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Objective Previous studies suggest that the brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) polymorphism may influence symptom onset in Alzheimer's disease (AD). Our recent cross-sectional findings suggest that Met66 may influence clinical expression in dominantly inherited AD (DIAD) through its effects on tau. However, it remains unclear whether carriage of Met66 in DIAD results in faster increases in cerebrospinal fluid (CSF) tau and ptau181 , and whether these increases are associated with accelerated brain volume loss and memory decline. Methods A total of 211 subjects (101 mutation noncarriers, 110 mutation carriers), who were cognitively normal, as defined by a Clinical Dementia Rating global score of 0, completed assessments of cognitive function, neuroimaging, and CSF sampling over 3.5 years as part of the Dominantly Inherited Alzheimer's Network. Results In mutation carriers, Met66 carriers showed faster memory decline (4×), hippocampal volume loss (16×), and CSF tau and ptau181 increases (6×) than Val66 homozygotes. BDNF did not influence rates of cortical β-amyloid accumulation or change in CSF Aβ42 levels in mutation carriers. In mutation noncarriers, BDNF genotype had no effect on change in cognition, brain volume, cortical β-amyloid accumulation, or change in any CSF measures of tau, ptau181 , and CSF Aβ42 . Interpretation As in sporadic AD, the deleterious effects of β-amyloid on cognitive function, brain volume loss, and CSF tau in DIAD mutation carriers are less in Val66 homozygotes. The BDNF Val66Met polymorphism should be considered as a potential moderator of clinical trial outcomes in current treatment and prevention trials in DIAD and sporadic AD. Ann Neurol 2018;84:424-435.

We used whole-exome sequencing to identify variants other than APOE associated with the rate of hippocampal atrophy in amnestic mild cognitive impairment. An in-silico predicted missense variant in REST (rs3796529) was found exclusively in subjects with slow hippocampal volume loss and validated using unbiased whole-brain analysis and meta-analysis across 5 independent cohorts. REST is a master regulator of neurogenesis and neuronal differentiation that has not been previously implicated in Alzheimer's disease. These findings nominate REST and its functional pathways as protective and illustrate the potential of combining next-generation sequencing with neuroimaging to discover novel disease mechanisms and potential therapeutic targets.

Naturally occurring antibodies directed against beta-amyloid (Abeta) were detected in intravenous immunoglobulin preparations. After intravenous immunoglobulin treatment in patients with different neurological diseases, total Abeta and Abeta(1-42) in the cerebrospinal fluid was reduced significantly compared with baseline values. In the serum, total Abeta levels increased after intravenous immunoglobulin treatment, whereas no significant change was observed in Abeta(1-42) levels. Antibodies against Abeta were found to be increased in the serum and cerebrospinal fluid after intravenous immunoglobulin treatment. This study provides evidence that intravenous immunoglobulin or purified Abeta antibodies may modify Abeta and Abeta(1-42) levels, suggesting potential utility as a therapy for Alzheimer disease.

Rapid-onset dystonia-parkinsonism (RPD) is an autosomal dominant movement disorder characterized by sudden onset of persistent dystonia and parkinsonism, generally during adolescence or early adulthood. Symptoms evolve over hours or days, and generally stabilize within a few weeks, with slow or no progression. Other features include little or no response to L-dopa, and low levels of homovanillic acid in the central nervous system. Neuroimaging studies indicate no degeneration of dopaminergic nerve terminals in RDP, suggesting that this disorder results from a functional deficit, as in dystonia, rather than neuronal loss, as in Parkinson's disease. We studied 81 members of two midwestern US families with RDP, 16 of whom exhibited classic features of RDP. We found significant evidence for linkage in these two families to markers on chromosome 19q13, with the highest multipoint LOD score at D19S198 (z = 5.77 at theta = 0.0). The flanking markers D19S587 and D19S900 define a candidate region of approximately 8 cM. Although RDP itself is a rare condition, it is important because it has clinical and biochemical similarities to both Parkinson's disease and dystonia. Identification of the genetic defect in RDP holds promise for understanding the underlying disease processes of both of these more common diseases.

