Frontotemporal Neurocognitive Disorder

Figure 1. FTLD is associated with the shrinking of the frontal and temporal lobes of the brain and shares some characteristics of Alzheimer’s disease, including misfolded proteins and loss of brain cells.

Damage to the brain’s frontal and temporal lobes causes forms of neurocognitive disorders (dementia) called frontotemporal lobar degeneration (FTLD) or frontotemporal disorders.

Frontotemporal disorders (FTLD) are the result of damage to neurons (nerve cells) in parts of the brain called the frontal and temporal lobes. As neurons die in the frontal and temporal regions, these lobes atrophy, or shrink. Gradually, the damage causes difficulties in thinking and behaviors normally controlled by these parts of the brain. Many possible symptoms can result, including unusual behaviors, emotional problems, trouble communicating, difficulty with work, or difficulty with walking.

Frontotemporal disorders (FTLD) are forms of dementia caused by a family of brain diseases known as frontotemporal lobar degeneration. Dementia is defined as a severe loss of thinking abilities that interferes with a person’s ability to perform daily activities such as working, driving, and preparing meals. Other brain diseases that can cause dementia include Alzheimer’s disease and multiple strokes. Scientists think that FTLD is the most common cause of dementia in people younger than age 60. Roughly 60% of people with FTLD are 45–64 years old. People with FTLD have changes in the brain due to another form of tau or the protein TDP43 and the range of symptoms can include unusual behaviors, emotional problems, communication difficulties, motor coordination (i.e., difficulty walking), and executive functions (i.e., difficulty with employment). In comparison, Alzheimer’s is primarily associated with amyloid and tau proteins and is characterized predominately by memory problems.

People can live with frontotemporal disorders for up to 10 years, sometimes longer, but it is difficult to predict the time course for an individual patient. The frontotemporal disorders are progressive. In the early stages of FTLD, people may exhibit only one symptom. As FTLD progresses, patients will begin to experience other types of symptoms as more parts of the brain are affected.

Currently, there is no cure or treatments that slow or stop the progression of frontotemporal disorders. However, as awareness and understanding of FTLD expand, research has increased development to include advancements on better diagnosis, improved care, and, eventually, new treatments.

Frontotemporal disorders affect the frontal and temporal lobes of the brain. Frontotemporal disorder can begin in the frontal lobe, the temporal lobe, or both. Initially, frontotemporal disorders leave other brain regions untouched, including those that control short-term memory.

The frontal lobes, situated above the eyes and behind the forehead on the right and left sides of the brain, direct executive functioning. Direct executive functioning includes planning and sequencing (thinking through which steps come first, second, third, and so on), prioritizing (doing more important activities first and less important activities last), multitasking (shifting from one activity to another as needed), and monitoring and correcting errors. Symptoms are determined by which part of the lobe is affected first. The frontal lobe is responsible for decision-making, so the first symptom might be trouble managing finances.

When the frontal lobes are functioning well, the frontal lobes also help manage emotional responses. The frontal lobes enable people to avoid inappropriate social behaviors, such as shouting loudly in a library or at a funeral. The frontal lobes also help people make decisions that make sense for a given situation. When the frontal lobes are damaged, people may focus on insignificant details and ignore important aspects of a situation or engage in purposeless activities. The frontal lobes are also involved in language, particularly linking words to form sentences, and in motor functions, such as moving the arms, legs, and mouth.

Figure 2. Brain MRI of a female, 65-year-old patient with Pick’s disease. Cortex and white matter atrophy of the frontal lobes is clearly visible.

The temporal lobes, located below and to the side of each frontal lobe on the right and left sides of the brain, contain essential areas for memory but also play a major role in language and emotions. The temporal lobes help people understand words, speak, read, write, and connect words with their meanings. The temporal lobes also allow people to recognize objects and to relate appropriate emotions to objects and events. When the temporal lobes are dysfunctional, people may have difficulty recognizing emotions and responding appropriately to them. Issues in the part of the temporal lobe that connects emotions to objects may show an inability to recognize potentially dangerous objects. Examples would be a person reaching for a snake or plunging a hand into boiling water.

It was first described by Arnold Pick in 1892 and was originally called Pick’s disease, a term now reserved for Pick disease, one specific type of frontotemporal dementia. A defining characteristic of the disease is a buildup of tau proteins in neurons, accumulating into silver-staining, spherical aggregations known as Pick bodies. Common early symptoms noticed are changes in personality and emotion and deterioration of language.

