Omics-derived biological modules reflect metabolic brain changes in Alzheimer's disease.

INTRODUCTION: Brain glucose hypometabolism, indexed by the fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) imaging, is a metabolic signature of Alzheimer's disease (AD). However, the underlying biological pathways involved in these metabolic changes remain elusive. METHODS: Here, we integrated [18F]FDG-PET images with blood and hippocampal transcriptomic data from cognitively unimpaired (CU, n = 445) and cognitively impaired (CI, n = 749) individuals using modular dimension reduction techniques and voxel-wise linear regression analysis. RESULTS: Our results showed that multiple transcriptomic modules are associated with brain [18F]FDG-PET metabolism, with the top hits being a protein serine/threonine kinase activity gene cluster (peak-t(223) = 4.86, P value < 0.001) and zinc-finger-related regulatory units (peak-t(223) = 3.90, P value < 0.001). DISCUSSION: By integrating transcriptomics with PET imaging data, we identified that serine/threonine kinase activity-associated genes and zinc-finger-related regulatory units are highly associated with brain metabolic changes in AD. HIGHLIGHTS: We conducted an integrated analysis of system-based transcriptomics and fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) at the voxel level in Alzheimer's disease (AD). The biological process of serine/threonine kinase activity was the most associated with [18F]FDG-PET in the AD brain. Serine/threonine kinase activity alterations are associated with brain vulnerable regions in AD [18F]FDG-PET. Zinc-finger transcription factor targets were associated with AD brain [18F]FDG-PET metabolism.

The glutamatergic system in Alzheimer's disease: a systematic review with meta-analysis.

Glutamatergic neurotransmission system dysregulation may play an important role in the pathophysiology of Alzheimer's disease (AD). However, reported results on glutamatergic components across brain regions are contradictory. Here, we conducted a systematic review with meta-analysis to examine whether there are consistent glutamatergic abnormalities in the human AD brain. We searched PubMed and Web of Science (database origin-October 2023) reports evaluating glutamate, glutamine, glutaminase, glutamine synthetase, glutamate reuptake, aspartate, excitatory amino acid transporters, vesicular glutamate transporters, glycine, D-serine, metabotropic and ionotropic glutamate receptors in the AD human brain (PROSPERO #CDRD42022299518). The studies were synthesized by outcome and brain region. We included cortical regions, the whole brain (cortical and subcortical regions combined), the entorhinal cortex and the hippocampus. Pooled effect sizes were determined with standardized mean differences (SMD), random effects adjusted by false discovery rate, and heterogeneity was examined by I2 statistics. The search retrieved 6 936 articles, 63 meeting the inclusion criteria (N = 709CN/786AD; mean age 75/79). We showed that the brain of AD individuals presents decreased glutamate (SMD = -0.82; I2 = 74.54%; P < 0.001) and aspartate levels (SMD = -0.64; I2 = 89.71%; P = 0.006), and reuptake (SMD = -0.75; I2 = 83.04%; P < 0.001. We also found reduced α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPAR)-GluA2/3 levels (SMD = -0.63; I2 = 95.55%; P = 0.046), hypofunctional N-methyl-D-aspartate receptor (NMDAR) (SMD = -0.60; I2 = 91.47%; P < 0.001) and selective reduction of NMDAR-GluN2B subunit levels (SMD = -1.07; I2 = 41.81%; P < 0.001). Regional differences include lower glutamate levels in cortical areas and aspartate levels in cortical areas and in the hippocampus, reduced glutamate reuptake, reduced AMPAR-GluA2/3 in the entorhinal cortex, hypofunction of NMDAR in cortical areas, and a decrease in NMDAR-GluN2B subunit levels in the entorhinal cortex and hippocampus. Other parameters studied were not altered. Our findings show depletion of the glutamatergic system and emphasize the importance of understanding glutamate-mediated neurotoxicity in AD. This study has implications for the development of therapies and biomarkers in AD.

Cross-species comparative hippocampal transcriptomics in Alzheimer's disease.

