The two infant cases were diagnosed with the characteristic cranial deformities with aggravation of the deformity over time, but sagittal suture closure was not evident on CT. All patients underwent cranial remodeling surgery. In the two infant cases, the histopathological findings showed that the anterior part of the sagittal suture was firmly fused with fibrous tissue without bony fusion. These findings suggested that narrowing of the cranium posterior to the coronal suture might be due to functional fusion of the anterior portion of the sagittal suture prior to bony fusion. In an infant presenting with such a deformity that shows aggravation of the deformity over time, surgical treatment should be considered.

Data-driven cranial suture growth model enables predicting phenotypes of craniosynostosis.

We present the first data-driven pediatric model that explains cranial sutural growth in the pediatric population. We segmented the cranial bones in the neurocranium from the cross-sectional CT images of 2068 normative subjects (age 0-10 years), and we used a 2D manifold-based cranial representation to establish local anatomical correspondences between subjects guided by the location of the cranial sutures. We designed a diffeomorphic spatiotemporal model of cranial bone development as a function of local sutural growth rates, and we inferred its parameters statistically from our cross-sectional dataset. We used the constructed model to predict growth for 51 independent normative patients who had longitudinal images. Moreover, we used our model to simulate the phenotypes of single suture craniosynostosis, which we compared to the observations from 212 patients. We also evaluated the accuracy predicting personalized cranial growth for 10 patients with craniosynostosis who had pre-surgical longitudinal images. Unlike existing statistical and simulation methods, our model was inferred from real image observations, explains cranial bone expansion and displacement as a consequence of sutural growth and it can simulate craniosynostosis. This pediatric cranial suture growth model constitutes a necessary tool to study abnormal development in the presence of cranial suture pathology.

Technical evolution of pediatric neurosurgery: craniosynostosis from 1972 to 2023 and beyond.

Very few clinical entities have undergone so many different treatment approaches over such a short period of time as craniosynostosis. Surgical treatments for this condition have ranged from simple linear craniectomies, accounting for the specific role of cranial sutures in assuring the normal growth of the skull, to more complex cranial vault reconstructions, based on the perceived role of the skull base in affecting the growth of the skull. While a great deal of evolution has occurred, there remains controversy regarding the ideal treatment including the best surgical technique, the optimal age for surgery, and the long-term morphological and neurodevelopmental outcomes. The evolution of the surgical management of craniosynostosis in the last 50 years has been affected by several factors. This includes the awareness of needing to operate on affected children during infancy to achieve the best results, the use of multistage operations, the availability of more sophisticated surgical tools, and improved perioperative care. In some forms of craniosynostosis, the operations can be carried out at a very young age with low morbidity, and with the postoperative use of a molding helmet, springs, or distractors, these operations prove to be as effective as traditional larger cranial reconstructions performed in older children. As a consequence, complex surgical operations have become progressively less utilized. A second relevant advance was the more recent advent of a molecular diagnosis, which allowed us to understand the pathogenesis of some associated malformations and neurodevelopmental issues that were observed in some children despite appropriate surgical treatment. Future research should focus on improving the analysis of longer-term outcomes and understanding the natural history of craniofacial conditions, including what issues persist despite optimal surgical correction. Progress in molecular investigations concerning the normal and pathological development of cranial sutures could be a further significant step in the management of craniosynostosis, possibly favoring a "medical" treatment in the near future. Artificial intelligence will likely have a role in establishing the diagnosis with less reliance on radiographic studies and in assisting with surgical planning. Overall, much progress has been made, but there remains much to do.

Familial monoallelic CYP26B1 truncating variant causes a syndromic craniosynostosis due to haploinsufficiency ?

Autosomal recessive CYP26B1 disorder is characterised by syndromic craniosynostosis of variable severity, and survival ranging from prenatal lethality to survival into adulthood. Here we report on two related individuals of Asian-Indian origin with syndromic craniosynostosis characterised by craniosynostosis, and dysplastic radial heads, caused by monoallelic CYP26B1 likely pathogenic variant NM_019885.4:c.86C > A:p. (Ser29Ter). We propose the possibility of autosomal dominant phenotype of CYP26B1 variant.

Review of Recurrently Mutated Genes in Craniosynostosis Supports Expansion of Diagnostic Gene Panels.

