John M. Ringman

Clinical and Biomarker Changes in Dominantly Inherited Alzheimer's Disease

BACKGROUND The order and magnitude of pathologic processes in Alzheimers disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimers disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease. METHODS In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participants age at baseline assessment and the parents age at the onset of symptoms of Alzheimers disease to calculate the estimated years from expected symptom onset (age of the participant minus parents age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes. RESULTS Concentrations of amyloid-beta (Aβ)(42) in the CSF appeared to decline 25 years before expected symptom onset. Aβ deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini-Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset. CONCLUSIONS We found that autosomal dominant Alzheimers disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimers disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimers disease. (Funded by the National Institute on Aging and others; DIAN ClinicalTrials.gov number, NCT00869817.).

A Potential Role of the Curry Spice Curcumin in Alzheimer’s Disease

There is substantial in-vitro data indicating that curcumin has antioxidant, anti-inflammatory, and anti-amyloid activity. In addition, studies in animal models of Alzheimers disease (AD) indicate a direct effect of curcumin in decreasing the amyloid pathology of AD. As the widespread use of curcumin as a food additive and relatively small short-term studies in humans suggest safety, curcumin is a promising agent in the treatment and/or prevention of AD. Nonetheless, important information regarding curcumin bioavailability, safety and tolerability, particularly in an elderly population is lacking. We are therefore performing a study of curcumin in patients with AD to gather this information in addition to data on the effect of curcumin on biomarkers of AD pathology.

Autosomal-dominant Alzheimer's disease: a review and proposal for the prevention of Alzheimer's disease

Autosomal-dominant Alzheimers disease has provided significant understanding of the pathophysiology of Alzheimers disease. The present review summarizes clinical, pathological, imaging, biochemical, and molecular studies of autosomal-dominant Alzheimers disease, highlighting the similarities and differences between the dominantly inherited form of Alzheimers disease and the more common sporadic form of Alzheimers disease. Current developments in autosomal-dominant Alzheimers disease are presented, including the international Dominantly Inherited Alzheimer Network and this networks initiative for clinical trials. Clinical trials in autosomal-dominant Alzheimers disease may test the amyloid hypothesis, determine the timing of treatment, and lead the way to Alzheimers disease prevention.

Frequency, risk factors, anatomy, and course of unilateral neglect in an acute stroke cohort

Objective: To delineate the frequency, course, risk factors, and neuroanatomy of hemispatial neglect in a large stroke cohort. Methods: One thousand two hundred eighty-one patients with acute stroke were enrolled in a multicenter trial of an anticoagulant. Presence and severity of neglect were assessed with the NIH Stroke Scale (NIHSS) neglect item, assessing tactile extinction and visuospatial neglect at entry, daily for 1 week, and at 3 months. Head CT scans were obtained on day 7, and infarct location and size were characterized. Results: Neglect was common at presentation, occurring in 43% of right brain-lesioned (RBL) patients and 20% of left brain-lesioned (LBL) patients (p < 0.001). At 3 months, neglect was present in 17% of RBL patients and in 5% of LBL patients (p < 0.001). In RBL patients, neglect was most frequently associated with lesions involving the (in descending order) temporal, parietal, frontal, occipital lobes, basal ganglia, and thalamus. Neglect was more common and persistent with cortical than with subcortical lesions. Increasing age was associated with increased risk of neglect in RBL patients, whereas gender and handedness did not significantly affect neglect frequency. Conclusions: This series confirms that hemispatial neglect may occur with damage to several supratentorial structures but is most common and persistent with lesions of the right temporoparietal cortex. Increasing age is associated with neglect, particularly after right brain lesions. Gender and handedness do not exert a marked effect on the likelihood of the occurrence of neglect.

Ineffective phagocytosis of amyloid-β by macrophages of Alzheimer's disease patients

The defective clearance of amyloid-beta (Abeta) in the brain of Alzheimers disease (AD) patients is unexplained. The immunohistochemical studies of the frontal lobe and hippocampus show perivascular and intraplaque infiltration by blood-borne macrophages containing intracellular Abeta but only inefficient clearance of beta deposits. Neurons and neuronal nuclei, respectively, express interleukin-1beta and the chemokine RANTES, which could induce the inflammatory cell infiltration. To clarify the pathophysiology ofbeta clearance, we examined Abeta phagocytosis by monocytes and macrophages isolated from the blood of age-matched patients and controls. Control monocytes display excellent differentiation into macrophages and intracellular phagocytosis of Abeta followed by beta degradation or export. AD monocytes show poor differentiation and only surface uptake of Abeta and suffer apoptosis. HLA DR and cyclooxygenase-2 are abnormally expressed on neutrophils and monocytes of AD patients. AD patients have higher levels of intracellular cytokines compared to controls. Thus Abeta clearance is not restricted to brain microglia and involves systemic innate immune responses. In AD, however, macrophage phagocytosis is defective, which may elicit compensatory response by the adaptive immune system.