Alzheimer's disease (AD) is a multifactorial pathology, with most cases having a sporadic origin. Recently, knock-in (KI) mouse models, such as the novel humanized amyloid-ß (hAß)-KI, have been developed to better resemble sporadic human AD. METHODS: Here, we compared hippocampal publicly available transcriptomic profiles of transgenic (5xFAD and APP/PS1) and KI (hAß-KI) mouse models with early- (EOAD) and late- (LOAD) onset AD patients. RESULTS: The three mouse models presented more Gene Ontology biological processes terms and enriched signaling pathways in common with LOAD than with EOAD individuals. Experimental validation of consistently dysregulated genes revealed five altered in mice (SLC11A1, S100A6, CD14, CD33, and C1QB) and three in humans (S100A6, SLC11A1, and KCNK). Finally, we identified 17 transcription factors potentially acting as master regulators of AD. CONCLUSION: Our cross-species analyses revealed that the three mouse models presented a remarkable similarity to LOAD, with the hAß-KI being the more specific one.

Association of the fibronectin type III domain-containing protein 5 rs1746661 single nucleotide polymorphism with reduced brain glucose metabolism in elderly humans.

Fibronectin type III domain-containing protein 5 (FNDC5) and its derived hormone, irisin, have been associated with metabolic control in humans, with described FNDC5 single nucleotide polymorphisms being linked to obesity and metabolic syndrome. Decreased brain FNDC5/irisin has been reported in subjects with dementia due to Alzheimer's disease. Since impaired brain glucose metabolism develops in ageing and is prominent in Alzheimer's disease, here, we examined associations of a single nucleotide polymorphism in the FNDC5 gene (rs1746661) with brain glucose metabolism and amyloid-ß deposition in a cohort of 240 cognitively unimpaired and 485 cognitively impaired elderly individuals from the Alzheimer's Disease Neuroimaging Initiative. In cognitively unimpaired elderly individuals harbouring the FNDC5 rs1746661(T) allele, we observed a regional reduction in low glucose metabolism in memory-linked brain regions and increased brain amyloid-ß PET load. No differences in cognition or levels of cerebrospinal fluid amyloid-ß42, phosphorylated tau and total tau were observed between FNDC5 rs1746661(T) allele carriers and non-carriers. Our results indicate that a genetic variant of FNDC5 is associated with low brain glucose metabolism in elderly individuals and suggest that FNDC5 may participate in the regulation of brain metabolism in brain regions vulnerable to Alzheimer's disease pathophysiology. Understanding the associations between genetic variants in metabolism-linked genes and metabolic brain signatures may contribute to elucidating genetic modulators of brain metabolism in humans.

The GABAergic system in Alzheimer's disease: a systematic review with meta-analysis.

The γ-aminobutyric acid (GABA)ergic system is the primary inhibitory neurotransmission system in the mammalian brain. Its dysregulation has been shown in multiple brain conditions, but in Alzheimer's disease (AD) studies have provided contradictory results. Here, we conducted a systematic review with meta-analysis to investigate whether the GABAergic system is altered in AD patients compared to healthy controls (HC), following the PRISMA 2020 Statement. We searched PubMed and Web of Science from database inception to March 18th, 2023 for studies reporting GABA, glutamate decarboxylase (GAD) 65/67, GABAA, GABAB, and GABAC receptors, GABA transporters (GAT) 1-3 and vesicular GAT in the brain, and GABA levels in the cerebrospinal fluid (CSF) and blood. Heterogeneity was estimated using the I2 index, and the risk of bias was assessed with an adapted questionnaire from the Joanna Briggs Institute Critical Appraisal Tools. The search identified 3631 articles, and 48 met the final inclusion criteria (518 HC, mean age 72.2, and 603 AD patients, mean age 75.6). Random-effects meta-analysis [standardized mean difference (SMD)] revealed that AD patients presented lower GABA levels in the brain (SMD = -0.48 [95% CI = -0.7, -0.27], adjusted p value (adj. p) < 0.001) and in the CSF (-0.41 [-0.72, -0.09], adj. p = 0.042), but not in the blood (-0.63 [-1.35, 0.1], adj. p = 0.176). In addition, GAD65/67 (-0.67 [-1.15, -0.2], adj. p = 0.006), GABAA receptor (-0.51 [-0.7, -0.33], adj. p < 0.001), and GABA transporters (-0.51 [-0.92, -0.09], adj. p = 0.016) were lower in the AD brain. Here, we showed a global reduction of GABAergic system components in the brain and lower GABA levels in the CSF of AD patients. Our findings suggest the GABAergic system is vulnerable to AD pathology and should be considered a potential target for developing pharmacological strategies and novel AD biomarkers.

Hippocampal GFAP-positive astrocyte responses to amyloid and tau pathologies.