Vascular Disease

Another possible cause of neurocognitive disorder is a cardiovascular disease affecting the supply of blood to the brain. This condition, called vascular neurocognitive disorder (VaD) is highly prevalent, considered the second most common form of dementia after Alzheimer’s disease (AD) in older adults. One study found that in the United States, the prevalence of vascular dementia in all people over the age of 71 is 2.43%, and another found that the prevalence of the vascular neurocognitive disorder (VaD) doubles with every 5.1 years of age.^[1]

Vascular neurocognitive disorder (VaD) is caused by problems in the supply of blood to the brain, typically caused by a series of minor strokes, leading to worsening cognitive decline that occurs step by step. The term refers to a syndrome consisting of a complex interaction of cerebrovascular disease and risk factors that lead to changes in the brain structures due to strokes and lesions, and resulting changes in cognition. The temporal relationship between stroke and cognitive effects is needed to make the diagnosis.

Figure 3. Vascular neurocognitive disorder affects the supply of blood to the brain.

People with vascular neurocognitive disorder present with progressive cognitive impairment, acutely or subacutely as in mild cognitive impairment, frequently step-wise, after multiple cerebrovascular events (strokes). Some people may appear to improve between events and decline after further silent strokes. A rapidly deteriorating condition may lead to death from a stroke, heart disease, or infection.

Signs and symptoms are cognitive, motor, behavioral, and a significant proportion of patients also show affective symptoms. These signs and symptoms typically occur over a period of five to 10 years. Signs of vascular neurocognitive disorder are typically the same as other dementias, but primarily include cognitive decline and memory impairment of sufficient severity that these impairments interfere with a person’s ability to complete activities of daily living.

In order to diagnose, clinicians will look for the presence of focal neurological signs and evidence of features consistent with a cerebrovascular disease on brain imaging (CT or MRI). The observable neurologic signs localizing to certain areas of the brain include hemiparesis, bradykinesia, hyperreflexia, extensor plantar reflexes, ataxia, pseudobulbar palsy, gait problems, and swallowing difficulties. People with vascular neurocognitive disorder may have deficits in terms of cognitive testing, though individuals tend to have better free recall and fewer recall intrusions when compared to patients with Alzheimer’s disease. In the more severely affected patients or patients affected by infections in Wernicke’s or Broca’s areas, specific problems with speaking called dysarthrias and aphasia may be present.

In small vessel disease, such as vascular disease, the frontal lobes are often affected. Consequently, patients with vascular dementia tend to perform worse than their Alzheimer’s disease counterparts in frontal lobe tasks, such as verbal fluency, and may present with frontal lobe problems: apathy, abulia (lack of will or initiative), problems with attention, orientation, and urinary incontinence. VaD patients may also present with a general slowing of processing ability, difficulty shifting sets, and impairment in abstract thinking. Apathy early in the disease is more suggestive of vascular dementia.

Many studies have been conducted to determine the average survival of patients with dementia. The studies were frequently small and limited, which caused contradictory results in the connection of mortality to the type of dementia and the patient’s gender. A very large study conducted in the Netherlands in 2015 found that the one-year mortality was three to four times higher in patients after their first referral to a day clinic for dementia when compared to the general population. If the patient was hospitalized for dementia, the mortality was even higher than in patients hospitalized for cardiovascular disease. Vascular dementia was found to have either comparable or worse survival rates when compared to Alzheimer’s Disease; another very large 2014 Swedish study found that the prognosis for VaD patients was worse for male and older patients. Unlike Alzheimer’s Disease, which weakens the patient, causing them to succumb to bacterial infections like pneumonia, vascular dementia can be a direct cause of death due to the possibility of a fatal interruption in the brain’s blood supply.

Currently, there are no medications that have been approved specifically for the prevention or treatment of vascular dementia. Smoking cessation and the Mediterranean diet have not been found to help patients with cognitive impairment; physical activity was consistently the most effective method of preventing cognitive decline.

Neurocognitive Disorder Due to Prion Disease

Neurocognitive disorder due to prion disease is a rare neurological disorder that researchers believe is caused by an infectious agent that results in abnormal protein accumulations in the brain, known as prions. Prions are misfolded proteins with the ability to transmit their misfolded shape onto normal variants of the same protein. Prions characterize several fatal and transmissible neurodegenerative diseases in humans and many other animals. Prion variants of the prion protein (PrP), whose specific function is uncertain, are hypothesized as the cause of transmissible spongiform encephalopathies (meaning that large holes develop in brain tissue), including scrapie in sheep, chronic wasting disease (CWD) in deer, bovine spongiform encephalopathy (BSE) in cattle (commonly known as mad cow disease) and Creutzfeldt–Jakob disease (CJD) in humans. All known prion diseases in mammals affect the structure of the brain or other neural tissue; all are progressive, have no known effective treatment, and are always fatal.

Figure 3. Features of CJD can be accompanied by physical problems like balance and coordination dysfunction.

