Luis D. Medina

Biochemical markers in persons with preclinical familial Alzheimer disease.

Background: Persons at risk for familial Alzheimer disease (FAD) provide a model in which biomarkers can be studied in presymptomatic disease. Methods: Twenty-one subjects at risk for presenilin-1 (n = 17) or amyloid precursor protein (n = 4) mutations underwent evaluation with the Clinical Dementia Rating (CDR) scale. We obtained plasma from all subjects and CSF from 11. Plasma (Aβ40, Aβ42, F2-isoprostanes) and CSF (F2-isoprostanes, t-tau, p-tau181, Aβ40, Aβ42, and Aβ42/Aβ40 ratio) levels were compared between FAD mutation carriers (MCs) and noncarriers (NCs). Results: Plasma Aβ42 levels (25.1 pM vs 15.5 pM, p = 0.031) and the ratio of Aβ42/Aβ40 (0.16 vs 0.11, p = 0.045) were higher in presymptomatic MCs. Among MCs, those with CDR scores of 0.5 had lower plasma Aβ42 levels than those with CDR scores of 0 (14.1 pM vs 25.1, p = 0.02). The ratio of Aβ42 to Aβ40 was also reduced in the CSF (0.08 vs 0.15, p = 0.046) of nondemented MCs compared to NCs. Total CSF tau and p-tau181 levels were elevated in presymptomatic FAD MCs. CSF levels of F2-isoprostanes were also elevated in MCs (n = 7, 48.6 pg/mL) compared to NCs (n = 4, 21.6 pg/mL, p = 0.031). Conclusions: Our data indicate that Aβ42 is elevated in plasma in familial Alzheimer disease (FAD) mutation carriers (MCs) and suggests that this level may decrease with disease progression prior to the development of overt dementia. We also demonstrated that the ratio of Aβ42 to Aβ40 was reduced in the CSF of nondemented MCs and that elevations of t-tau and p-tau181 are sensitive indicators of presymptomatic disease. Our finding of elevated F2-isoprostane levels in the CSF of preclinical FAD MCs suggests that oxidative stress occurs downstream to mismetabolism of amyloid precursor protein.

The A431E mutation in PSEN1 causing Familial Alzheimer's Disease originating in Jalisco State, Mexico: An additional fifteen families

Nine families with autosomal dominant Alzheimer’s disease (AD), all of whom had the Ala431Glu substitution in the PSEN1 gene and came from Jalisco State in Mexico, have been previously reported. As they shared highly polymorphic flanking dinucleotide marker alleles, this strongly suggests that this mutation arose from a common founder. In the current letter, we expand this observation by describing an additional 15 independent families with the Ala431Glu substitution in the PSEN1 gene and conclude that this mutation is not an uncommon cause of early-onset autosomal dominant AD in persons of Mexican origin.

Regional brain volume differences in symptomatic and presymptomatic carriers of familial Alzheimer's disease mutations

Background Mutations in the presenilin (PSEN1, PSEN2) and amyloid precursor protein (APP) genes cause familial Alzheimers disease (FAD) in a nearly fully penetrant, autosomal dominant manner, providing a unique opportunity to study presymptomatic individuals who can be predicted to develop Alzheimers disease (AD) with essentially 100% certainty. Using tensor-based morphometry (TBM), we examined brain volume differences between presymptomatic and symptomatic FAD mutation carriers and non-carrier (NC) relatives. Methods Twenty-five mutation carriers and 10 NC relatives underwent brain MRI and clinical assessment. Four mutation carriers had dementia (MUT-Dem), 12 had amnestic mild cognitive impairment (MUT-aMCI) and nine were cognitively normal (MUT-Norm). TBM brain volume maps of MUT-Norm, MUT-aMCI and MUT-Dem subjects were compared to NC subjects. Results MUT-Norm subjects exhibited significantly smaller volumes in the thalamus, caudate and putamen. MUT-aMCI subjects had smaller volumes in the thalamus, splenium and pons, but not in the caudate or putamen. MUT-Dem subjects demonstrated smaller volumes in temporal, parietal and left frontal regions. As non-demented carriers approached the expected age of dementia diagnosis, this was associated with larger ventricular and caudate volumes and a trend towards smaller temporal lobe volume. Conclusions Cognitively intact FAD mutation carriers had lower thalamic, caudate and putamen volumes, and we found preliminary evidence for increasing caudate size during the predementia stage. These regions may be affected earliest during prodromal stages of FAD, while cortical atrophy may occur in later stages, when carriers show cognitive deficits. Further studies of this population will help us understand the progression of neurobiological changes in AD.

