Margaret McKernan, MD, PhD – Brain Blogger Health and Science Blog Covering Brain Topics Wed, 30 May 2018 15:00:03 +0000 en-US hourly 1 Does HIV Make the Brain Old Before Its Time? Sat, 08 Sep 2012 11:00:16 +0000 Approximately 10% of HIV-positive individuals develop profound memory loss, cognitive problems and severe depression. This HIV-associated dementia closely mimics dementia typically seen in the elderly, who are decades older than the individuals most commonly infected with HIV.  What makes the brains of these young people act old before their time? The answer may lie in a small protein called a growth factor.

The cells of the body, brain cells included, are in a constantly shifting balance. Old and damaged cells undergo a form of programmed cell death known as apoptosis. While it sounds ominous, apoptosis is necessary to maintain the balance between new cell growth and cell death. Shifting the balance toward uncontrolled cell growth can result in cancer. However, when the balance shifts the other way and too many cells are destroyed, diseases can also arise. In the brain, this excess destruction of cells can lead to dementia.

Researchers at Georgetown University Medical Center discovered that HIV does not directly infect nerve cells, but instead blocks the formation of a growth factor known as mature BDNF (brain derived neurotrophic factor). When the level of this protein decreases in the brain, brain cells are unable to create the long dendritic and axonal branches required to communicate with each other, and die.

The researchers also uncovered the underlying mechanism for this premature cell death. Brain cells release a precursor to the BDNF growth factor called proBDNF. This must be divided by enzymes in the brain to release the active BDNF form, which nourishes brain cells and maintains the connections between them. HIV blocks this division, resulting in high circulating levels of proBDNF.  proBDNF binds to a receptor on brain cells that contains a ‘death domain’, triggering apoptosis (cell death).

This HIV-induced imbalance between toxic proBDNF and the healthy form of mature BDNF is similar to the imbalance seen in the aging brain. In a news release from Georgetown University, lead investigator Italo Mocchetti stated ‘“We believe we have discovered a general mechanism of neuronal decline that even explains what happens in some elderly folks. The HIV-infected patients who develop this syndrome are usually quite young, but their brains act old.” Lack of mature BDNF may also play a role in other chronic neurological conditions, including Parkinson’s and Huntington’s Diseases.

The hope is that this new research may eventually lead to the development of drugs effective in multiple forms of dementia. Blocking the receptor for proBDNF could stop the deadly cascade leading to premature cell death, and slow the relentless pace of dementia in both patients with HIV and the elderly.


Bachis A, Avdoshina V, Zecca L, Parsadanian M, & Mocchetti I (2012). Human immunodeficiency virus type 1 alters brain-derived neurotrophic factor processing in neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience, 32 (28), 9477-84 PMID: 22787033

Hogan C, & Wilkins E (2011). Neurological complications in HIV. Clinical medicine (London, England), 11 (6), 571-5 PMID: 22268312

Nosheny RL, Mocchetti I, & Bachis A (2005). Brain-derived neurotrophic factor as a prototype neuroprotective factor against HIV-1-associated neuronal degeneration. Neurotoxicity research, 8 (1-2), 187-98 PMID: 16260395

Wendelken LA, & Valcour V (2012). Impact of HIV and aging on neuropsychological function. Journal of neurovirology, 18 (4), 256-63 PMID: 22528478

Image via Sebastian Kaulitzki / Shutterstock.

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The Silent Stalker – Alzheimer’s Changes the Brain Years Before First Symptoms Sat, 04 Aug 2012 11:00:11 +0000 Twenty-five years before the first clinical symptoms, Alzheimer’s disease has already produced permanent changes in the brain. New research published in the New England Journal of Medicine traces the timeline of the disease, challenging current perceptions about this devastating form of dementia.

Most cases of Alzheimer’s are sporadic, meaning that they arise in a seemingly random fashion, without a family history or other identifiable cause. However, a small proportion — approximately 1% — of individuals with Alzheimer’s have a special genetically inherited form. The Dominantly Inherited Alzheimer Network (DIAN) was formed to facilitate the study of families carrying these genetic mutations; members have been recruited from across the US, as well as Australia and the United Kingdom. While the 128 subjects in the current study are presently asymptomatic (showing no signs of dementia), approximately half of them are expected to eventually develop clinical Alzheimer’s disease.

Children who inherit one of these three mutations leading to Alzheimer’s disease tend to develop signs of dementia at approximately the same age as their parents. This allowed researchers at Washington University in St Louis to work backwards to construct a timeline of the changes in the brain seen with Alzheimer’s disease.

The earliest biomarkers of Alzheimer’s are associated with the formation of beta-amyloid plaques. Plaques represent clumps of a specific protein (beta-amyloid) intermixed with neurons (brain cells). Beta-amyloid plaques are believed to interfere with communication between nerve cells, and possibly trigger nerve cell damage. Twenty-five years before the expected onset of Alzheimer’s symptoms, the level of amyloid proteins decreases in the cerebrospinal fluid (CSF).

Fifteen years before the onset of symptoms, beta-amyloid plaque formation begins. These plaques are visible on noninvasive PET-CT scans of the brain. Atrophy, or shrinking of the brain tissue, also begins around this time.

Ten years before the onset of clinical Alzheimer’s, parts of the brain become hypometabolic, or less active. There is also subtle impairment in episodic memory, a subtype of long-term memory involving the recollection of specific events.

Furthermore, the appearance of these markers is specific for Alzheimer’s disease; family members without the Alzheimer’s mutations demonstrate no changes in brain chemistry or structure. This suggests that biomarkers may eventually be used to screen for Alzheimer’s in asymptomatic individuals, much like blood glucose levels are used to screen for diabetes or PSA levels for prostate cancer.

In a news release from Washington University, first author Randall Bateman, MD stated “As we learn more about the origins of Alzheimer’s to plan preventive treatments, this Alzheimer’s timeline will be invaluable for successful drug trials.”

The researchers plan to start clinical trials later this year aimed at blocking the formation of beta-amyloid plaques. The hope is that targeting Alzheimer’s at this early preclinical stage, before significant memory loss and impairment take hold, may represent the best chance for effective prevention and treatment.


Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC, Marcus DS, Cairns NJ, Xie X, Blazey TM, Holtzman DM, Santacruz A, Buckles V, Oliver A, Moulder K, Aisen PS, Ghetti B, Klunk WE, McDade E, Martins RN, Masters CL, Mayeux R, Ringman JM, Rossor MN, Schofield PR, Sperling RA, Salloway S, Morris JC, & the Dominantly Inherited Alzheimer Network (2012). Clinical and Biomarker Changes in Dominantly Inherited Alzheimer’s Disease. The New England journal of medicine PMID: 22784036

Price JL, & Morris JC (1999). Tangles and plaques in nondemented aging and “preclinical” Alzheimer’s disease. Annals of neurology, 45 (3), 358-68 PMID: 10072051

Jack CR Jr, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, Petersen RC, & Trojanowski JQ (2010). Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet neurology, 9 (1), 119-28 PMID: 20083042

Image via John Wollwerth / Shutterstock.

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