Craniosynostosis, the premature fusion of the cranial sutures, affects ~1 in 2000 children. Although many patients with a genetically determined cause harbor a variant in one of just seven genes or have a chromosomal abnormality, over 60 genes are known to be recurrently mutated, thus comprising a long tail of rarer diagnoses. Genome sequencing for the diagnosis of rare diseases is increasingly used in clinical settings, but analysis of the data is labor intensive and involves a trade-off between achieving high sensitivity or high precision. PanelApp, a crowd-sourced disease-focused set of gene panels, was designed to enable prioritization of variants in known disease genes for a given pathology, allowing enhanced identification of true-positives. For heterogeneous disorders like craniosynostosis, these panels must be regularly updated to ensure that diagnoses are not being missed. We provide a systematic review of genetic literature on craniosynostosis over the last 5 years, including additional results from resequencing a 42-gene panel in 617 affected individuals. We identify 16 genes (representing a 25% uplift) that should be added to the list of bona fide craniosynostosis disease genes and discuss the insights that these new genes provide into pathophysiological mechanisms of craniosynostosis.

Histopathologic and Spectrometric Evaluation of Bony Components of Synostotic Suture and Parietal Bone in Children with Sagittal Synostosis.

AIM: To understand the characterization of the ossification process both in the synostotic suture, and the adjacent parietal bone. MATERIAL AND METHODS: The surgical procedure for the 28 patients diagnosed with sagittal synostosis consisted of removing the synostotic bone as a whole, if possible, "Barrel-Stave" relaxation osteotomies, and strip osteotomies to the parietal and temporal bones perpendicular to the synostotic suture. The synostotic (group I) and parietal (group II) bone segments are obtained during osteotomies. Atomic absorption spectrometry was used to determine the amount of calcium in both groups, which is an indicator of ossification. Scanning electron microscopy and immunohistochemistry were employed to assess trabecular bone formation, osteoblastic density, and osteopontin, which is one of the in vivo indicators of new bone formation. RESULTS: Histopathologically, trabecular bone formation scores did not indicate any significant difference between the groups. However, the osteoblastic density and calcium accumulation in group I were higher than those in group II, and the difference was significant. Osteopontin staining scores in cells showing membranous and cytoplasmic staining with osteopontin antibodies significantly increased in group II. CONCLUSION: In this study, we found reduced differentiation of osteoblasts despite their increase in number. Moreover, the osteoblastic maturation rate was low in synostotic sutures, bone resorption becomes slower than new bone formation, and the remodeling rate is low in sagittal synostosis.

Molecular Scalpels: The Future of Pediatric Craniofacial Surgery?

SUMMARY: CRISPR-Cas genome editing tools are among the most substantial advances in the life sciences in modern history. Single-dose gene therapies to correct pathogenic mutations have moved quickly from bench to bedside, with several therapeutics designed by CRISPR pioneers entering various stages of clinical investigation. Applications of these genetic technologies are poised to reshape the practice of both medicine and surgery. Many of the most morbid conditions treated by craniofacial surgeons are syndromic craniosynostoses caused by mutations in fibroblast growth factor receptor genes, including Apert, Pfeiffer, Crouzon, and Muenke syndromes. The fact that pathogenic mutations in these genes are recurrent in the majority of affected families presents a unique opportunity to develop "off-the-shelf" gene editing therapies to correct these mutations in affected children. The therapeutic potential of these interventions could reshape pediatric craniofacial surgery, potentially first eliminating the need for midface advancement procedures in affected children.

An algorithmic clinicoradiological approach to paediatric cranial vault lesions: distinguishing normal variants from pathologies.

Lesions of the paediatric cranial vault are diverse both in their presentation and aetiology. As such, they pose a diagnostic challenge to the paediatric neurosurgeon and neuroradiologist. In this article, we delineate the spectrum of paediatric calvarial pathology into four distinct groups: (1) lytic lesion(s); (2) focal sclerotic lesion(s); (3) diffuse cranial vault sclerosis; and (4) abnormal shape of the cranial vault. It is our aim that this more pragmatic, algorithmic approach may mitigate diagnostic uncertainty and aid the more accurate diagnosis of paediatric calvarial lesions.

Systematic Review of the Clinical and Experimental Research Assessing the Effects of Craniosynostosis on the Brain.