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.

Innate immunity and transcription of MGAT-III and Toll-like receptors in Alzheimer's disease patients are improved by bisdemethoxycurcumin.

We have tested a hypothesis that the natural product curcuminoids, which has epidemiologic and experimental rationale for use in AD, may improve the innate immune system and increase amyloid-β (Aβ) clearance from the brain of patients with sporadic Alzheimers disease (AD). Macrophages of a majority of AD patients do not transport Aβ into endosomes and lysosomes, and AD monocytes do not efficiently clear Aβ from the sections of AD brain, although they phagocytize bacteria. In contrast, macrophages of normal subjects transport Aβ to endosomes and lysosomes, and monocytes of these subjects clear Aβ in AD brain sections. Upon Aβ stimulation, mononuclear cells of normal subjects up-regulate the transcription of β-1,4-mannosyl-glycoprotein 4-β-N-acetylglucosaminyltransferase (MGAT3) (P < 0.001) and other genes, including Toll like receptors (TLRs), whereas mononuclear cells of AD patients generally down-regulate these genes. Defective phagocytosis of Aβ may be related to down-regulation of MGAT3, as suggested by inhibition of phagocytosis by using MGAT3 siRNA and correlation analysis. Transcription of TLR3, bditTLR4, TLR5, bditTLR7, TLR8, TLR9, and TLR10 upon Aβ stimulation is severely depressed in mononuclear cells of AD patients in comparison to those of control subjects. In mononuclear cells of some AD patients, the curcuminoid compound bisdemethoxycurcumin may enhance defective phagocytosis of Aβ, the transcription of MGAT3 and TLRs, and the translation of TLR2–4. Thus, bisdemethoxycurcumin may correct immune defects of AD patients and provide a previously uncharacterized approach to AD immunotherapy.

Regional variability of imaging biomarkers in autosomal dominant Alzheimer’s disease

Significance Beta-amyloid plaque accumulation, glucose hypometabolism, and neuronal atrophy are hallmarks of Alzheimer’s disease. However, the regional ordering of these biomarkers prior to dementia remains untested. In a cohort with Alzheimer’s disease mutations, we performed an integrated whole-brain analysis of three major imaging techniques: amyloid PET, [18F]fluro-deoxyglucose PET, and structural MRI. We found that most gray-matter structures with amyloid plaques later have hypometabolism followed by atrophy. Critically, however, not all regions lose metabolic function, and not all regions atrophy, even when there is significant amyloid deposition. These regional disparities have important implications for clinical trials of disease-modifying therapies. Major imaging biomarkers of Alzheimer’s disease include amyloid deposition [imaged with [11C]Pittsburgh compound B (PiB) PET], altered glucose metabolism (imaged with [18F]fluro-deoxyglucose PET), and structural atrophy (imaged by MRI). Recently we published the initial subset of imaging findings for specific regions in a cohort of individuals with autosomal dominant Alzheimer’s disease. We now extend this work to include a larger cohort, whole-brain analyses integrating all three imaging modalities, and longitudinal data to examine regional differences in imaging biomarker dynamics. The anatomical distribution of imaging biomarkers is described in relation to estimated years from symptom onset. Autosomal dominant Alzheimer’s disease mutation carrier individuals have elevated PiB levels in nearly every cortical region 15 y before the estimated age of onset. Reduced cortical glucose metabolism and cortical thinning in the medial and lateral parietal lobe appeared 10 and 5 y, respectively, before estimated age of onset. Importantly, however, a divergent pattern was observed subcortically. All subcortical gray-matter regions exhibited elevated PiB uptake, but despite this, only the hippocampus showed reduced glucose metabolism. Similarly, atrophy was not observed in the caudate and pallidum despite marked amyloid accumulation. Finally, before hypometabolism, a hypermetabolic phase was identified for some cortical regions, including the precuneus and posterior cingulate. Additional analyses of individuals in which longitudinal data were available suggested that an accelerated appearance of volumetric declines approximately coincides with the onset of the symptomatic phase of the disease.

Oral curcumin for Alzheimer's disease: tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study

