Todd A. Tishler

Brain ferritin iron may influence age- and gender-related risks of neurodegeneration

BACKGROUND Brain iron promotes oxidative damage and protein oligomerization that result in highly prevalent age-related proteinopathies such as Alzheimers disease (AD), Parkinsons disease (PD), and Dementia with Lewy Bodies (DLB). Men are more likely to develop such diseases at earlier ages than women but brain iron levels increase with age in both genders. We hypothesized that brain iron may influence both the age- and gender-related risks of developing these diseases. METHODS The amount of iron in ferritin molecules (ferritin iron) was measured in vivo with MRI by utilizing the field dependent relaxation rate increase (FDRI) method. Ferritin iron was measured in four subcortical nuclei [caudate (C), putamen (P), globus pallidus (G), thalamus (T)], three white matter regions [frontal lobe (Fwm), genu and splenium of the corpus callosum (Gwm, Swm)] and hippocampus (Hipp) in 165 healthy adults aged 19-82. RESULTS There was a high correlation (r>0.99) between published post-mortem brain iron levels and FDRI. There were significant age-related changes in ferritin iron (increases in Hipp, C, P, G, and decreases in Fwm). Women had significantly lower ferritin iron than men in five regions (C, T, Fwm, Gwm, Swm). CONCLUSIONS This is the first demonstration of gender differences in brain ferritin iron levels. It is possible that brain iron accumulation is a risk factor that can be modified. MRI provides the opportunity to assess brain iron levels in vivo and may be useful in targeting individuals or groups for preventive therapeutic interventions.

MRI evaluation of brain iron in earlier- and later-onset Parkinson's disease and normal subjects.

Tissue iron levels in the extrapyramidal system of earlier- and later-onset Parkinsons disease (PD) subjects were evaluated in vivo using a magnetic resonance imaging (MRI) method. The method involves scanning subjects in both high- and low-field MRI instruments, measuring tissue relaxation rate (R2), and calculating the field-dependent R2 increase (FDRI) which is the difference between the R2 measured with the two MRI instruments. In tissue, only ferritin iron is known to increase R2 in a field-dependent manner and the FDRI measure is a specific measure of this tissue iron pool. Two groups of male subjects with PD and two age-matched groups of normal control males were studied. The two groups of six subjects with PD consisted of subjects with earlier- or later-onset (before or after age 60) PD. FDRI was measured in five subcortical structures: the substantia nigra reticulata (SNR), substantia nigra compacta (SNC), globus pallidus, putamen, and caudate nucleus, and in one comparison region; the frontal white matter. Earlier-onset PD subjects had significant (p < 0.05) increases in FDRI in the SNR, SNC, putamen, and globus pallidus, while later-onset PD subjects had significantly decreased FDRI in the SNR when compared to their respective age-matched controls. Controlling for illness duration or structure size did not meaningfully alter the results. Published post-mortem studies on SN iron levels indicate decreased ferritin levels and increased free iron levels in the SN of older PD subjects, consistent with the decreased FDRI observed in our later-onset PD sample, which was closely matched in age to the post-mortem PD samples. The FDRI results suggest that disregulation of iron metabolism occurs in PD and that this disregulation may differ in earlier- versus later-onset PD.

Brain Ferritin Iron as a Risk Factor for Age at Onset in Neurodegenerative Diseases

Abstract: Tissue iron can promote oxidative damage. Brain iron increases with age and is abnormally elevated early in the disease process in several neurodegenerative disorders, including Alzheimers disease (AD) and Parkinsons disease (PD). Higher iron levels in males may contribute to higher risk for younger‐onset PD and recent studies have linked the presence of the hemochromatosis gene with a younger age at onset of AD. We examined whether age at onset of PD and AD was associated with increased brain ferritin iron. Ferritin iron can be measured with specificity in vivo with MRI utilizing the field‐dependent relaxation rate increase (FDRI) method. FDRI was assessed in three basal ganglia regions (caudate, putamen, and globus pallidus) and frontal lobe white matter for younger‐ and older‐onset male PD and AD patients and healthy controls. Significant increases in basal ganglia FDRI levels were observed in the younger‐onset groups of both diseases compared to their respective control groups, but were absent in the older‐onset patients. The results support the suggestion that elevated ferritin iron and its associated toxicity is a risk factor for age at onset of neurodegenerative diseases such as AD and PD. Clinical phenomena such as gender‐associated risk of developing neurodegenerative diseases and the age at onset of such diseases may be associated with brain iron levels. In vivo MRI can measure and track brain ferritin iron levels and provides an opportunity to design therapeutic interventions that target high‐risk populations early in the course of illness, possibly even before symptoms appear.