Although neurocognitive impairment has been considered as the main argument for the surgical treatment of craniosynostosis (CS), recent studies reported subtle deficits in neurological function even in operated patients. However, the cause of these deficits remains poorly understood. This systematic review sought to examine the impact of CS on the brain microstructure, mainly on functional connectivity, and comprehensively summarize the clinical and experimental research available on this topic. A systematic review was performed considering the publications of the last 20 years in PubMed and Web of Science, including relevant human and animal studies of the types of brain-microstructure disturbances in CS. Among the 560 papers identified, 11 were selected for analysis. Seven of those were conducted in humans and 4 in animal models. Resting-state functional magnetic resonance imaging, task-based magnetic resonance imaging, and diffusion tensor imaging were the main instruments used to investigate brain connectivity in humans. The main findings were increased connectivity of the posterior segment of cingulum gyri, reduced interconnectivity of the frontal lobes, and reduced diffusivity on diffusion tensor imaging, which were associated with hyperactivity behaviors and poorer performance on neurocognitive tests. Conversely, despite the lack of evidence of brain dysfunction in animal studies, they reported a tendency toward the development of hyperactive behaviors and impairment of neurocognitive function. Skull restriction caused by CS apparently chronically increases the intracranial pressure and produces white matter injuries. The current evidence supports the contention that an early surgical approach could minimize brain-connectivity impairment in this context.

Brachycephalic obstructive airway syndrome: much more than a surgical problem.

Brachycephalic obstructive airway syndrome (BOAS) is a chronic, lifelong, debilitating, primarily obstructive airway disease which adversely affects the quality of life of many popular dog breeds. Respiratory restriction in bulldog breeds, pugs and Boston terriers frequently co-exist with pathologies of the gastrointestinal tract. In addition, many brachycephalic dogs that appear clinically normal are, in fact suffering from chronic hypoxia and its systemic consequences. Concurrent gastroesophageal reflux-associated conditions, sleep disorders and systemic hypertension further impact the welfare of affected dogs. Acceptance of BOAS and associated clinical signs as being 'normal for the breed' is common amongst owners. While surgical correction of the upper airway is the mainstay of treatment, the provision of subsequent, frequently lifelong medical management is equally important for the maintenance of an acceptable quality of life, at least for some affected patients. Here we review the current knowledge concerning brachycephaly, combine it with shared clinical experience in the management of this debilitating condition, and discuss ethical considerations and the responsibility of veterinarians to contribute public education and to support appropriate breed standards for animals under our care.

Diploic vein morphology in normal and craniosynostotic adult human skulls.

Diploic veins (DV) run within the cranial diploe, where they leave channels that can be studied in osteological samples. This study investigates overall DV variability in human adults and the effects of sex, age, cranial dimensions, and dysmorphogenesis associated with craniosynostosis (CS). The morphology of macroscopic diploic channels was analyzed in a set of the qualitative and quantitative variables in computed tomography-images of crania of anatomically normal and craniosynostotic adult individuals. Macroscopic diploic channels occur most frequently in the frontal and parietal bones, often with a bilaterally symmetrical pattern. DV-features (especially DV-pattern) are characterized by high individual diversity. On average, there are 5.4 ± 3.5 large macroscopic channels (with diameters >1 mm) per individual, with a mean diameter of 1.7 ± 0.4 mm. Age and sex have minor effects on DV, and cranial proportions significantly influence DV only in CS skulls. CS is associated with changes in the DV numbers, distributions, and diameters. Craniosynostotic skulls, especially brachycephalic skulls, generally present smaller DV diameters, and dolichocephalic skulls display increased number of frontal DV. CS, associated with altered cranial dimensions, suture imbalance, increased intracranial pressure, and with changes of the endocranial craniovascular system, significantly also affects the macroscopic morphology of DV in adults, in terms of both structural (topological redistribution) and functional factors. The research on craniovascular morphology and CS may be of interest in biological anthropology, paleopathology, medicine (e.g., surgical planning), but also in zoology and paleontology.

[Assessment of clinical signs of brachycephalic obstructive airway syndrome and other breed-specific diseases in pug dogs - an online survey]. / Einschätzung von Symptomen des brachyzephalen obstruktiven Atemwegssyndroms und anderen rassetypischen Erkrankungen bei Mops-Hunden ­ eine Online-Umfrage.