alpha-1-Antichymotrypsin (ACT) is present in neuritic plaques in which it participates in the inflammatory cascade of Alzheimer's disease (AD). Reports of blood ACT levels in AD, and its usefulness as a disease biomarker, have been conflicting. In an effort to clarify this, we measured plasma ACT levels in 516 white subjects including 359 subjects with probable or possible AD, 44 subjects with other late-life dementias, and 113 nondemented people. Subjects with systemic inflammatory diseases or who were taking antiinflammatory medications were excluded. All patients underwent extensive medical and detailed neuropsychological examinations at the time their blood was drawn. We found that plasma ACT levels were elevated in AD patients compared with the control group (p = 0.01) and were associated with severity of AD dementia; there was a negative association with the Mattis Dementia Rating Scale (a global measure of cognition) and a positive association with the Clinical Dementia Rating Scale (a global functional assessment). These relationships remained significant after controlling for demographic and genetic variables. When AD subjects were stratified into subgroups by dementia severity, matched by age, education, and gender, increased serum ACT correlated with Clinical Dementia Rating Scale (p = 0.0041) or Mattis Dementia Rating Scale (p = 0.0031) scores. ACT measurements in cerebrospinal fluid from an additional 34 AD cases and 16 controls showed elevated levels (p = 0.02) in AD. There was a negative correlation (p = 0.037) between cerebrospinal fluid ACT levels and clinical severity as measured by the Mini-Mental State Examination. Our results demonstrate that peripheral ACT levels are elevated in AD, but not in dementias other than AD, and they increase with progression of AD dementia. Although not useful as a diagnostic biomarker, ACT may reflect disease severity and may be helpful as a within subject biomarker in interventions (particularly with antiinflammatory agents) directed at slowing or halting progression of disease.

Rapid-onset dystonia-parkinsonism (RDP) is characterized by sudden onset over hours to days of dystonia, dysphagia, dysarthria, and parkinsonism. RDP has been reported by our group in two apparently unrelated families. We now report analysis of cerebrospinal fluid metabolites of dopamine, norepinephrine, and serotonin for mild and severely affected individuals, known asymptomatic gene carriers, and at-risk individuals from both families with RDP. Levels of the dopamine metabolite homovanillic acid (HVA) were decreased in severely affected patients and in some asymptomatic gene carriers. HVA levels increased with treatment in some affected individuals, but this increase did not predict clinical response to carbidopa/levodopa. We suggest that a low HVA level is a biological marker with modest association to the diagnosis of RDP.

We sequenced the prion protein gene and studied the biochemical characteristics and the intracerebral distribution of protease-resistant prion protein with Western blot and immunohistochemistry in 19 cases of sporadic Creutzfeldt-Jakob disease. We identified four groups of subjects defined by the genotype at codon 129 of the prion protein gene, the site of a common methionine/valine polymorphism, and two types of protease-resistant prion proteins that differed in size and glycosylation. The four Creutzfeldt-Jakob disease groups showed distinct clinicopathological features that corresponded to previously described variants. The typical Creutzfeldt-Jakob disease phenotype or myoclonic variant and the Heidenhain variant were linked to methionine homozygosity at codon 129 and to "type 1" protease-resistant prion protein. The atypical and rarer variants such as that with dementia of long duration, the ataxic variant, and the variant with kuru plaques were linked to different genotypes at codon 129 and shared the "type 2" protease-resistant prion protein. Our data indicate that the sporadic form of Creutzfeldt-Jakob disease comprises a limited number of variants. The methionine/valine polymorphism at codon 129 of the prion protein gene and two types of protease-resistant prion proteins are the major determinants of these variants. These findings suggest the existence of prion strains in humans and provide the molecular basis for a novel classification of sporadic Creutzfeldt-Jakob disease.

As part of a community-based study of Alzheimer's disease (AD) in the African-American population age 65 and over, we have determined apolipoprotein E (Apo E) genotypes in 85 subjects (31 AD patients and 54 controls). The epsilon 4 allele of Apo E was strongly associated with AD in this population sample. The epsilon 4 allele frequency in AD patients was 40.3% compared with 13.9% in the control group, and 22.6% of the AD patients were homozygous for this allele compared with 3.7% of the control subjects (p = 0.01). This study extends the association of Apo E-epsilon 4 and AD to nonwhite populations and provides further evidence that the observed allelic association is biologically relevant.