INTRODUCTION: In Alzheimer's disease clinical research, glial fibrillary acidic protein (GFAP) released/leaked into the cerebrospinal fluid and blood is widely measured and perceived as a biomarker of reactive astrogliosis. However, it was demonstrated that GFAP levels differ in individuals presenting with amyloid-ß (Aß) or tau pathologies. The molecular underpinnings behind this specificity are little explored. Here we investigated biomarker and transcriptomic associations of hippocampal GFAP-positive astrocytes with Aß and tau pathologies in humans and mouse models. METHODS: We studied 90 individuals with plasma GFAP, Aß- and Tau-PET to investigate the association between biomarkers. Then, transcriptomic analysis in hippocampal GFAP-positive astrocytes isolated from mouse models presenting Aß (PS2APP) or tau (P301S) pathologies was conducted to explore differentially expressed genes (DEGs), Gene Ontology terms, and protein-protein interaction networks associated with each phenotype. RESULTS: In humans, we found that plasma GFAP associates with Aß but not tau pathology. Unveiling the unique nature of hippocampal GFAP-positive astrocytic responses to Aß or tau pathologies, mouse transcriptomics showed scarce overlap of DEGs between the Aß. and tau mouse models. While Aß GFAP-positive astrocytes were overrepresented with DEGs associated with proteostasis and exocytosis-related processes, tau hippocampal GFAP-positive astrocytes presented greater abnormalities in functions related to DNA/RNA processing and cytoskeleton dynamics. CONCLUSION: Our results offer insights into Aß- and tau-driven specific signatures in hippocampal GFAP-positive astrocytes. Characterizing how different underlying pathologies distinctly influence astrocyte responses is critical for the biological interpretation of astrocyte biomarkers and suggests the need to develop context-specific astrocyte targets to study AD. FUNDING: This study was supported by Instituto Serrapilheira, Alzheimer's Association, CAPES, CNPq and FAPERGS.

Genetic risk for attention-deficit/hyperactivity disorder predicts cognitive decline and development of Alzheimer's disease pathophysiology in cognitively unimpaired older adults.

Attention-deficit/hyperactivity disorder (ADHD) persists in older age and is postulated as a risk factor for cognitive impairment and Alzheimer's Disease (AD). However, these findings rely primarily on electronic health records and can present biased estimates of disease prevalence. An obstacle to investigating age-related cognitive decline in ADHD is the absence of large-scale studies following patients with ADHD into older age. Alternatively, this study aimed to determine whether genetic liability for ADHD, as measured by a well-validated ADHD polygenic risk score (ADHD-PRS), is associated with cognitive decline and the development of AD pathophysiology in cognitively unimpaired (CU) older adults. We calculated a weighted ADHD-PRS in 212 CU individuals without a clinical diagnosis of ADHD (55-90 years). These individuals had baseline amyloid-ß (Aß) positron emission tomography, longitudinal cerebrospinal fluid (CSF) phosphorylated tau at threonine 181 (p-tau181), magnetic resonance imaging, and cognitive assessments for up to 6 years. Linear mixed-effects models were used to test the association of ADHD-PRS with cognition and AD biomarkers. Higher ADHD-PRS was associated with greater cognitive decline over 6 years. The combined effect between high ADHD-PRS and brain Aß deposition on cognitive deterioration was more significant than each individually. Additionally, higher ADHD-PRS was associated with increased CSF p-tau181 levels and frontoparietal atrophy in CU Aß-positive individuals. Our results suggest that genetic liability for ADHD is associated with cognitive deterioration and the development of AD pathophysiology. Findings were mostly observed in Aß-positive individuals, suggesting that the genetic liability for ADHD increases susceptibility to the harmful effects of Aß pathology.

Endocannabinoid System Biomarkers in Alzheimer's Disease.

Background: Alterations in the endocannabinoid system (ES) have been described in Alzheimer's disease (AD) pathophysiology. In the past years, multiple ES biomarkers have been developed, promising to advance our understanding of ES changes in AD. Discussion: ES biomarkers, including positron emission tomography with cannabinoid receptors tracers and biofluid-based endocannabinoids, are associated with AD disease progression and pathological features. Conclusion: Although not specific enough for AD diagnosis, ES biomarkers hold promise for prognosis, drug-target engagement, and a better understanding of the disease. Here, we summarize currently available ES biomarker findings and discuss their potential applications in the AD research field.

Comment on "Microglial activation states drive glucose uptake and FDG-PET alterations in neurodegenerative diseases".