OBJECTIVE: The aim of the study was to investigate the awareness for the breed-related brachycephalic obstructive airway syndrome (BOAS) and the occurrence of other breed-typical diseases within the framework of an online survey for pug owners. MATERIAL AND METHODS: A digital questionnaire for owners was created, distributed via social media and subsequently evaluated. RESULTS: The questionnaire was completed by 1220 pug owners. According to the owners, 32 % (344/1073) of the animals that did not undergo airway dilatation surgery show slight and 3 % (34/1073) show distinct breathing sounds when at rest. 86 % (326/378) of the owners perceive these breathing sounds as "normal, breed-specific" and 14 % (51/378) consider them as sign of "disease". 20 % (210/1073) of the animals are considered "somewhat" and 5 % (57/1073) "frequently tired and quickly short of breath" after a small amount of time. 24 % (245/1220) of all animals suffer from ocular diseases, 10 % (122/1220) from skin diseases and 11 % (134/1220) from spinal diseases, among others. CONCLUSION: The survey shows that with 67 % (814/1220) more than half of the pug owners perceive clinical signs of BOAS and/or other breed-specific diseases in their animals, however, a large proportion consider these as being non-problematic. CLINICAL RELEVANCE: The present study reveals that the animals' clinical limitations associated with brachycephaly are oftentimes not perceived as being pathologic and are hence underestimated by the owners.

Intrafamilial variability in six family members with ERF-related craniosynostosis syndrome type 4.

ERF-related craniosynostosis syndrome type 4 (CRS4, OMIM #600775) is a rare autosomal dominant malformation syndrome, caused by pathogenic variants in the ERF gene and characterized by craniosynostosis, developmental delay, and dysmorphic features such as hypertelorism, exophthalmos, depressed nasal bridge, and retrognathia. So far, there are mostly individual reports and only a few descriptions of families with more than two affected patients, allowing statements about the penetrance of a certain variant and its variability only to a limited extent. In this study, we report an in-depth analysis of the clinical course of six family members from three generations with the novel heterozygous nonsense variant c.286A>T (p.Lys96*) in the ERF gene. At the time of examination, all of the six patients showed mild dysmorphic features and brachydactyly, five were overweight/obese and had delayed speech development, and four were short in stature. Hyperactivity, a short concentration span and a history of learning difficulties were found in half of the affected family members. To this day, none of the patients developed increased intracranial hypertension that would require surgical intervention. This work provides further information on the expressive variability of an ERF variant in six members of one family and focuses on the need for close neuropediatric surveillance.

Intracranial Volumes of Healthy Children in the First 3 Years of Life: An Analysis of 270 Magnetic Resonance Imaging Scans.

BACKGROUND: There is a paucity of data on normal intracranial volumes for healthy children during the first few years of life, when cranial growth velocity is greatest. The aim of this study was to generate a normative predictive model of intracranial volumes based on brain magnetic resonance imaging from a large sample of healthy children to serve as a reference tool for future studies on craniosynostosis. METHODS: Structural magnetic resonance imaging data for healthy children up to 3 years of age was acquired from the National Institutes of Health Pediatric MRI Data Repository. Intracranial volumes were calculated using T1-weighted scans with FreeSurfer (version 6.0.0). Mean intracranial volumes were calculated and best-fit logarithmic curves were generated. Results were compared to previously published intracranial volume curves. RESULTS: Two-hundred seventy magnetic resonance imaging scans were available: 118 were collected in the first year of life, 97 were collected between years 1 and 2, and 55 were collected between years 2 and 3. A best-fit logarithmic growth curve was generated for male and female patients. The authors' regression models showed that male patients had significantly greater intracranial volumes than female patients after 1 month of age. Predicted intracranial volumes were also greater in male and female patients in the first 6 months of life as compared to previously published intracranial volume curves. CONCLUSIONS: To the authors' knowledge, this is the largest series of demographically representative magnetic resonance imaging-based intracranial volumes for children aged 3 years and younger. The model generated in this study can be used by investigators as a reference for evaluating craniosynostosis patients.

The outcome of targeted NGS screening in patients with syndromic forms of sagittal and pansynostosis - IL11RA is an emerging core-gene for pansynostosis.