Myelin Breakdown and Iron Changes in Huntington’s Disease: Pathogenesis and Treatment Implications

BackgroundPostmortem and in vivo imaging data support the hypothesis that premature myelin breakdown and subsequent homeostatic remyelination attempts with increased oligodendrocyte and iron levels may contribute to Huntington’s Disease (HD) pathogenesis and the symmetrical progress of neuronal loss from earlier-myelinating striatum to later-myelinating regions. A unique combination of in vivo tissue integrity and iron level assessments was used to examine the hypothesis.MethodsA method that uses two Magnetic resonance imaging (MRI) instruments operating at different field-strengths was used to quantify the iron content of ferritin molecules (ferritin iron) as well as tissue integrity in eight regions in 11 HD and a matched group of 27 healthy control subjects. Three white matter regions were selected based on their myelination pattern (early to later-myelinating) and fiber composition. These were frontal lobe white matter (Fwm) and splenium and genu of the corpus callosum (Swm and Gwm). In addition, gray matter structures were also chosen based on their myelination pattern and fiber composition. Three striatum structures were assessed [caudate, putamen, and globus pallidus (C, P, and G)] as well as two comparison gray matter regions that myelinate later in development and are relatively spared in HD [Hippocampus (Hipp) and Thalamus (Th)].ResultsCompared to healthy controls, HD ferritin iron levels were significantly increased in striatum C, P, and G, decreased in Fwm and Gwm, and were unchanged in Hipp, Th, and Swm. Loss of tissue integrity was observed in C, P, Fwm, and especially Swm but not Hipp, Th, G, or Gwm. This pattern of findings was largely preserved when a small subset of HD subjects early in the disease process was examined.ConclusionsThe data suggest early in the HD process, myelin breakdown and changes in ferritin iron distribution underlie the pattern of regional toxicity observed in HD. Prospective studies are needed to verify myelin breakdown and increased iron levels are causal factors in HD pathogenesis. Tracking the effects of novel interventions that reduce myelin breakdown and iron accumulation in preclinical stages of HD could hasten the development of preventive treatments.

Increased Iron Levels and Decreased Tissue Integrity in Hippocampus of Alzheimer's Disease Detected in vivo with Magnetic Resonance Imaging

BACKGROUND Iron can catalyze damaging free radical reactions. With age, iron accumulates in brain gray matter regions and may contribute to the risk of developing age-related diseases such as Alzheimers disease (AD). Prior MRI studies demonstrated increased iron deposits in basal ganglia regions; however, the hippocampus (Hipp), which is heavily damaged in AD, and comparator regions that are resistant to AD damage, such as thalamus (Th), have rarely been examined. OBJECTIVE To assess iron levels and evidence of tissue damage in Hipp and Th of AD subjects and healthy controls. METHODS Thirty-one AD and sixty-eight healthy control subjects participated in this study. High- and low-field strength MRI instruments were used in combination to quantify iron content of ferritin molecules (ferritin iron) using the field dependent relaxation rate increase (FDRI) method. Decreased transverse relaxation rate (R2) was used as an index of tissue damage. RESULTS Compared with healthy controls, AD subjects had increased ferritin iron in Hipp (p = 0.019) but not Th (p = 0.637), and significantly decreased R2 in Hipp (p < 0.001) but not Th (p = 0.37). In the entire sample, FDRI and R2 were negatively correlated. CONCLUSION The data shows that in AD, Hipp damage occurs in conjunction with ferritin iron accumulation. Prospective studies are needed to evaluate how increasing iron levels may influence the trajectory of tissue damage and cognitive and pathologic manifestations of AD.