Astrocytes might be the major contributor to the radioactive signal captured by PET in the microglia-dependent modulation of FDG-PET.

Clozapine induces astrocyte-dependent FDG-PET hypometabolism.

PURPOSE: Advances in functional imaging allowed us to visualize brain glucose metabolism in vivo and non-invasively with [18F]fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) imaging. In the past decades, FDG-PET has been instrumental in the understanding of brain function in health and disease. The source of the FDG-PET signal has been attributed to neuronal uptake, with hypometabolism being considered as a direct index of neuronal dysfunction or death. However, other brain cells are also metabolically active, including astrocytes. Based on the astrocyte-neuron lactate shuttle hypothesis, the activation of the glutamate transporter 1 (GLT-1) acts as a trigger for glucose uptake by astrocytes. With this in mind, we investigated glucose utilization changes after pharmacologically downregulating GLT-1 with clozapine (CLO), an anti-psychotic drug. METHODS: Adult male Wistar rats (control, n = 14; CLO, n = 12) received CLO (25/35 mg kg-1) for 6 weeks. CLO effects were evaluated in vivo with FDG-PET and cortical tissue was used to evaluate glutamate uptake and GLT-1 and GLAST levels. CLO treatment effects were also assessed in cortical astrocyte cultures (glucose and glutamate uptake, GLT-1 and GLAST levels) and in cortical neuronal cultures (glucose uptake). RESULTS: CLO markedly reduced in vivo brain glucose metabolism in several brain areas, especially in the cortex. Ex vivo analyses demonstrated decreased cortical glutamate transport along with GLT-1 mRNA and protein downregulation. In astrocyte cultures, CLO decreased GLT-1 density as well as glutamate and glucose uptake. By contrast, in cortical neuronal cultures, CLO did not affect glucose uptake. CONCLUSION: This work provides in vivo demonstration that GLT-1 downregulation induces astrocyte-dependent cortical FDG-PET hypometabolism-mimicking the hypometabolic signature seen in people developing dementia-and adds further evidence that astrocytes are key contributors of the FDG-PET signal.

Soluble amyloid-beta isoforms predict downstream Alzheimer's disease pathology.

BACKGROUND: Changes in soluble amyloid-beta (Aß) levels in cerebrospinal fluid (CSF) are detectable at early preclinical stages of Alzheimer's disease (AD). However, whether Aß levels can predict downstream AD pathological features in cognitively unimpaired (CU) individuals remains unclear. With this in mind, we aimed at investigating whether a combination of soluble Aß isoforms can predict tau pathology (T+) and neurodegeneration (N+) positivity. METHODS: We used CSF measurements of three soluble Aß peptides (Aß1-38, Aß1-40 and Aß1-42) in CU individuals (n = 318) as input features in machine learning (ML) models aiming at predicting T+ and N+. Input data was used for building 2046 tuned predictive ML models with a nested cross-validation technique. Additionally, proteomics data was employed to investigate the functional enrichment of biological processes altered in T+ and N+ individuals. RESULTS: Our findings indicate that Aß isoforms can predict T+ and N+ with an area under the curve (AUC) of 0.929 and 0.936, respectively. Additionally, proteomics analysis identified 17 differentially expressed proteins (DEPs) in individuals wrongly classified by our ML model. More specifically, enrichment analysis of gene ontology biological processes revealed an upregulation in myelinization and glucose metabolism-related processes in CU individuals wrongly predicted as T+. A significant enrichment of DEPs in pathways including biosynthesis of amino acids, glycolysis/gluconeogenesis, carbon metabolism, cell adhesion molecules and prion disease was also observed. CONCLUSIONS: Our results demonstrate that, by applying a refined ML analysis, a combination of Aß isoforms can predict T+ and N+ with a high AUC. CSF proteomics analysis highlighted a promising group of proteins that can be further explored for improving T+ and N+ prediction.

Astrocyte Biomarkers in Alzheimer Disease: A Systematic Review and Meta-analysis.

