Neurological Disorders

Parkinson's disease (PD) is a progressive disorder of the nervous system that affects movement. PD is the second most common neurodegenerative disorder after Alzheimer's disease and affects approximately seven million people globally and one million people in the United States. The prevalence (proportion in a population at a given time) of PD is about 0.3% of the whole population in industrialized countries. PD is more common in the elderly and prevalence rises from 1% in those over 60 years of age to 4% of the population over 80. The mean age of onset is around 60 years, although 510% of cases, classified as young onset, begin between the ages of 20 and 50.

Although Parkinson's disease can't be cured, medications may markedly improve your symptoms. It develops gradually, sometimes starting with a barely noticeable tremor in just one hand. But while tremor may be the most well-known sign of Parkinson's disease, the disorder also commonly causes stiffness or slowing of movement. In the early stages of Parkinson's disease, face may show little or no expression, or arms may not swing when you walk. Speech may become soft or slurred. Parkinson's disease symptoms worsen as condition progresses over time. Medical management can often improve the quality of life of patients with PD.

Our Laboratory Investigates:

Quantification of tissue injury at the cellular level in the substantia nigra (SN) region in the patients with PD with advanced MRI techniques such as Magnetic Resonance Spectroscopy (MRS), Diffusion Tensor Imaging (DTI) and Magnetization Transfer Ratio (MTR). We are developing biomarkers that quantify tissue injury and response to therapy. This will also enable us to test new therapies for PD. Below are some examples of our exploratory imaging studies in PD:

MR spectroscopy of the substantia nigra, the region that produces dopamine	Phase contrast image to identify substantia nigra (SN)
Whole Brain tissue Apparent Diffusion Coefficients (ADC) map of DTI	Whole Brain Tissue Fractional Anisotropy (FA) map of DTI
Whole brain tissue Magnetization Transfer Ratio (MTR) map	Whole brain tissue Diffusion Tensor Imaging (DTI) map

Multiple sclerosis (MS) is an inflammatory disease which damages the insulating covers of nerve cells in the brain and spinal cord, known as myelin. This damage results in a wide range of signs and symptoms including physical and cognitive. MS is usually of two types: with new symptoms either occurring in isolated attacks (relapsing form or RRMS) or slow progression of symptoms from the onset (progressive form or PPMS). However, there is no complete remission as permanent neurological problems may occur over time.

There is no known cure for multiple sclerosis. Treatments attempt to improve function after an attack and prevent new attacks. They may also slow disease from progression. There are 10 treatments approved by the FDA for the treatment of relapsing forms of MS but none for the progressive form. Several new trails are underway to test therapies for PPMS. As of 2008, between 2 and 2.5 million people are affected globally with rates varying widely in different regions of the world and among different populations. The disease usually begins between the ages of 20 and 40 and is three times as common in women as in men. It is widely believed that the earliest detailed description of MS was in 1868 by Jean-Martin Charcot. While the cause is not clear, the underlying mechanism is thought to be either destruction by the immune system or failure of the myelin-producing cells. Proposed causes include genetics and environmental factors such as infections or vitamin D deficiency. MS is usually diagnosed based on the presenting signs and symptoms and the investigations, of which brain MRI scan is the most useful.

Our Laboratory Investigates:

Quantification of tissue injury that includes lesion volume and morphology, brain volume, grey and white matter injury, corpus callosum volume, MTR, DTI, and voxel-wise MTR analysis to detect myelin signal in-vivo.

By using whole brain MTR, we can quantify the myelin content of the whole brain. Quantification of myelin loss at cellular level in a particular lesion over time is also performed by using one of the advanced techniques: Voxel-wised MTR. Microscopic movement of water in tissues is quantified by using DTI.

T1-W Image showing lesion in dark in ROIs (Red)	T2-W image showing lesion as hyper-intensity in ROIs (Red)
Voxel -wised analysis of the lesion. Green- remyelination: Blue- stable region; Red- demyelination	Whole brain tissue Magnetization Transfer Ratio (MTR) map
Spinal Cord volume measurement shown in ROI (Red)	Axial FLAIR image used as reference image to estimate lesion volume

Alzheimer's disease is an irreversible, progressive brain disease that slowly destroys memory and thinking skills, and eventually even the ability to carry out the simplest tasks. In most people with Alzheimer's, symptoms first appear after the age 60. Estimates vary, but experts suggest that as many as 5.1 million Americans may have Alzheimer's disease. In 2006, there were 26.6 million sufferers worldwide. Alzheimer's is predicted to affect 1 in 85 people globally by 2050.