Gender and Iron Genes May Modify Associations Between Brain Iron and Memory in Healthy Aging

Brain iron increases with age and is abnormally elevated early in the disease process in several neurodegenerative disorders that impact memory including Alzheimers disease (AD). Higher brain iron levels are associated with male gender and presence of highly prevalent allelic variants in genes encoding for iron metabolism proteins (hemochromatosis H63D (HFE H63D) and transferrin C2 (TfC2)). In this study, we examined whether in healthy older individuals memory performance is associated with increased brain iron, and whether gender and gene variant carrier (IRON+) vs noncarrier (IRON−) status (for HFE H63D/TfC2) modify the associations. Tissue iron deposited in ferritin molecules can be measured in vivo with magnetic resonance imaging utilizing the field-dependent relaxation rate increase (FDRI) method. FDRI was assessed in hippocampus, basal ganglia, and white matter, and IRON+ vs IRON− status was determined in a cohort of 63 healthy older individuals. Three cognitive domains were assessed: verbal memory (delayed recall), working memory/attention, and processing speed. Independent of gene status, worse verbal-memory performance was associated with higher hippocampal iron in men (r=−0.50, p=0.003) but not in women. Independent of gender, worse verbal working memory performance was associated with higher basal ganglia iron in IRON− group (r=−0.49, p=0.005) but not in the IRON+ group. Between-group interactions (p=0.006) were noted for both of these associations. No significant associations with white matter or processing speed were observed. The results suggest that in specific subgroups of healthy older individuals, higher accumulations of iron in vulnerable gray matter regions may adversely impact memory functions and could represent a risk factor for accelerated cognitive decline. Combining genetic and MRI biomarkers may provide opportunities to design primary prevention clinical trials that target high-risk groups.

Multisystem Component Phenotypes of Bipolar Disorder for Genetic Investigations of Extended Pedigrees

IMPORTANCE Genetic factors contribute to risk for bipolar disorder (BP), but its pathogenesis remains poorly understood. A focus on measuring multisystem quantitative traits that may be components of BP psychopathology may enable genetic dissection of this complex disorder, and investigation of extended pedigrees from genetically isolated populations may facilitate the detection of specific genetic variants that affect BP as well as its component phenotypes. OBJECTIVE To identify quantitative neurocognitive, temperament-related, and neuroanatomical phenotypes that appear heritable and associated with severe BP (bipolar I disorder [BP-I]) and therefore suitable for genetic linkage and association studies aimed at identifying variants contributing to BP-I risk. DESIGN, SETTING, AND PARTICIPANTS Multigenerational pedigree study in 2 closely related, genetically isolated populations: the Central Valley of Costa Rica and Antioquia, Colombia. A total of 738 individuals, all from Central Valley of Costa Rica and Antioquia pedigrees, participated; among them, 181 have BP-I. MAIN OUTCOMES AND MEASURES Familial aggregation (heritability) and association with BP-I of 169 quantitative neurocognitive, temperament, magnetic resonance imaging, and diffusion tensor imaging phenotypes. RESULTS Of 169 phenotypes investigated, 126 (75%) were significantly heritable and 53 (31%) were associated with BP-I. About one-quarter of the phenotypes, including measures from each phenotype domain, were both heritable and associated with BP-I. Neuroimaging phenotypes, particularly cortical thickness in prefrontal and temporal regions as well as volume and microstructural integrity of the corpus callosum, represented the most promising candidate traits for genetic mapping related to BP based on strong heritability and association with disease. Analyses of phenotypic and genetic covariation identified substantial correlations among the traits, at least some of which share a common underlying genetic architecture. CONCLUSIONS AND RELEVANCE To our knowledge, this is the most extensive investigation of BP-relevant component phenotypes to date. Our results identify brain and behavioral quantitative traits that appear to be genetically influenced and show a pattern of BP-I association within families that is consistent with expectations from case-control studies. Together, these phenotypes provide a basis for identifying loci contributing to BP-I risk and for genetic dissection of the disorder.

Myelin breakdown mediates age-related slowing in cognitive processing speed in healthy elderly men ☆

BACKGROUND To assess the hypothesis that in a sample of very healthy elderly men selected to minimize risk for Alzheimers disease (AD) and cerebrovascular disease, myelin breakdown in late-myelinating regions mediates age-related slowing in cognitive processing speed (CPS). MATERIALS AND METHODS The prefrontal lobe white matter and the genu of the corpus callosum myelinate later in brain development (late-myelinating white matter; LMWM) and are more vulnerable to breakdown due to the effects of normal aging. An in vivo MRI biomarker of myelin integrity (transverse relaxation rates; R(2)) of LMWM was obtained for 38 very healthy elderly adult men (mean age=66.3 years; SD=6.0; range=55-76). To evaluate regional specificity, we also assessed a contrasting early-myelinating region (splenium of the corpus callosum; SWM), which primarily contains axons involved in visual processing. CPS was assessed using the Trail Making Test. RESULTS LMWM R(2) and CPS measures were significantly correlated (r=.515, p=.0009), but no significant association between R(2) and CPS was detected in the splenium (p=.409). LMWM R(2), but not SWM R(2), was a significant mediator of the relationship between age and CPS (p=.037). CONCLUSIONS In this very healthy elderly sample, age-related slowing in CPS is mediated by myelin breakdown in highly vulnerable late-myelinating regions but not in the splenium.

