Did you know?
Copper depletion is the only consistent metal imbalance found across Alzheimer’s, Parkinson’s disease with dementia, and dementia with Lewy bodies—suggesting it may play a central role in the development of neurodegeneration.
Metallomics in Neurodegenerative Diseases: A mini-review
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Karen Pendergrass
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Karen Pendergrass
Karen Pendergrass is a microbiome researcher specializing in microbiome-targeted interventions (MBTIs). She systematically analyzes scientific literature to identify microbial patterns, develop hypotheses, and validate interventions. As the founder of the Microbiome Signatures Database, she bridges microbiome research with clinical practice. In 2012, based on her own investigative research, she became the first documented case of FMT for Celiac Disease—four years before the first published case study.
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Kimberly Eyer
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Kimberly Eyer
Kimberly Eyer, a Registered Nurse with 30 years of nursing experience across diverse settings, including Home Health, ICU, Operating Room Nursing, and Research. Her roles have encompassed Operating Room Nurse, RN First Assistant, and Acting Director of a Same Day Surgery Center. Her specialty areas include Adult Cardiac Surgery, Congenital Cardiac Surgery, Vascular Surgery, and Neurosurgery.
This review highlights how neurodegenerative diseases like Alzheimer’s disease (D), Parkinson’s disease (D), and dementia with Lewy bodies (LB) exhibit disease-specific metallomic signatures, with copper depletion as a shared feature. Metal imbalances reflect both cause and consequence in neurodegeneration and may offer diagnostic potential when captured through region-specific elemental analysis.
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Karen Pendergrass
Researched by:
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Karen Pendergrass
ID
Karen Pendergrass
Fact-checked by:
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Kimberly Eyer
ID
Kimberly Eyer
Microbiome Signatures identifies and validates condition-specific microbiome shifts and interventions to accelerate clinical translation. Our multidisciplinary team supports clinicians, researchers, and innovators in turning microbiome science into actionable medicine.
Karen Pendergrass
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References Overview
Neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and related dementias often feature disrupted metal homeostasis in the brain. The brain is a metabolically active organ that requires metals (for example, copper and zinc are essential for neurotransmitter synthesis and antioxidant enzymes), yet an excess of certain redox-active metals (like iron or copper) can promote oxidative stress and protein aggregation. Metallomic analyses of post-mortem brains have indeed revealed disease-specific metal imbalances. For instance, in Alzheimer’s and in Parkinson’s disease with dementia (PDD), studies consistently find widespread decreases in copper levels in affected brain regions. [1] In addition, more localized alterations in other elements have been documented. AD and PDD brains show region-specific changes in sodium, potassium, manganese, iron, zinc, and selenium compared to healthy brains.[2] These shifts likely reflect both cause and effect in neurodegeneration: copper deficiency, for example, may impair cuproenzyme activities (exacerbating oxidative damage), while excessive iron or manganese in certain brain nuclei can catalyze the formation of reactive oxygen species and contribute to neuronal loss.
A classical illustration is manganese-induced parkinsonism (manganism), a condition observed in welders or miners overexposed to Mn, which produces PD-like symptoms via basal ganglia iron/manganese accumulation and toxicity. Such observations underscore how critical balanced metal levels are for neuronal health. [3]
Disease-Specific Metallomic Signatures
Notably, different neurodegenerative diseases appear to have distinct metallomic “fingerprints” or “metallomic signatures.” A recent study compared the metallome of brains from patients with dementia with Lewy bodies (DLB) – a neurodegenerative dementia – to those from AD and PDD patients.[4] Using ICP-MS to quantify multiple elements in ten brain regions, researchers found that DLB brains exhibit a unique signature: elevated sodium and decreased copper in several cortical regions, along with selective changes in calcium, iron, manganese, and selenium. [5] While all three diseases (AD, PDD, DLB) shared a common feature of copper depletion in the brain, the pattern of other elemental changes differed. By applying principal component analysis to the multi-element data, the authors were able to clearly distinguish DLB cases from AD and PDD based on metallomic profiles in certain brain areas.[6]
Implications for Pathogenesis and Diagnosis
This suggests that each neurodegenerative disorder may perturb metal homeostasis in characteristic ways, reflecting differences in pathogenesis (for example, the regional distribution of pathology or the involvement of specific metalloenzymes). It is hypothesized that in AD, the accumulation of amyloid-β plaques and tau tangles might sequester metals like zinc and iron, whereas in DLB and PD, alpha-synuclein aggregation and mitochondrial dysfunction could drive a different metal imbalance. Beyond offering mechanistic clues, these findings raise the intriguing possibility that metallomic signatures could aid in differentiating clinically overlapping dementias. Indeed, if such metal alterations (like cortical sodium and copper levels) could be measured non-invasively in living patients – perhaps through advanced imaging or cerebrospinal fluid analysis – they may contribute to the differential diagnosis of conditions such as DLB versus AD. [7]
In conclusion, aberrant metal distribution is a recurring theme in neurodegeneration, and metallomics is providing new insights into how elemental imbalances correlate with neuronal death, protein misfolding, and cognitive decline.