The cause and progression of Alzheimer's disease are not well understood. Research indicates that the disease is associated with plaques and tangles in the brain. Current treatments only help with the symptoms of the disease. There are no available treatments that stop or reverse the progression of the disease. As of 2012, more than 1,000 clinical trials have been or are being conducted to test various compounds in AD.

Our Laboratory Investigates:

Quantification of tissue injury and the loss of cortical and grey matter tissue in patients with AD. In this context, we are undertaking investigations in patients with AD that use novel imaging techniques such as DTI, MTR, MRS, gray matter segmentation and morphometric studies of the cortical gray matter.

Segmentation of White matter (in Red) from the whole brain tissue in T1-W image	Segmentation of Grey matter (in Red) from the whole brain tissue in T1-W image
Input image- 3D T1-weighted (MPRAGE, SPGR) image for cortical thickness measurement	Output Image- Segmented & parcellated conformed volume
	>
Whole brain tissue- Axial diffusivity map of DTI	Whole brain tissue- Radial diffusivity map of DTI

Stroke is an emergency that result from cutting off vital blood flow and oxygen to the brain. The statistics below give a perspective on stroke and its devastating impact:

• In the United States, stroke is the fourth leading cause of death, killing over 133,000 people each year, and a leading cause of serious, long-term adult disability.
• There are an estimated 7,000,000 stroke survivors in the U.S. over age 20.
• Approximately 795,000 strokes will occur this year, one occurring every 40 seconds, and taking a life approximately every four minutes.
• Stroke can happen to anyone at any time, regardless of race, sex or age.
• From 1998 to 2008, the annual stroke death rate fell approximately 35 percent, and the actual number of deaths fell by 19 percent.
• Approximately 55,000 more women than men have a stroke each year.
• African Americans have almost twice the risk of first-ever stroke compared with whites.
• Two million brain cells die every minute during stroke, increasing risk of permanent brain damage, disability or death. Recognizing symptoms and acting FAST to get medical attention can save a life and limit disabilities.
• Women are twice more likely to die from stroke than breast cancer annually.
• The estimated direct and indirect cost of stroke in the United States in 2010 is $73.7 billion.

During an acute ischemic event, cellular adenosine triphosphate is depleted, leading to failure of cell membrane sodium-potassium pumps. This (along with other chemical effects) leads to an acute influx of water into cells with swelling of the affected cells (cytotoxic edema). The end result is that the increased intracellular water (which shows less overall diffusion than does extracellular interstitial water) demonstrates a decrease in the amount of net diffusion of water present in brain parenchyma experiencing cytotoxic edema. There are alternative explanations for what is occurring at the cellular level, but the end result is the same with respect to imaging.

Our Laboratory Investigates:

Quantification of tissue injury and repair following stroke. This can be done in various ways but understating water diffusion is key to acute stroke biology. Net diffusion of water on a DWI MR scan. Areas of decreased water diffusion will be seen as areas of increased signal on d MR and can be seen as early as 22 minutes after an ischemic insult. Scans or ADC maps are usually considered evidence of irreversible ischemic damage, though there are reports of reversal of DWI MR findings after successful recanalization of a blood vessel with intra-arterial thrombolysis. Similarly, although DWI MR is considered a sensitive method for ruling out infarction, there have also been case reports of patients with initially (within 4 hours) negative DWI MR scans who went on to cerebral infarction.

Our interest is in quantifying tissue injury and repair occurring after stroke and how it may affect clinical outcomes. Despite several advances in the field of stroke including the clot busting drug "tPA", it is not clear why repair following acute stroke varies from person to person after adjusting for all variables such as hypertension, high cholesterol, diabetes, weight, smoking, and etc.

Newer imaging techniques such as DTI, MTR, and MRS will provide quantitative information regarding tissue injury and repair potential after stroke.

It is also well known that stroke occurs more commonly in African-Americans than Caucasians. and that African-Americans tend to experience a worse outcome after stroke. The reasons for these are not entirely clear, especially relating to repair in the brain in African-Americans with stroke. These investigations could help design strategies to improve outcomes and recovery from stroke.

CT perfusion maps of cerebral blood volume; white oval shows a region of decreased blood volume	CT perfusion maps of cerebral blood flow; black oval shows a region of decreased blood flow
DWI showing acute infarct in the left MCA region	DWI showing acute infarct in the left MCA region

Amyotrophic lateral sclerosis (ALS), often referred to as "Lou Gehrig's Disease," is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. Motor neurons reach from the brain to the spinal cord and from the spinal cord to the muscles throughout the body. The progressive degeneration of the motor neurons in ALS eventually leads to their death. When the motor neurons die, the ability of the brain to initiate and control muscle movement is lost. With voluntary muscle action progressively affected, patients in the later stages of the disease may become totally paralyzed.

