The Brain Health Assessment for Detecting and Diagnosing Neurocognitive Disorders.

BACKGROUND/OBJECTIVES: Brief cognitive screens lack the sensitivity to detect mild cognitive impairment (MCI) or support differential diagnoses. The objective of this study was to validate the 10-minute, tablet-based University of California, San Francisco (UCSF) Brain Health Assessment (BHA) to overcome these limitations. DESIGN: Cross-sectional. SETTING: UCSF Memory and Aging Center. PARTICIPANTS: Older adults (N = 347) (neurologically healthy controls (n = 185), and individuals diagnosed with MCI (n = 99), dementia (n = 42), and as normal with concerns (n = 21)). MEASUREMENTS: The BHA includes subtests of memory, executive function and speed, visuospatial skills, and language and an optional informant survey. Participants completed the Montreal Cognitive Assessment (MoCA) and criterion-standard neuropsychological tests. Standardized structural 3T brain magnetic resonance imaging was performed in 145 participants. RESULTS: At a fixed 85% specificity rate, the BHA had 100% sensitivity to dementia and 84% to MCI; the MoCA had 75% sensitivity to dementia and 25% to MCI. The BHA had 83% sensitivity to MCI likely due to AD and 88% to MCI unlikely due to AD, and the MoCA had 58% sensitivity to MCI likely AD and 24% to MCI unlikely AD. The BHA subtests demonstrated moderate to high correlations with the criterion-standard tests from their respective cognitive domains. Memory test performance correlated with medial temporal lobe volumes; executive and speed with frontal, parietal, and basal ganglia volumes; and visuospatial with right parietal volumes. CONCLUSION: The BHA had excellent combined sensitivity and specificity to detect dementia and MCI, including MCI due to diverse etiologies. The subtests provide efficient, valid measures of neurocognition that are critical in making a differential diagnosis.

Mutations in FLVCR1 cause posterior column ataxia and retinitis pigmentosa.

The study of inherited retinal diseases has advanced our knowledge of the cellular and molecular mechanisms involved in sensory neural signaling. Dysfunction of two specific sensory modalities, vision and proprioception, characterizes the phenotype of the rare, autosomal-recessive disorder posterior column ataxia and retinitis pigmentosa (PCARP). Using targeted DNA capture and high-throughput sequencing, we analyzed the entire 4.2 Mb candidate sequence on chromosome 1q32 to find the gene mutated in PCARP in a single family. Employing comprehensive bioinformatic analysis and filtering, we identified a single-nucleotide coding variant in the feline leukemia virus subgroup C cellular receptor 1 (FLVCR1), a gene encoding a heme-transporter protein. Sanger sequencing confirmed the FLVCR1 mutation in this family and identified different homozygous missense mutations located within the protein's transmembrane channel segment in two other unrelated families with PCARP. To determine whether the selective pathologic features of PCARP correlated with FLVCR1 expression, we examined wild-type mouse Flvcr1 mRNA levels in the posterior column of the spinal cord and the retina via quantitative real-time reverse-transcriptase PCR. The Flvcr1 mRNA levels were most abundant in the retina, followed by the posterior column of the spinal cord and other brain regions. These results suggest that aberrant FLVCR1 causes a selective degeneration of a subpopulation of neurons in the retina and the posterior columns of the spinal cord via dysregulation of heme or iron homeostasis. This finding broadens the molecular basis of sensory neural signaling to include common mechanisms that involve proprioception and vision.

HS1-BP3 gene variant is common in familial essential tremor.

Essential tremor (ET) is a movement disorder characterized by a postural or kinetic tremor of the hands, head, or voice. It is typically a familial condition and affects 1% to 4% of the general population. The trait is genetically linked to chromosome 2p in some families. A variant (828C-->G) in exon 7 of the hematopoietic-specific protein 1 binding protein 3 gene (HS1-BP3) on chromosome 2p recently has been found to segregate with ET in 2 families. To determine the frequency of this variant in a larger series, we studied patients with ET, Parkinson disease (PD), and controls without tremor. Affected singletons representing 73 families from the United States with dominantly inherited ET, 35 individuals with PD, and 304 healthy controls older than age 60 were tested for the 828C-->G variant in exon 7 of the HS1-BP3 gene by a BseYI restriction enzyme digest of the polymerase chain reaction product. Heterozygous carriers of the mutant allele were identified in 12 individuals with ET (16.4%) and in 1 individual with PD and postural tremor (3%). All of the healthy controls (608 chromosomes) were homozygous for the wild-type allele. The 828C-->G genetic variant in the HS1-BP3 gene occurs relatively frequently in subjects with ET. The variant may also be found in some individuals with PD and postural tremor. The HS1-BP3 gene plays a putative role in regulating catecholamine and serotonin metabolism, but the functional consequences of the amino acid substitution (A265G) caused by this genetic variant is unknown.

A mutation in a novel ATP-dependent Lon protease gene in a kindred with mild mental retardation.

BACKGROUND: Identifying the genetic factors that contribute to memory and learning is limited by the complexity of brain development and the lack of suitable human models for mild disorders of cognition. METHODS: Previously, a disease locus was mapped for a mild type of nonsyndromic mental retardation (IQ between 50 and 70) to a 4.2-MB interval on chromosome 3p25-pter in a large kindred. The genes and transcripts within the candidate region were systematically analyzed for mutations by single-strand polymorphism analysis and DNA sequencing. RESULTS: A nonsense mutation causing a premature stop codon in a novel gene (cereblon; CRBN) was identified that encodes for an ATP-dependent Lon protease. The predicted protein sequence is highly conserved across species, and it belongs to a family of proteins that selectively degrade short-lived polypeptides and regulate mitochondrial replication and transcription. One member of the Lon-containing protein family is regionally expressed in the human hippocampus, an important neuroanatomic region that is involved in long-term potentiation and learning. The mutation in the CRBN gene described interrupts an N-myristoylation site and eliminates a casein kinase II phosphorylation site at the C terminus. CONCLUSIONS: A gene on chromosome 3p that is associated with mild mental retardation in a large kindred is reported. This finding implicates a role for the ATP-dependent degradation of proteins in memory and learning.