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Adult-onset Niemann–Pick disease type C (NPC) is an infrequent presentation of a rare neurovisceral lysosomal lipid storage disorder caused by autosomal recessive mutations in NPC1 (∼95%) or NPC2 (∼5%). Our patient was diagnosed at age 33 when he presented with a 10-yr history of difficulties in judgment, concentration, speech, and coordination. A history of transient neonatal jaundice and splenomegaly with bone marrow biopsy suggesting a lipid storage disorder pointed to NPC; biochemical (“variant” level cholesterol esterification) and ultrastructural studies in adulthood confirmed the diagnosis. Genetic testing revealed two different missense mutations in the NPC1 gene—V950M and N1156S. Symptoms progressed over >20 yr to severe ataxia and spasticity, dementia, and dysphagia with aspiration leading to death. Brain autopsy revealed mild atrophy of the cerebrum and cerebellum. Microscopic examination showed diffuse gray matter deposition of balloon neurons, mild white matter loss, extensive cerebellar Purkinje cell loss with numerous “empty baskets,” and neurofibrillary tangles predominantly in the hippocampal formation and transentorhinal cortex. We performed whole-genome sequencing to examine whether the patient harbored variants outside of the NPC1 locus that could have contributed to his late-onset phenotype. We focused analysis on genetic modifiers in pathways related to lipid metabolism, longevity, and neurodegenerative disease. We identified no rare coding variants in any of the pathways examined nor was the patient enriched for genome-wide association study (GWAS) single-nucleotide polymorphisms (SNPs) associated with longevity or altered lipid metabolism. In light of these findings, this case provides support for the V950M variant being sufficient for adult-onset NPC disease.

Objectives To assess the utility of asking for presence of progressive forgetfulness (PF) prior to administering the Abbreviated Mental Test (AMT) when screening for dementia in the community-dwelling elderly Chinese. Methods This was a two-phased community-based survey of elderly subjects (≥50 yrs). In phase one, subjects were asked for PF and administered the AMT. Those having PF or an impaired AMT performance were evaluated clinically for dementia in phase two, which also included a randomly selected sample of 35 subjects with no PF and who passed the AMT. Results 2566 subjects completed phase one interview, of which 128 subjects completed phase two. Overall prevalence of PF, failed AMT and dementia were 2.4%, 2.2%, 0.9% respectively. The sensitivity of PF for dementia was 95.7% with specificity of 45.1%. PF was significantly associated with depression in the young-old (50–74 yrs) but not in the old-old (≥75 yrs) age group, after adjusting for dementia. The probability of subjects (%) in the four possible diagnostic combinations of PF and AMT in the young-old and (old-old) age groups were 0 (0.06) in the no PF/ passed AMT, 0 (0.44) in the no PF/failed AMT, 0.23 (9.2) in the PF/passed AMT and 3.6 (43) in the PF/failed AMT groups. Conclusion In screening for the most common dementias, AMT administration is not required if PF is absent. AMT is also of no added utility for diagnosing dementia in older subjects with PF. Younger subjects with PF should be closely evaluated for depression especially if they passed the AMT, and dementia, if they failed the AMT. Copyright © 2006 John Wiley & Sons, Ltd.

When Joseph Haydn died in 1809, the 77-year-old man was the most famous composer of his time. With increasing age, he complained of progressive forgetfulness preventing him from composing for about

Alzheimer's disease is a costly illness affecting large numbers of older Americans, and its prevalence is increasing. The major symptom of the condition is progressive forgetfulness. The course is variable, depending on which areas of the brain are affected earliest and most severely. In diagnosing Alzheimer's disease, it is important to rule out other types of dementia that may be treatable, as well as systemic and affective disorders and other brain diseases. The Mini-Mental State Examination and the category fluency test are often diagnostically useful. There is no evidence that any of the therapeutic agents studied so far are of much value, but pharmacologic agents can be useful in treating the depression, psychoses, and anxiety that may accompany cognitive decline. Patients cared for at home need a structured, orderly environment that has been modified for their safety.