FAQs
How do metal imbalances contribute to neurodegeneration in diseases like Alzheimer’s and Parkinson’s?
How do metal imbalances contribute to neurodegeneration in diseases like Alzheimer’s and Parkinson’s?
Metal homeostasis is essential for brain function, as metals like copper, zinc, iron, and manganese serve as cofactors for enzymes involved in neurotransmission, antioxidant defense, and mitochondrial function. However, disruption in metal levels can lead to neurotoxicity. For example, copper deficiency may impair cuproenzyme activity, weakening antioxidant defenses and exacerbating oxidative stress. Conversely, iron and manganese excess can catalyze the generation of reactive oxygen species through Fenton-type reactions, leading to protein aggregation and neuronal damage. These imbalances may act both as drivers and downstream consequences of neurodegenerative pathology.
Can metallomic signatures help distinguish between different neurodegenerative diseases?
Can metallomic signatures help distinguish between different neurodegenerative diseases?
Yes. Recent studies using inductively coupled plasma mass spectrometry (ICP-MS) have demonstrated that diseases such as Alzheimer’s disease (AD), Parkinson’s disease with dementia (PDD), and dementia with Lewy bodies (DLB) exhibit distinct regional metallomic profiles. While copper depletion is a shared hallmark across these disorders, specific combinations of altered metals—such as elevated sodium in the cortex in DLB or changes in manganese and selenium—can differentiate them. Advanced analytical techniques like principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA) have enabled researchers to distinguish DLB from AD and PDD with high specificity, suggesting that metallomic profiling may have diagnostic utility in clinically overlapping dementias.
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Metallomic analysis of brain tissues distinguishes between cases of dementia with Lewy bodies, Alzheimer’s disease, and Parkinson’s disease dementia
June 26, 2024
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Metallomic Signatures •
Metallomic Signatures
Did you know?
Metallomic signatures can reveal hidden drivers of disease by mapping how trace metals like nickel, iron, and cadmium shape microbial behavior and immune responses. These signatures not only help identify toxic exposures but also spotlight metal-dependent pathogens, offering new targets for precision-guided therapies.
Dementia with Lewy bodies (DLB) brains show widespread copper depletion and region-specific sodium, manganese, iron, and selenium alterations. While copper loss is common to AD and PDD, DLB presents a distinct metallomic fingerprint, enabling disease differentiation via PCA. Metallomic profiling may aid in diagnosing overlapping dementias and reveals unique pathophysiological signatures.
What was studied?
This original research study investigated whether the metallomic profile of dementia with Lewy bodies (DLB) differs from that of Alzheimer’s disease (AD) and Parkinson’s disease dementia (PDD). The study sought to determine if post-mortem changes in elemental concentrations—particularly in essential metals—could help differentiate these often-overlapping neurodegenerative conditions. Using ICP-MS (Inductively Coupled Plasma–Mass Spectrometry), the authors quantified concentrations of nine elements (Na, Mg, K, Ca, Mn, Fe, Cu, Zn, and Se) across 10 brain regions from DLB patients and age-/sex-matched controls. These findings were directly compared to previously published metallomic profiles for AD and PDD, produced using identical methodologies. Multivariate analyses (PCA and PLS-DA) were employed to assess the potential for disease discrimination based on metal signatures.
Who was studied?
The study analyzed post-mortem brain tissue from 23 DLB patients and 20 controls, collected across ten distinct brain regions. Comparative analyses included prior datasets from similarly matched AD and PDD patient cohorts.
What were the most important findings?
n this study, region-specific metallomic profiling revealed distinct trace element alterations in Dementia with Lewy Bodies (DLB). Copper (Cu) levels were consistently decreased in five of ten DLB brain regions, including the cingulate gyrus (CG), middle temporal gyrus (MTG), primary visual cortex (PVC), substantia nigra (SN), and putamen (PUT), suggesting a widespread Cu deficiency. Sodium (Na) was elevated in four regions—medulla (MED), cerebellum (CB), MTG, and CG—while more localized changes were observed for other metals. Iron (Fe) levels were increased in the motor cortex (MCX) and CG, whereas manganese (Mn) was decreased in both the PVC and MED. Calcium (Ca) was specifically reduced in the hippocampus, and selenium (Se) was also decreased in the PVC. No significant differences in magnesium, potassium, or zinc levels were observed between DLB and control brains. Multivariate analyses, including Principal Component Analysis (PCA) and Partial Least Squares-Discriminant Analysis (PLS-DA), demonstrated that DLB could be distinctly separated from Alzheimer’s disease (AD) and Parkinson’s disease dementia (PDD) based on metallomic signatures. Specifically, CG, MTG, and PVC profiles enabled discrimination between DLB and AD, while the PVC alone differentiated DLB from PDD. Notably, copper depletion emerged as the only common alteration across DLB, AD, and PDD, underscoring its potential central role in the pathogenesis of neurodegenerative diseases. The authors propose that these metallomic fingerprints may reflect disease-specific mechanisms, including variations in oxidative stress, protein aggregation, and mitochondrial dysfunction.
