Neuron number and size in prefrontal cortex of children with autism. Journal of the American Medical Association. 2011 Nov 9;306(18). Melodie J. Hallet, MS; Eric Courchesne, PhD; Michael E. Calhoun, PhD; Katerina Semendeferi, PhD; Clelia Ahrens-Barbeau, BS; Cynthia Carter Barnes, PhD; Peter R. Mouton, PhD; Karen Pierce, PhD

The Discovery: Male children with ASD have abnormally high levels of neurons in the region of the brain associated with social, emotional, communication, and cognitive development.

In this study, donated brain tissue from children diagnosed with autism was critical to determining that that male children with ASD had a significantly higher percentage of neurons—a type of brain cell and fundamental building block of the nervous system—in the region of the brain involved in higher-order social, emotional, communication, and cognitive development. Too many neurons in any part of the brain can lead to abnormal brain function and the development of brain disorders.

Impact: Since animals do not get autism this discovery would not have been possible without looking at the brain of someone with ASD. It is possible to then study the effects of too many neurons and how this might contribute to ASD.

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Age-dependent brain gene expression and copy number anomalies in autism suggest distinct pathological processes at young versus mature ages. PLoS Genetics. 2012;8(3). Chow ML, Pramparo T, Winn ME, Barnes CC, Li HR, Weiss L, Fan JB, Murray S, April C, Belinson H, Fu XD, Wynshaw-Boris A, Schork NJ, Courchesne E.

The Discovery: Critical genes involved in brain development and function such as those that control cell death and survival are altered in patients with ASD.

Donated brain tissue from children and adults was key to recent research from the University of California, Los Angeles. Changes in gene expression patterns were observed in brain tissue from donors diagnosed with ASD. Specifically, researchers found that children and adults with ASD had distinct changes in genes controlling the number of brain cells, depending on their age, resulting in either excess or reduced numbers of neurons in various brain regions associated with ASD, compared with individuals without ASD.

Impact: This study found that brain changes in ASD may be different depending on age and that gene expression is different in young vs. older people with ASD. This is a novel observation and important for understanding ASD in children and adults and may have implications for treatment at different ages.

Decreased expression of synapse-related genes and loss of synapses in major depressive disorder . Nature Medicine. 2012 Sep;18(9):1413-7. Kang HJ, Voleti B, Hajszan T, Rajkowska G, Stockmeier CA, Licznerski P, Lepack A, Majik MS, Jeong LS, Banasr M, Son H, Duman RS.

The Discovery: Patients with MDD have lower expression of genes related to how brain cells communicate in the brain region associated with working memory and executive function compared to controls.

In this study, analysis of post mortem brain tissue revealed that patients diagnosed with MDD had lower gene expression levels when compared to their healthy counterparts. The altered expression was observed for genes that are involved in synaptic function, the node between cells where they communicate. The synapse is critical to maintaining effective cell communication in the brain, and when disrupted, may contribute to changes in behaviors such as those observed in depressed individuals.

Impact: This study identifies specific molecular and cellular mechanisms that may contribute to depression. This research adds to our knowledge of the biology of MDD. Normalizing expression of these genes may be one strategy to develop more effective anti-depressive treatments.

Altered MicroRNA Expression Profiles in Postmortem Brain Samples from Individuals with Schizophrenia and Bipolar Disorder . BIOL PSYCHIATRY 2011;69:188–193 Moreau, MP, Bruse, SE, David-Rus, R, Buyske, S, Brzustowicz, LM.

The Discovery: Decreases in the abundance of a small number of microRNAs were found in bipolar disorder patients.

Utilizing donated brain tissue, researchers identified disorder-specific decreases in the abundance of microRNAs. These are a recently discovered type of RNA which regulates gene expression and a single microRNA may regulate many genes, amplifying the effect of even small changes in a small number of microRNA.

Impact: microRNAs role in normal brain development and function is still being elucidated. The finding that some of these are dysregulated in bipolar disorder provides an entirely new way to think about underlying causes and possible treatments.

Altered gene expression in the dorsolateral prefrontal cortex of individuals with schizophrenia . Molecular Psychiatry. 2013 Mar 26. Guillozet-Bongaarts AL, Hyde TM, Dalley RA, Hawrylycz MJ, Henry A, Hof PR, Hohmann J, Jones AR, Kuan CL, Royall J, Shen E, Swanson B, Zeng H, Kleinman JE.

The Discovery: Compared to healthy individuals, individuals diagnosed with schizophrenia have different gene expression patterns in a specific region of the brain associated with regulating executive function.

In this study, researchers utilized donated brain tissue from healthy people and those diagnosed with schizophrenia to examine the expression of a variety of genes in brain regions associated with schizophrenia, particularly genes in the dorsolateral prefrontal cortex (DLPFC). The DLPFC has been identified as one region that may be altered in schizophrenia. It has been shown to be crucial for verbal memory and fluency as well as working memory processes. Results from this study indicate that patients with schizophrenia do in fact have altered gene expression patterns, specifically in a part of the prefrontal cortex. These alterations may contribute to cell loss, which is frequently observed when analyzing brain tissue obtained from people with schizophrenia.

Impact: This study highlights previously unknown genes that may be altered in schizophrenia which may lead to new drug targets or new ideas about risk factors for schizophrenia.

Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination . Annals of Neurology. 2000 Jun;47(6):707-17. Lucchinetti C, Brück W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H.

The Discovery: Researchers identified that subgroups of patients with MS, such as those with differing stages of the disease, do not exhibit the same patterns of demyelination.

In this study, researchers used human post-mortem brain tissue to analyze patterns of myelin loss, or demyelination, in patients diagnosed with MS. The researchers found that the target of nerve cell injury and the causes for demyelination are distinctly different in subgroups of the disease and at different stages of disease.

Impact: The observation that there are fundamentally different disease processes going on in distinct subgroups or stages of MS, suggests that a therapy that may be useful in one group of patients or at one stage of the disease may not be helpful or might even be deleterious in another. This study also led to the establishment of lesion categories for MS.

Monocarboxylate transporter 1 is deficient on microvessels in the human epileptogenic hippocampus. Neurobiology of Disease. 2011 Feb;41(2):577-84. Lauritzen F, de Lanerolle NC, Lee TS, Spencer DD, Kim JH, Bergersen LH, Eid T.

The Discovery: Individuals with temporal lobe epilepsy (TLE) have lower levels of monocarboxylate transporter 1 (MCT1) compared to healthy people.

Impaired brain energy metabolism and resistance to antiepileptic drugs are common features of TLE. In order to better understand the underlying mechanisms of TLE, researchers at Yale University School of Medicine assessed the distribution of monocarboxylate transporter 1 (MCT1) in individuals diagnosed with epilepsy that did not respond to drug treatment. MCT1 is a key transporter that facilitates the transport of important metabolic fuels that are critical for normal brain function and some anti-epileptic drugs. Analysis of post-mortem brain tissue revealed that individuals diagnosed with TLE had significantly lower levels of MCT1. These studies suggest that the loss of MCT1 may contribute to seizures and resistance to common epilepsy drug treatments.

Impact: This study presents strong evidence that the loss of MCT1 contributes to drug resistance in individuals with TLE. Approaches that aim to restore MCT1 may represent a novel therapeutic approach for this disease and lead to more effective treatments.

Inflammation and white matter degeneration persist for years after a single traumatic brain injury . Brain. 2013: 136; 28–42. Johnson VE, Stewart JE, Begbie FD, Trojanowski JQ, Smith DH, Stewart.

The Discovery: Using post-mortem tissue, researchers discovered evidence of ongoing inflammatory processes that persisted for many years following a single TBI. Researchers analyzed the density and morphology of microglia in 53 cases of TBI (ranging from 10 h to 47 years post injury) and 44 age-matched, uninjured control subjects using tissue from the Glasgow Traumatic Brain Injury archive. Approximately 25% of the chronic TBI cases displayed extensive, densely packed, reactive microglia, a pathology that was not seen in control subjects or acutely injured cases. In cases displaying this inflammatory pathology, evidence of ongoing white matter degradation was also observed.

Impact: These data demonstrate the value of neuropathological assessment in understanding mechanisms of acute and chronic phases of TBI.

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The spectrum of disease in chronic traumatic encephalopathy . Brain. 2013: 136; 43–64. McKee AC, Stein TD, Nowinski CJ, Stern RA, Daneshvar DA, Alvarez VE, Lee H-S, Hall G, Wojtowicz SM, Baugh CM, Riley DO, Kubilus CK, Cormier KA, Jacobs MA, Martin BR, Abraham CR, Ikezu T, Reichard RR, Wolozin BL, Budson AE, Goldstein LE, Kowall NW, Cantu RC.

The Discovery: Researchers found evidence of CTE in the brains of 80% of individuals with a history of repetitive mild TBI. 85 subjects with histories of repetitive mild TBI and 18 age- and gender-matched control subjects were examined for evidence of CTE. In the cohort with repetitive mild TBI, researchers observed a spectrum of tau pathology that they used to develop criteria for staging the progression of CTE (stages 1 – IV). They also compared the neuropathology of CTE to other neurodegenerative diseases.

Impact: This is one of the largest and most recent studies undertaken on CTE neuropathology. This study demonstrates that in some individuals, there may be significant long-term consequences of repetitive brain trauma that have traditionally been considered only mild.

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Amyloid Imaging With Carbon 11–Labeled Pittsburgh Compound B for Traumatic Brain Injury . JAMA Neurol. 2014 January; 71(1): 23–31. Hong YT, Veenith T, Dewar D, Outtrim JG, Mani V, Williams C, Pimlott S, Hutchinson PJA, Tavares Ad, Canales R, Mathis CA, Klunk WE, Aigbirhio FI, Coles JP, Baron J-C, Pickard JD, Fryer TD, Stewart W, Menon DKM.

The Discovery: Brain imaging studies demonstrated that [11C]PiB PET was able to detect significant increases in amyloid deposition (a marker of neurodegeneration) in patients 1 – 321 days following a TBI (n = 15, ages 21 – 50 years) in comparison to age-matched controls (n = 11, ages 24 – 60 years). The discovery was validated with autoradiography and immunocytochemistry using postmortem brain tissue specimens of TBI cases (n = 16, ages 21 – 70) and control cases (n = 7, ages 29 – 71 years).

Impact: This study highlights the value of neuroimaging/neuropathology correlation studies and also the need for biospecimens from both patients and age-matched controls.