As motor neurons degenerate, they can no longer send impulses to the muscle fibers that normally result in muscle movement. Early symptoms of ALS often include increasing muscle weakness, especially involving the arms and legs, speech, swallowing or breathing. When muscles no longer receive the messages from the motor neurons that they require to function, the muscles begin to atrophy (become smaller). Limbs begin to look "thinner" as muscle tissue atrophies.

While there is not a cure or treatment today that halts or reverses ALS, there is one FDA approved drug, Riluzole that modestly slows the progression of ALS as well as several other drugs in clinical trials that hold promise.

Our Laboratory Investigates:

Quantification of tissue injury and develop an MR imaging biomarker that can be employed in early-stage pilot studies of promising compounds in ALS. By having a reliable biomarker, more potential drugs for ALS could be examined in less time requiring fewer patients. Our lab has developed multiple MRI approaches that focus on quantifying motor neuron injury including MRS, DTI, and MTR.

Single voxel 1H-MRS showing pons in VOI (voxel of interest outlined in square)	Region in Red showing pre and post central gyrus in the motor cortex region
Axial FLAIR image of ALS patient	Spinal cord ROI (Region of interest in Red) drawn in Axial T2-W image

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, usually called CADASIL, is an inherited condition that causes stroke and other impairments. This condition affects blood flow in small blood vessels, particularly cerebral vessels within the brain. The muscle cells surrounding these blood vessels (vascular smooth muscle cells) are abnormal and gradually die. In the brain, the resulting blood vessel damage (arteriopathy) can cause migraines, often with visual sensations or auras, or recurrent seizures (epilepsy).

1H-MRS CSI acquired in 6 X 6 matrixes to observe metabolite's concentration changes	MTR map showing 6 X 6 matrix to observe White Matter changes
Whole brain tissue Magnetic Transfer ratio (MTR) map	Axial FLAIR image identifying the tissue damage in the white matter

Huntington's disease (HD) is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and psychiatric problems. It typically becomes noticeable in mid-adult life. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea.

It is much more common in people of Western European descent than in those of Asian or African ancestry. The disease can affect both men and women. The disease is caused by an autosomal dominant mutation in either of an individual's two copies of a gene called Huntington, which means any child of an affected person typically has a 50% chance of inheriting the disease. Physical symptoms of Huntington's disease can begin at any age from infancy to old age, but usually begin between 35 and 44 years of age.

Everyone has the HD gene but it is those individuals that inherit the expansion of the gene who will develop HD and perhaps pass it onto each of their children. Presently, there is no effective treatment or cure. Although medications can relieve some symptoms, research has yet to find a means of slowing the deadly progression of HD. Current estimates are that 1 in every 10,000 Americans has HD and more than 250,000 others are at-risk of having inherited it from a parent. Once thought a rare disease, HD is now considered one of the more common hereditary disorders.

Our Laboratory Investigates:

Quantification of tissue injury by using a variety of imaging techniques including MRS, DTI, and MTR.

Coronal section of a patient with HD showing atrophy of the heads of the caudate nuclei and enlargement of the frontal horns of the lateral ventricles	Basal ganglia cells (ROI) (in red) and reference cells (in green). Hypo-intense pixels are displayed in yellow/orange.

Progressive multifocal leukoencephalopathy (PML) is a disease of the white matter of the brain, caused by a virus infection that targets cells that make myelin--the material that insulates nerve cells (neurons). Polyomavirus JC (often called JC virus) is carried by a majority of people and is harmless except among those with lowered immune defenses. The disease is rare and occurs in patients undergoing chronic corticosteroid or immunosuppressive therapy for organ transplant, or individuals with cancer (such as Hodgkin's disease or lymphoma). Individuals with autoimmune conditions such as multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosis, some of whom are treated with biological therapies that allow JC virus reactivation, are at risk for PML as well. PML is most common among individuals with HIV-1 infection/acquired immune deficiency syndrome (AIDS). Studies estimate that prior to effective antiretroviral therapy, as many as 5 percent of persons infected with HIV-1 eventually develop PML that is an AIDS-defining illness.

Our Laboratory Investigates:

Quantification of tissue injury that distinguishes between MS activity from that of PML is done by using certain MRI characteristics. Magnetization transfer ratio (MTR) studies may provide additional clues in improving early detection of PML in patients with pre-existing MS and warrant further investigation.

T2-W image showing Lesion in ROI (region of interest in Red)	T1-W image showing Lesion in ROI (region of interest in Red)
T1-W Post contrast image showing GAD enhancing Lesion in ROI (region of interest in Red)	Axial FLAIR image used as reference for estimating Lesion volume