What are the greatest implications of this study?
This study provides compelling evidence that distinct metallomic signatures exist across DLB, AD, and PDD, despite shared pathology such as copper depletion. It strengthens the emerging concept that trace metal dysregulation is disease-specific, rather than a general byproduct of neurodegeneration. The findings support the idea that metallomic profiling—potentially via cerebrospinal fluid or advanced imaging in living patients—could improve differential diagnosis of dementias with overlapping clinical features. Furthermore, the study reinforces the hypothesis that metal dyshomeostasis, particularly copper depletion, may be a contributing pathogenic mechanism, impairing antioxidant defenses and mitochondrial function. These findings could inform new diagnostic tools and therapeutic targets.
References
- Metallomic analysis of brain tissues distinguishes between cases of dementia with Lewy bodies, Alzheimer’s disease, and Parkinson’s disease dementia.. Scholefield M, Church SJ, Xu J, Cooper GJS.. (Front Neurosci. 2024)
- Metallomic analysis of brain tissues distinguishes between cases of dementia with Lewy bodies, Alzheimer’s disease, and Parkinson’s disease dementia.. Scholefield M, Church SJ, Xu J, Cooper GJS.. (Front Neurosci. 2024)
- Dose-dependent progression of parkinsonism in manganese-exposed welders.. Racette BA, Searles Nielsen S, Criswell SR, Sheppard L, Seixas N, Warden MN, Checkoway H.. (Neurology. 2017)
- Metallomic analysis of brain tissues distinguishes between cases of dementia with Lewy bodies, Alzheimer’s disease, and Parkinson’s disease dementia.. Scholefield M, Church SJ, Xu J, Cooper GJS.. (Front Neurosci. 2024)
- Metallomic analysis of brain tissues distinguishes between cases of dementia with Lewy bodies, Alzheimer’s disease, and Parkinson’s disease dementia.. Scholefield M, Church SJ, Xu J, Cooper GJS.. (Front Neurosci. 2024)
- Metallomic analysis of brain tissues distinguishes between cases of dementia with Lewy bodies, Alzheimer’s disease, and Parkinson’s disease dementia.. Scholefield M, Church SJ, Xu J, Cooper GJS.. (Front Neurosci. 2024)
- Metallomic analysis of brain tissues distinguishes between cases of dementia with Lewy bodies, Alzheimer’s disease, and Parkinson’s disease dementia.. Scholefield M, Church SJ, Xu J, Cooper GJS.. (Front Neurosci. 2024)
Scholefield M, Church SJ, Xu J, Cooper GJS.
Metallomic analysis of brain tissues distinguishes between cases of dementia with Lewy bodies, Alzheimer’s disease, and Parkinson’s disease dementia.Front Neurosci. 2024
Read ReviewScholefield M, Church SJ, Xu J, Cooper GJS.
Metallomic analysis of brain tissues distinguishes between cases of dementia with Lewy bodies, Alzheimer’s disease, and Parkinson’s disease dementia.Front Neurosci. 2024
Read ReviewRacette BA, Searles Nielsen S, Criswell SR, Sheppard L, Seixas N, Warden MN, Checkoway H.
Dose-dependent progression of parkinsonism in manganese-exposed welders.Neurology. 2017
Scholefield M, Church SJ, Xu J, Cooper GJS.
Metallomic analysis of brain tissues distinguishes between cases of dementia with Lewy bodies, Alzheimer’s disease, and Parkinson’s disease dementia.Front Neurosci. 2024
Read ReviewScholefield M, Church SJ, Xu J, Cooper GJS.
Metallomic analysis of brain tissues distinguishes between cases of dementia with Lewy bodies, Alzheimer’s disease, and Parkinson’s disease dementia.Front Neurosci. 2024
Read ReviewScholefield M, Church SJ, Xu J, Cooper GJS.
Metallomic analysis of brain tissues distinguishes between cases of dementia with Lewy bodies, Alzheimer’s disease, and Parkinson’s disease dementia.Front Neurosci. 2024
Read ReviewScholefield M, Church SJ, Xu J, Cooper GJS.
Metallomic analysis of brain tissues distinguishes between cases of dementia with Lewy bodies, Alzheimer’s disease, and Parkinson’s disease dementia.Front Neurosci. 2024
Read Review