Cerebrospinal Fluid Biomarkers and Proximity to Diagnosis in Preclinical Familial Alzheimer’s Disease

Background/Aims: Biological markers of utility in tracking Alzheimer’s disease (AD) during the presymptomatic prodromal phase are important for prevention studies. Changes in cerebrospinal fluid (CSF) levels of 42-amino-acid β-amyloid (Aβ42), total tau protein (t-tau) and phosphorylated tau at residue 181 (p-tau181) during this state are incompletely characterized. Methods: We measured CSF markers in 13 carriers of familial AD (FAD) mutations that are fully penetrant for causing AD (PSEN1 and APP) and in 5 non-mutation-carrying family members. Results: Even among the entirely presymptomatic mutation carriers (n = 9), Aβ42 was diminished (388.7 vs. 618.4 pg/ml, p = 0.004), and t-tau (138.5 vs. 50.5 pg/ml, p = 0.002) and p-tau181 (71.7 vs. 24.6 pg/ml, p = 0.003) were elevated. There was a negative correlation between Aβ42 levels and age relative to the family-specific age of dementia diagnosis. Conclusions: Our data are consistent with a decline in CSF Aβ42 levels occurring at least 20 years prior to clinical dementia in FAD.

Biochemical, neuropathological, and neuroimaging characteristics of early-onset Alzheimer’s disease due to a novel PSEN1 mutation

Familial Alzheimers disease (AD) due to PSEN1 mutations provides an opportunity to examine AD biomarkers in persons in whom the diagnosis is certain. We describe a 55 year-old woman with clinically probable AD and a novel PSEN1 mutation who underwent genetic, clinical, biochemical and magnetic resonance and nuclear imaging assessments. We also describe neuropathological findings in her similarly affected brother. Neuropsychological testing confirmed deficits in memory, visuospatial and language function. CSF t-tau and p-tau181 were markedly elevated and Aβ(42) levels reduced. FDG-PET revealed hypometabolism in the left parietotemporal cortex. FDDNP-PET showed increased binding of tracer in medial temporal and parietal lobes and in the head of the caudate and anterior putamen bilaterally. Neuropathological examination of her brother showed the typical findings of AD and the striatum demonstrated amyloid pathology and marked neurofibrillary pathology beyond that typically seen in late-onset AD. A novel S212Y substitution in PSEN1 was present in the index patient and her affected brother but not in an older unaffected sister. An in vitro assay in which the S212Y mutation was introduced in cell culture confirmed that it was associated with increased production of Aβ(42). We describe biochemical, imaging, and neuropathological changes in a pedigree with a novel PSEN1 mutation. This allows us to validate the pathogenicity of this mutation and the indices used to assess AD.

Effects of Risk Genes on BOLD Activation in Presymptomatic Carriers of Familial Alzheimer's Disease Mutations during a Novelty Encoding Task

Prior functional magnetic resonance imaging (fMRI) studies have found increased activity-related blood oxygen level-dependent (BOLD) signal in cognitively normal persons at genetic risk for Alzheimers disease (AD). This has been interpreted as a compensatory response to incipient AD pathology. We studied the effects of fully penetrant familial Alzheimers disease (FAD) mutations and apolipoprotein E (APOE) genotype on BOLD fMRI during a novelty encoding task in presymptomatic subjects. Twenty-three Mexican or Mexican-American persons at-risk for inheriting FAD mutations performed a block design novelty encoding task, and activation exhibited by FAD mutation carriers (MCs) was contrasted with that of noncarriers (NCs) and among APOE genotype groups. FAD MCs (n = 14) showed decreased BOLD activation in the anterior cingulate gyrus relative to 9 NCs. No increased activation was seen in MCs relative to NCs. Four APOE ε3/4 carriers demonstrated increased BOLD signal compared with 14 ε3/3 carriers in the occipital and perisylvian cortices bilaterally. There were no areas where ε3/3 carriers activated more than ε3/4 carriers. Our findings of increased fMRI activation associated with APOE genotype but not with FAD mutations suggest that APOE exerts an effect on the BOLD signal that is not readily explained as a compensatory phenomenon.

Cortical and hippocampal atrophy in patients with autosomal dominant familial Alzheimer's disease.