In humans, prions are believed to be the cause of Creutzfeldt–Jakob disease (CJD), CJD variant (vCJD), Gerstmann–Sträussler–Scheinker syndrome (GSS), fatal familial insomnia (FFI), and kuru (a rare, incurable, and fatal neurodegenerative disorder that was formerly common among the Fore people of Papua New Guinea). The most common type is Creutzfeldt-Jakob disease (CJD). Variant CJD is much rarer and is associated with bovine spongiform encephalopathy (BSE) or “mad cow disease,” and is transmitted through infected meat.

The first symptom of CJD is usually rapidly progressive dementia, leading to memory loss, personality changes, and hallucinations. Myoclonus (jerky movements) typically occurs in 90% of cases but may be absent at initial onset. Other frequently occurring features include anxiety, depression, paranoia, obsessive-compulsive symptoms, and psychosis. The occurring features are accompanied by physical problems such as speech impairment, balance, and coordination dysfunction (ataxia), changes in gait, and rigid posture. In most people with CJD, these symptoms are accompanied by involuntary movements.

Managing Creutzfeldt-Jakob disease

The duration of the disease varies greatly, but sporadic (non-inherited) CJD can be fatal within months or even weeks. Most victims die six months after initial symptoms appear, often of pneumonia due to impaired coughing reflexes. About 15% of people with CJD survive for two or more years, though there is currently no cure. Some of the symptoms like twitching can be managed, but otherwise, treatment is palliative care. Psychiatric symptoms like anxiety and depression can be treated with sedatives and antidepressants. Myoclonic jerks can be handled with clonazepam or sodium valproate. Opiates can help in pain. Seizures are very uncommon and can be treated with antiepileptic drugs.

Although CJD is the most common human prion disease, it is still believed to be rare, estimated to occur in about one out of every one million people every year. However, an autopsy study published in 1989 and others suggest that between three and 13% of people diagnosed with Alzheimer’s were actually misdiagnosed and instead had CJD. Presumably, those afflicted have become infected through prion-contaminated beef from cattle with subclinical atypical BSE (bovine spongiform encephalopathy), which has a very long incubation period. CJD usually affects people aged 45–75, most commonly appearing in people between the ages of 60–65. The exception to this is the more recently recognized variant CJD (vCJD), which occurs in younger people.

Neurocognitive Disorder Due to Huntington’s Disease

What Is Huntington’s Disease?

Huntington’s disease (HD) is an inherited disorder that causes brain cells, called neurons, to die in various areas of the brain, including those that help to control voluntary (intentional) movement. Symptoms of the disease, which gets progressively worse, include uncontrolled movements (called chorea); abnormal body postures; and changes in behavior, emotion, judgment, and cognition. People with Huntington’s disease (HD) also develop impaired coordination, slurred speech, and difficulty feeding and swallowing. Huntington’s disease (HD) typically begins between ages 30 and 50. An earlier onset form called juvenile HD occurs under age 20. HD’s symptoms differ somewhat from adult-onset HD and include rigidity, slowness, difficulty at school, rapid involuntary muscle jerks called myoclonus, and seizures. More than 30,000 Americans have HD.

Huntington’s disease is caused by a mutation in the gene for a protein called huntingtin. The defect causes the cytosine, adenine, and guanine (CAG) building blocks of DNA to repeat many more times than is normal. Each child of a parent with HD has a 50-50 chance of inheriting the HD gene. A child who does not inherit the HD gene will not develop the disease and generally cannot pass it to subsequent generations. A person who inherits the HD gene will eventually develop the disease. HD is generally diagnosed based on a genetic test, medical history, brain imaging, and neurological and laboratory tests.

The essential feature of neurocognitive disorder due to Huntington’s disease (HD) is the presence of dementia that is judged to be the direct pathophysiological consequence of Huntington’s disease.

Figure 4. Woody Guthrie, a famous American  folk singer (he wrote “This Land Is Your Land” among many others). He died of HD at the age of 55. His mother and two of his children also passed away from the disease. Increasingly unable to control his muscles, Guthrie was hospitalized during the last eleven years of his life at psychiatric facilities. Little was known about the disorder at the time, and Guthrie eventually lost his ability to speak and was known to experience emotional extremes during his final years.

Diagnostic Criteria

• The criteria are met for major or mild neurocognitive disorder.
• There is insidious onset and gradual progression.
• There is a clinically established Huntington’s disease, or risk for HD based on family history or genetic testing.
• The neurocognitive disorder is not attributable to another medical condition and is not better explained by another mental disorder.

Differential Diagnosis

Early symptoms of Huntington’s disease may include instability of mood, irritability, or compulsive behaviors that may suggest another mental disorder. However, genetic testing or the development of motor symptoms will distinguish the presence of Huntington’s disease.

The early symptoms of Huntington’s disease, particularly symptoms of executive dysfunction and impaired psychomotor speed, may resemble other neurocognitive disorders (NCDs), such as major or mild vascular NCD.

Prognosis

Treatment