OBJECTIVE: To perform a systematic review and meta-analysis to determine whether fluid and imaging astrocyte biomarkers are altered in Alzheimer's disease (AD). METHODS: PubMed and Web of Science databases were searched for articles reporting fluid or imaging astrocyte biomarkers in AD. Pooled effect sizes were determined with mean differences (SMD) using the Hedge's G method with random-effects to determine biomarker performance. Adapted questions from QUADAS-2 were applied for quality assessment. A protocol for this study has been previously registered in PROSPERO (registration number: CRD42020192304). RESULTS: The initial search identified 1,425 articles. After exclusion criteria were applied, 33 articles (a total of 3,204 individuals) measuring levels of GFAP, S100B, YKL-40 and AQP4 in the blood and cerebrospinal fluid (CSF), as well as MAO-B, indexed by positron emission tomography 11C-deuterium-L-deprenyl ([11C]-DED), were included. GFAP (SMD = 0.94; 95% CI = 0.71-1.18) and YKL-40 (SMD = 0.76; CI 95% = 0.63-0.89) levels in the CSF, S100B levels in the blood (SMD = 2.91; CI 95% = 1.01-4.8) were found significantly increased in AD patients. CONCLUSIONS: Despite significant progress, applications of astrocyte biomarkers in AD remain in their early days. The meta-analysis demonstrated that astrocyte biomarkers are consistently altered in AD and supports further investigation for their inclusion in the AD clinical research framework for observational and interventional studies.

Pro-inflammatory interleukin-6 signaling links cognitive impairments and peripheral metabolic alterations in Alzheimer's disease.

Alzheimer's disease (AD) is associated with memory impairment and altered peripheral metabolism. Mounting evidence indicates that abnormal signaling in a brain-periphery metabolic axis plays a role in AD pathophysiology. The activation of pro-inflammatory pathways in the brain, including the interleukin-6 (IL-6) pathway, comprises a potential point of convergence between memory dysfunction and metabolic alterations in AD that remains to be better explored. Using T2-weighted magnetic resonance imaging (MRI), we observed signs of probable inflammation in the hypothalamus and in the hippocampus of AD patients when compared to cognitively healthy control subjects. Pathological examination of post-mortem AD hypothalamus revealed the presence of hyperphosphorylated tau and tangle-like structures, as well as parenchymal and vascular amyloid deposits surrounded by astrocytes. T2 hyperintensities on MRI positively correlated with plasma IL-6, and both correlated inversely with cognitive performance and hypothalamic/hippocampal volumes in AD patients. Increased IL-6 and suppressor of cytokine signaling 3 (SOCS3) were observed in post-mortem AD brains. Moreover, activation of the IL-6 pathway was observed in the hypothalamus and hippocampus of AD mice. Neutralization of IL-6 and inhibition of the signal transducer and activator of transcription 3 (STAT3) signaling in the brains of AD mouse models alleviated memory impairment and peripheral glucose intolerance, and normalized plasma IL-6 levels. Collectively, these results point to IL-6 as a link between cognitive impairment and peripheral metabolic alterations in AD. Targeting pro-inflammatory IL-6 signaling may be a strategy to alleviate memory impairment and metabolic alterations in the disease.

Fluid and imaging biomarkers for Alzheimer's disease: Where we stand and where to head to.

There is increasing evidence that a number of potentially informative biomarkers for Alzheimer disease (AD) can improve the accuracy of diagnosing this form of dementia, especially when used as a panel of diagnostic assays and interpreted in the context of neuroimaging and clinical data. Moreover, by combining the power of CSF biomarkers with neuroimaging techniques to visualize Aß deposits (or neurodegenerative lesions), it might be possible to better identify individuals at greatest risk for developing MCI and converting to AD. The objective of this article was to review recent progress in selected imaging and chemical biomarkers for prediction, early diagnosis and progression of AD. We present our view point of a scenario that places CSF and imaging markers on the verge of general utility based on accuracy levels that already match (or even surpass) current clinical precision.

Imaging Alzheimer's disease pathophysiology with PET / A fisiopatologia da Doença de Alzheimer através do PET

ABSTRACT Alzheimer's disease (AD) has been reconceptualised as a dynamic pathophysiological process characterized by preclinical, mild cognitive impairment (MCI), and dementia stages. Positron emission tomography (PET) associated with various molecular imaging agents reveals numerous aspects of dementia pathophysiology, such as brain amyloidosis, tau accumulation, neuroreceptor changes, metabolism abnormalities and neuroinflammation in dementia patients. In the context of a growing shift toward presymptomatic early diagnosis and disease-modifying interventions, PET molecular imaging agents provide an unprecedented means of quantifying the AD pathophysiological process, monitoring disease progression, ascertaining whether therapies engage their respective brain molecular targets, as well as quantifying pharmacological responses. In the present study, we highlight the most important contributions of PET in describing brain molecular abnormalities in AD.