Here, we have studied the prevalence and spectrum of genetic alterations in syndromic forms of sagittal and pansynostosis. Eighteen patients with sagittal synostosis (isolated or combined with other synostoses, except coronal) or pansynostosis were phenotypically assessed by retrospective analysis of medical records, three-dimensional computed tomography skull reconstructions, and registered photos. Patient DNAs were analyzed using a targeted next-generation sequencing (NGS) panel including 63 craniosynostosis (CS) related genes. Pathogenic and likely pathogenic variants were found in 72% of the cases, mainly affecting FGFR2, TWIST1, IL11RA, and SKI. Two patients that were negative at NGS screening - one with a supernumerary marker chromosome with duplication of 15q25.2q26.3 and one with a pathogenic PHEX variant - were identified using microarray and single gene analysis, respectively. The overall diagnostic rate in the cohort was thus 83%. We identified two novel likely pathogenic variants in FGFR2 (NM_022970.3: c.811_812delGGinsCC, p.Gly271Pro) and TWIST1 (NM_000474.3: c.476T > A, p.Leu159His), and a novel variant of unclear phenotypic significance in RUNX2 (NM_001024630.3: c.340G > A, p.Val114Ile) which could suggest a modulatory effect. Notably, we also identified three new patients with pansynostosis and a Crouzon-like phenotype with IL11RA mutation. Targeted NGS using a broad panel of CS-related genes is a simple and powerful tool for detecting pathogenic mutations in patients with syndromic forms of CS and multiple suture involvement, in particular pansynostosis. Our results provide additional evidence of an association between pansynostosis and IL11RA, an emerging core gene for autosomal recessive CS.

Genetic Influence on Neurodevelopment in Nonsyndromic Craniosynostosis.

BACKGROUND: Nonsyndromic craniosynostosis is one of the most common anomalies treated by craniofacial surgeons. Despite optimal surgical management, nearly half of affected children have subtle neurocognitive deficits. Whereas timing and type of surgical intervention have been studied, the possibility of genetic influence on neurodevelopment in nonsyndromic craniosynostosis patients remains unexplored. METHODS: The authors performed whole-exome sequencing for 404 case-parent trios with sporadic nonsyndromic craniosynostosis. Statistical analyses were performed to assess the burden of de novo mutations in cases compared to both expectation and 1789 healthy control trios. Individuals with and without each mutation class were analyzed, and the presence or absence of various types of neurodevelopmental delay were recorded alongside demographic information. RESULTS: The authors identified a highly significant burden of damaging de novo mutations in mutation-intolerant [probability of loss of function intolerance (pLI) >0.9] genes in nonsyndromic craniosynostosis probands (p = 5.9 × 10-6). Children with these mutations had a two-fold higher incidence of neurodevelopmental delay (p = 0.001) and a more than 20-fold greater incidence of intellectual disability (p = 7.2 × 10-7), and were 3.6-fold more likely to have delays that persisted past 5 years of age (p = 4.4 × 10-4) in comparison with children with nonsyndromic craniosynostosis without these mutations. Transmitted loss of function mutations in high-pLI genes also conferred a 1.9-fold greater risk of neurodevelopmental delay (p = 4.5 ×10-4). CONCLUSIONS: These findings implicate genetic lesions concurrently impacting neurodevelopment and cranial morphogenesis in the pathoetiology of nonsyndromic craniosynostosis and identify a strong genetic influence on neurodevelopmental outcomes in affected children. These findings may eventually prove useful in determining which children with nonsyndromic craniosynostosis are most likely to benefit from surgical intervention. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

The growth and expansion of meningeal lymphatic networks are affected in craniosynostosis.

Skull malformations are associated with vascular anomalies that can impair fluid balance in the central nervous system. We previously reported that humans with craniosynostosis and mutations in TWIST1 have dural venous sinus malformations. It is still unknown whether meningeal lymphatic networks, which are patterned alongside the venous sinuses, are also affected. We now show that the growth and expansion of meningeal lymphatics are perturbed in Twist1 craniosynostosis models. Changes to the local meningeal environment, including hypoplastic dura and venous malformations, affect the ability of lymphatic networks to sprout and remodel. Dorsal networks along the transverse sinus are hypoplastic with reduced branching. By contrast, basal networks closer to the skull base are more variably affected, showing exuberant growth in some animals, suggesting they are compensating for vessel loss in dorsal networks. Injecting a molecular tracer into cerebrospinal fluid reveals significantly less drainage to the deep cervical lymph nodes, which is indicative of impaired lymphatic function. Collectively, our results show that meningeal lymphatic networks are affected in craniosynostosis, suggesting that the clearance of ß-amyloid and waste from the central nervous system may be impeded.