Background: Both familial and sporadic Alzheimer’s disease (AD) result in progressive cortical and subcortical atrophy. Familial autosomal dominant AD (FAD) allows us to study AD brain changes presymptomatically. Methods: 33 subjects at risk for FAD (25 for PSEN1 and 8 for APP mutations; 22 mutation carriers and 11 controls) and 3 demented PSEN1 mutation carriers underwent T1-weighted MPRAGE 1.5T MRI. Using the hippocampal radial distance and cortical pattern matching techniques, we investigated the effects of carrier status and dementia diagnosis on cortical and hippocampal atrophy. All analyses were corrected for age and relative age (years to median age of disease onset in the family). Results: The dementia cases had pronounced cortical atrophy in the lateral and medial parietal, posterior cingulate and frontal cortices and hippocampal atrophy bilaterally relative to both nondemented carriers and controls. Nondemented carriers did not show significant cortical thinning or hippocampal atrophy relative to controls. Conclusions: FAD is associated with thinning of the posterior association and frontal cortices and hippocampal atrophy. Larger sample sizes may be necessary to reliably identify cortical atrophy in presymptomatic carriers.

The Thr354Ile substitution in PSEN1: Disease-causing mutation or polymorphism?

Alterations in the gene ( PSEN1 ) encoding for the presenilin-1 protein (PS1) are thought to cause early-onset familial Alzheimer disease (FAD) through altered γ-secretase cleavage of amyloid precursor protein, leading to a relative increase in the amount of β-amyloid protein-42 (Aβ42)1 produced. That this form of the protein aggregates more readily than the more abundant Aβ40 species and its early presence in the amyloid plaques characteristic of the illness have provided support for the “amyloid hypothesis” of AD pathogenesis. A few alterations in the PSEN1 gene associated with AD occur in the portion of the gene coding for the cytoplasmic loop domain.2 The function of this portion of the protein remains unclear as deletion of the hydrophilic cytoplasmic domain from residues 304 to 371 has no effect on Aβ42 production.3 We report a case that raises the question as to whether alterations in this portion of PS1 consistently cause early-onset FAD. A 46-year-old man presented with cognitive decline over 5 …

Increased prevalence of significant recurrent headache in preclinical familial Alzheimer's disease mutation carriers.

Background/Aims: A previous study found a high prevalence of headaches in persons with familial Alzheimer’s disease (FAD) due to a PSEN1 mutation. In our study we compared the prevalence of headaches between nondemented FAD mutation carriers (MCs) and non-mutation-carrying controls (NCs). Methods: A headache questionnaire that assessed the prevalence of significant headaches and diagnosis of migraine and aura by ICHD-2 criteria was administered to 27 individuals at risk for FAD. Frequency of significant headaches, migraine, and aura were compared between MCs and NCs by χ2 or Fisher’s exact tests. Results: Twenty-three subjects were at risk for PSEN1 mutations and 4 for an APP substitution. The majority of subjects were female (23/27). MCs were more likely to report significant recurrent headache than NCs (67 vs. 25%, p = 0.031). Forty percent of MCs had headaches that met criteria for migraine whereas 17% of NCs met such criteria. The tendency for a higher prevalence of headaches in MCs held for different PSEN1 and APP mutations but was not significant unless all families were combined. Conclusions: In this population, headache was more common in nondemented FAD MCs than NCs. Possible mechanisms for this include cerebral inflammation, aberrant processing of Notch3, or disrupted intracellular calcium regulation.

Memory performance and fMRI signal in presymptomatic familial Alzheimer's disease

Rare autosomal dominant mutations result in familial Alzheimers disease (FAD) with a relatively consistent age of onset within families. This provides an estimate of years until disease onset (relative age) in mutation carriers. Increased AD risk has been associated with differences in functional magnetic resonance imaging (fMRI) activity during memory tasks, but most of these studies have focused on possession of apolipoprotein E allele 4 (APOE4), a risk factor, but not causative variant, of late‐onset AD. Evaluation of fMRI activity in presymptomatic FAD mutation carriers versus noncarriers provides insight into preclinical changes in those who will certainly develop AD in a prescribed period of time. Adults from FAD mutation‐carrying families (nine mutation carriers, eight noncarriers) underwent fMRI scanning while performing a memory task. We examined fMRI signal differences between carriers and noncarriers, and how signal related to fMRI task performance within mutation status group, controlling for relative age and education. Mutation noncarriers had greater retrieval period activity than carriers in several AD‐relevant regions, including the left hippocampus. Better performing noncarriers showed greater encoding period activity including in the parahippocampal gyrus. Poorer performing carriers showed greater retrieval period signal, including in the frontal and temporal lobes, suggesting underlying pathological processes. Hum Brain Mapp 34:3308–3319, 2013.