RESUMO A doença de Alzheimer tem sido reconceitualizada como um processo patofisiológico dinâmico caracterizado pelos estágios pré-clínico, comprometimento cognitivo leve e demência. A tomografia por emissão de pósitrons associada a vários agentes de imagem molecular revela numerosos aspectos da patofisiologia da demência tais como amiloidose cerebral, acúmulo de tau, mudanças em neurorreceptores, anormalidades de metabolismo e neuroinflamação nestes pacientes. No contexto de um crescimento em direção ao diagnóstico precoce pré-sintomático e intervenções modificadores da doença, a imagem de PET com agentes moleculares fornece meio para quantificar o processo patofisiológico da DA sem precedentes, monitorizar a progressão da doença, bem como quantificar resposta farmacológica. Aqui, nós realçamos as mais importantes contribuições do PET na descrição de anormalidades moleculares cerebrais na DA.

Imaging Alzheimer's disease pathophysiology with PET.

Alzheimer's disease (AD) has been reconceptualised as a dynamic pathophysiological process characterized by preclinical, mild cognitive impairment (MCI), and dementia stages. Positron emission tomography (PET) associated with various molecular imaging agents reveals numerous aspects of dementia pathophysiology, such as brain amyloidosis, tau accumulation, neuroreceptor changes, metabolism abnormalities and neuroinflammation in dementia patients. In the context of a growing shift toward presymptomatic early diagnosis and disease-modifying interventions, PET molecular imaging agents provide an unprecedented means of quantifying the AD pathophysiological process, monitoring disease progression, ascertaining whether therapies engage their respective brain molecular targets, as well as quantifying pharmacological responses. In the present study, we highlight the most important contributions of PET in describing brain molecular abnormalities in AD.

A doença de Alzheimer tem sido reconceitualizada como um processo patofisiológico dinâmico caracterizado pelos estágios pré-clínico, comprometimento cognitivo leve e demência. A tomografia por emissão de pósitrons associada a vários agentes de imagem molecular revela numerosos aspectos da patofisiologia da demência tais como amiloidose cerebral, acúmulo de tau, mudanças em neurorreceptores, anormalidades de metabolismo e neuroinflamação nestes pacientes. No contexto de um crescimento em direção ao diagnóstico precoce pré-sintomático e intervenções modificadores da doença, a imagem de PET com agentes moleculares fornece meio para quantificar o processo patofisiológico da DA sem precedentes, monitorizar a progressão da doença, bem como quantificar resposta farmacológica. Aqui, nós realçamos as mais importantes contribuições do PET na descrição de anormalidades moleculares cerebrais na DA.

Frequency of the different mutations causing spinocerebellar ataxia (SCA1, SCA2, MJD/SCA3 and DRPLA) in a large group of Brazilian patients

Spinocerebellar ataxia type 1 (SCA1), spinocerebellar ataxia type 2 (SCA2) and Machado-Joseph disease or spinocerebellar ataxia type 3 (MJD/SCA3) are three distinctive forms of autosomal dominant spinocerebellar ataxia (SCA) caused by expansions of an unstable CAG repeat localized in the coding region of the causative genes. Another related disease, dentatorubropallidoluysian atrophy (DRPLA) is also caused by an unstable triplet repeat and can present as SCA in late onset patients. We investigated the frequency of the SCA1, SCA2, MJD/SCA3 and DRPLA mutations in 328 Brazilian patients with SCA, belonging to 90 unrelated families with various patterns of inheritance and originating in different geographic regions of Brazil. We found mutations in 35 families (39 percent), 32 of them with a clear autosomal dominant inheritance. The frequency of the SCA1 mutation was 3 percent of all patients; and 6 percent in the dominantly inherited SCAs. We identified the SCA2 mutation in 6 percent of all families and in 9 percent of the families with autosomal dominant inheritance. The MJD/SCA3 mutation was detected in 30 percent of all patients; and in the 44 percent of the dominantly inherited cases. We found no DRPLA mutation. In addition, we observed variability in the frequency of the different mutations according to geographic origin of the patients, which is probably related to the distinct colonization of different parts of Brazil. These results suggest that SCA may be occasionally caused by the SCA1 and SCA2 mutations in the Brazilian population, and that the MJD/SCA3 mutation is the most common cause of dominantly inherited SCA in Brazil.