Prevalent iron metabolism gene variants associated with increased brain ferritin iron in healthy older men.

Prevalent gene variants involved in iron metabolism [hemochromatosis (HFE) H63D and transferrin C2 (TfC2)] have been associated with higher risk and earlier age at onset of Alzheimers disease (AD), especially in men. Brain iron increases with age, is higher in men, and is abnormally elevated in several neurodegenerative diseases, including AD and Parkinsons disease, where it has been reported to contribute to younger age at onset in men. The effects of the common genetic variants (HFE H63D and/or TfC2) on brain iron were studied across eight brain regions (caudate, putamen, globus pallidus, thalamus, hippocampus, white matter of frontal lobe, genu, and splenium of corpus callosum) in 66 healthy adults (35 men, 31 women) aged 55 to 76. The iron content of ferritin molecules (ferritin iron) in the brain was measured with MRI utilizing the Field Dependent Relaxation Rate Increase (FDRI) method. 47% of the sample carried neither genetic variant (IRON-) and 53% carried one and/or the other (IRON+). IRON+ men had significantly higher FDRI compared to IRON- men (p=0.013). This genotype effect was not observed in women who, as expected, had lower FDRI than men. This is the first published evidence that these highly prevalent genetic variants in iron metabolism genes can influence brain iron levels in men. Clinical phenomena such as differential gender-associated risks of developing neurodegenerative diseases and age at onset may be associated with interactions between iron genes and brain iron accumulation. Clarifying mechanisms of brain iron accumulation may help identify novel interventions for age-related neurodegenerative diseases.

Brain structure–function associations in multi-generational families genetically enriched for bipolar disorder

Recent theories regarding the pathophysiology of bipolar disorder suggest contributions of both neurodevelopmental and neurodegenerative processes. While structural neuroimaging studies indicate disease-associated neuroanatomical alterations, the behavioural correlates of these alterations have not been well characterized. Here, we investigated multi-generational families genetically enriched for bipolar disorder to: (i) characterize neurobehavioural correlates of neuroanatomical measures implicated in the pathophysiology of bipolar disorder; (ii) identify brain-behaviour associations that differ between diagnostic groups; (iii) identify neurocognitive traits that show evidence of accelerated ageing specifically in subjects with bipolar disorder; and (iv) identify brain-behaviour correlations that differ across the age span. Structural neuroimages and multi-dimensional assessments of temperament and neurocognition were acquired from 527 (153 bipolar disorder and 374 non-bipolar disorder) adults aged 18-87 years in 26 families with heavy genetic loading for bipolar disorder. We used linear regression models to identify significant brain-behaviour associations and test whether brain-behaviour relationships differed: (i) between diagnostic groups; and (ii) as a function of age. We found that total cortical and ventricular volume had the greatest number of significant behavioural associations, and included correlations with measures from multiple cognitive domains, particularly declarative and working memory and executive function. Cortical thickness measures, in contrast, showed more specific associations with declarative memory, letter fluency and processing speed tasks. While the majority of brain-behaviour relationships were similar across diagnostic groups, increased cortical thickness in ventrolateral prefrontal and parietal cortical regions was associated with better declarative memory only in bipolar disorder subjects, and not in non-bipolar disorder family members. Additionally, while age had a relatively strong impact on all neurocognitive traits, the effects of age on cognition did not differ between diagnostic groups. Most brain-behaviour associations were also similar across the age range, with the exception of cortical and ventricular volume and lingual gyrus thickness, which showed weak correlations with verbal fluency and inhibitory control at younger ages that increased in magnitude in older subjects, regardless of diagnosis. Findings indicate that neuroanatomical traits potentially impacted by bipolar disorder are significantly associated with multiple neurobehavioural domains. Structure-function relationships are generally preserved across diagnostic groups, with the notable exception of ventrolateral prefrontal and parietal association cortex, volumetric increases in which may be associated with cognitive resilience specifically in individuals with bipolar disorder. Although age impacted all neurobehavioural traits, we did not find any evidence of accelerated cognitive decline specific to bipolar disorder subjects. Regardless of diagnosis, greater global brain volume may represent a protective factor for the effects of ageing on executive functioning.