IntroductionCurcumin is a polyphenolic compound derived from the plant Curcuma Long Lin that has been demonstrated to have antioxidant and anti-inflammatory effects as well as effects on reducing beta-amyloid aggregation. It reduces pathology in transgenic models of Alzheimers disease (AD) and is a promising candidate for treating human AD. The purpose of the current study is to generate tolerability and preliminary clinical and biomarker efficacy data on curcumin in persons with AD.MethodsWe performed a 24-week randomized, double blind, placebo-controlled study of Curcumin C3 Complex® with an open-label extension to 48 weeks. Thirty-six persons with mild-to-moderate AD were randomized to receive placebo, 2 grams/day, or 4 grams/day of oral curcumin for 24 weeks. For weeks 24 through 48, subjects that were receiving curcumin continued with the same dose, while subjects previously receiving placebo were randomized in a 1:1 ratio to 2 grams/day or 4 grams/day. The primary outcome measures were incidence of adverse events, changes in clinical laboratory tests and the Alzheimers Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) at 24 weeks in those completing the study. Secondary outcome measures included the Neuropsychiatric Inventory (NPI), the Alzheimers Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) scale, levels of Aβ1-40 and Aβ1-42 in plasma and levels of Aβ1-42, t-tau, p-tau181 and F2-isoprostanes in cerebrospinal fluid. Plasma levels of curcumin and its metabolites up to four hours after drug administration were also measured.ResultsMean age of completers (n = 30) was 73.5 years and mean Mini-Mental Status Examination (MMSE) score was 22.5. One subject withdrew in the placebo (8%, worsened memory) and 5/24 subjects withdrew in the curcumin group (21%, 3 due to gastrointestinal symptoms). Curcumin C3 Complex® was associated with lowered hematocrit and increased glucose levels that were clinically insignificant. There were no differences between treatment groups in clinical or biomarker efficacy measures. The levels of native curcumin measured in plasma were low (7.32 ng/mL).ConclusionsCurcumin was generally well-tolerated although three subjects on curcumin withdrew due to gastrointestinal symptoms. We were unable to demonstrate clinical or biochemical evidence of efficacy of Curcumin C3 Complex® in AD in this 24-week placebo-controlled trial although preliminary data suggest limited bioavailability of this compound.Trial registrationClinicalTrials.gov Identifier: NCT00099710.

Longitudinal Change in CSF Biomarkers in Autosomal-Dominant Alzheimer’s Disease

Longitudinal cerebrospinal fluid biomarker analyses reveal decreases in neuronal injury markers in later stages of autosomal-dominant Alzheimer’s disease. Biphasic Changes in CSF Biomarkers in AD Data from clinicopathological and biomarker studies of Alzheimer’s disease (AD) have converged to support the existence of a long “preclinical” (asymptomatic) stage during which pathologies develop before the appearance of cognitive symptoms. Substantiating the longitudinal change in biomarkers over time will advance our basic understanding of the disease and provide information critical for the design and interpretation of disease-modifying clinical trials that use biomarkers for subject enrollment, for proof of target engagement, or as outcome measures. Biomarkers are required to identify individuals in the preclinical stage to target them for secondary prevention trials designed to preserve normal cognitive function. Study of families with autosomal-dominant AD (ADAD) mutations permits characterization of biomarker changes during the full range of the disease process because of the certainty of eventual dementia in mutation carriers and the relatively predictable ages at symptom onset within families. Analysis of cerebrospinal fluid (CSF) collected longitudinally in research participants in the Dominantly Inherited Alzheimer Network (DIAN), a multicenter, international biomarker study of ADAD, revealed reductions in amyloid-β1–42 (indicating the presence of amyloid plaques) and increases in markers of neuronal injury (tau, ptau181, and VILIP-1) in mutation carriers during the early presymptomatic stage. However, concentrations of injury-related markers in carriers at later stages of the disease decreased over time, suggesting a slowing of acute neurodegenerative processes with symptomatic disease progression. If corroborated, this longitudinal pattern of neurodegeneration-related biomarker change will likely influence the definition and interpretation of a positive versus negative effect of a therapy on disease progression. Clinicopathological evidence suggests that the pathology of Alzheimer’s disease (AD) begins many years before the appearance of cognitive symptoms. Biomarkers are required to identify affected individuals during this asymptomatic (“preclinical”) stage to permit intervention with potential disease-modifying therapies designed to preserve normal brain function. Studies of families with autosomal-dominant AD (ADAD) mutations provide a unique and powerful means to investigate AD biomarker changes during the asymptomatic period. In this biomarker study, we collected cerebrospinal fluid (CSF), plasma, and in vivo amyloid imaging cross-sectional data at baseline in individuals from ADAD families enrolled in the Dominantly Inherited Alzheimer Network. Our study revealed reduced concentrations of CSF amyloid-β1–42 (Aβ1–42) associated with the presence of Aβ plaques, and elevated concentrations of CSF tau, ptau181 (phosphorylated tau181), and VILIP-1 (visinin-like protein-1), markers of neurofibrillary tangles and neuronal injury/death, in asymptomatic mutation carriers 10 to 20 years before their estimated age at symptom onset (EAO) and before the detection of cognitive deficits. When compared longitudinally, however, the concentrations of CSF biomarkers of neuronal injury/death within individuals decreased after their EAO, suggesting a slowing of acute neurodegenerative processes with symptomatic disease progression. These results emphasize the importance of longitudinal, within-person assessment when modeling biomarker trajectories across the course of the disease. If corroborated, this pattern may influence the definition of a positive neurodegenerative biomarker outcome in clinical trials.