ROAD TO THE CURE UPDATE MARCH 2016

What Are Lewy Bodies? – Lewy bodies (LBs) are spherical masses of aggregated protein that disrupt the normal function of the brain. In 1912, a German neurologist Dr. Friedrich Lewy discovered these abnormal deposits now known as “Lewy bodies” in the autopsied brains of Parkinson’s patients. Lewy bodies per se are not pathogenic. In fact, they may be protecting neurons by scavenging oligomeric forms of alpha-synuclein that have been shown to cause neurotoxicity. For example, Lewy body-containing neurons have been found to be morphologically (the study of how things are put together) healthier than neighboring non-Lewy body-containing neurons in the brain autopsies.

What Are Lewy Bodies Made Of? – Lewy bodies are made of a protein called alpha-synuclein. In the healthy brain, alpha-synuclein plays a number of important roles in neurons (nerve cells) in the brain, especially at synapses, where brain cells communicate with each other. Unfortunately, due to genetic and environmental factors when our body starts generating alpha-synuclein on a scale the body cannot metabolize fast enough, an unwanted and almost lethal process known as mis-folding of alpha-synuclein starts, which leads to clumping and neuronal toxicity. Other proteins associated with Lewy bodies are Tau, ubiquitin and alpha B crystallin. However, the primary structural component of Lewy bodies is alpha-synuclein.

Brain Regions Where Lewy Bodies Are Found  The cerebral cortex, which controls many functions, including information processing, perception, thought, and language; The limbic cortex, which plays a major role in emotions and behavior; The hippocampus, which is essential to forming new memories; The midbrain, including the substantia nigra, which is involved in movement; The brain stem, which is important in regulating sleep and maintaining alertness, and; Brain regions important in recognizing smells (olfactory pathways).

Lewy Body Disease (LBD) – Although LBs are considered not harmful, their aberrant mass production and topographical distribution in the brain results in LBD and Parkinson Disease - related clinical symptoms. LBD may cause a wide range of symptoms such as loss of memory, lack of focus, movement problems, confusion and muscle stiffness.

Lewy Body Dementia or Dementia with Lewy Bodies (DLB) – The progressive spread of LB pathology from the brainstem to the neocortex has been suggested to finally result in dementia, which is defined as severe loss of thinking abilities that interferes with a person’s capacity to perform daily activities such as household tasks, personal care, and handling finances. In simple words, neurodegenerative dementia results from the abnormal clumps made of alpha-synuclein in the brain. These clumps are found in neurons throughout the outer layer of the brain known as the cerebral cortex and deep inside the mid-brain and brain stem. These deposits affect chemicals in the brain whose changes, in turn, can lead to problems with thinking, movement, behavior, and mood. DLB is one of the most common causes of dementia, after Alzheimer’s disease and vascular disease. Individuals with DLB experience progressive cognitive decline, although symptoms may vary between patients. Common symptoms are movement disorders, visual hallucinations, and fluctuations in thinking skills or attention. Dementia can be due to several reasons some of which are shown below. Depression and vitamin deficiency (not listed in the diagram below) can also cause dementia.

Figure: Pathology of Dementia Parkinson’s disease with dementia (PDD) versus dementia Lewy bodies Dementia (DLB) – Some patients with Parkinson’s experience no or only subtle cognitive decline and their primary limitation is their motor disorder. However, many patients with Parkinson’s disease will develop dementia as a consequence of the disease. When dementia develops after an established motor disorder, we call the disease PDD. In contrast, when the dementia develops prior to or at the same time as the motor disorder, we call the disease LBD. Although the initial sequence of symptoms differs in PDD and DLB, as the disorders progress, the symptoms and the underlying brain changes are much more similar than they are different. As such, many researchers and clinicians think of PDD and DLB as being on a continuum of a similar disease process rather than as two distinct entities.

Signs & symptoms – The parkinsonian motor syndrome is similar in PDD and DLB that may include slowed movement (bradykinesia), rigidity (muscles feel still and resist movement), tremor and gait difficulties. Cognition can progressively decline resulting in problems involving visual spatial processing, attention, executive dysfunction (e.g., planning and multi-tasking) and memory. Psychiatric symptoms are common and can include anxiety, depression, hallucinations (usually visual) and delusions (false beliefs). Sleep problems including excessive daytime drowsiness and difficulty staying asleep are common. Many patients exhibit REM sleep behavior disorder (RBD) that manifests by the patient acting out his or her dreams. Constipation, repeated falls, syncope and loss of smell are also the common symptoms.

Diagnosis – There are no clinical diagnostics for Lewy body diseases such as DLB and PDD. Even today the diagnosis is made by excluding other diseases. An extensive neurological and neuropsychological evaluation is essential for Lewy body dementia diagnosis. Structural brain imaging (e.g., MRI or CT) and laboratory tests are used to rule out other diagnoses. Lewy body dementias can be difficult to diagnose because they can resemble and overlap with other causes of dementia like Alzheimer’s disease, other parkinsonian syndromes [examples: progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal syndrome], and vascular dementia. As in many neurodegenerative diseases, a definitive diagnosis in only available after an autopsy. Disease progression – Onset of the disorder usually occurs in older adults, and disease risk increases with age. There is substantial variability in the course of the illness. In general, symptoms progress over several years as cognitive decline becomes more prominent and psychiatric symptoms emerge or worsen. The progression of symptoms represents increasing pathology in the brain including more widespread Lewy bodies, loss of neurotransmitters (examples: dopamine and acetylcholine) and nerve cell death.

Management and treatment of Lewy body dementias – There are no treatments to halt or slow down the progression of dementia. The current therapy only treats symptoms for a short while. What ICBI is doing to overcome dementia, a global problem – As shown in the figure above, there are several diseases involved in causing different types of dementia. The aberrant problematic proteins implicated in causing these different diseases have been identified. ICBI has developed unprecedented and possibly disease altering blood-brain barrier (BBB) permeable SMART Molecules (SMs) for many of the aberrant proteins. These SMs have shown to hit their intended targets in the brain. Their work has been recognized by the MJFF with two grants. What ICBI needs to do now is to mass produce these SMs on a bigger scale to demonstrate their safety first in a large number of mice, get an IND approved by the FDA and start clinical trials. The Company is trying to raise funds for these tasks.