• behavioral variant FrontoTemporal Dementia (bvFTD)
  • semantic variant Primary Progressive Aphasia (svPPA)
  • nonfluent/agrammatic variant Primary Progressive Aphasia (nfvPPA)
  • CorticoBasal Degeneration (CBD)
  • Progressive Supranuclear Palsy (PSP)
  • Treatment Guidelines

Behavioral variant frontotemporal dementia (bvFTD) has also been referred to as “frontal variant FTD” (fvFTD) or “Pick’s disease.” Approximately 60% of people with any form of FTD have bvFTD.

Amyloid Imaging Top row: amyloid levels in a patient with Alzheimer’s disease;
Bottom row: the same imaging type in an FTLD patient.

Symptoms
This form of FTD affects social skills, emotions, personal conduct, and self-awareness. Deficits in these functions most often reflect damage to specific regions within the frontal and temporal lobes. With damage to these areas, people may show mood and behavior changes including stubbornness, emotional coldness or distance, apathy, and selfishness. Unlike Alzheimer’s disease, which affects a different area of the brain, many people with bvFTD don’t show any confusion or forgetfulness about where they are or what day it is, at least at first.

bvFTD

Diagnosis
The diagnosis of bvFTD is made by reviewing the data from a neurological exam, neuropsychological testing, laboratory tests, and neuroimaging studies.

Treatment
As of yet, there are no medications available to cure or delay the progression of bvFTD, but there are a number of medications that alleviate the symptoms. Medical management includes treatment of concomitant medical conditions such as infections, parkinsonian symptoms, seizures, pain and improving nutritional status. All medications the patient is taking should be fully reassessed for optimal response at the dose prescribed, and the patient should only be on necessary medications that are effective in treating the underlying conditions.

Semantic variant primary progressive aphasia (svPPA), which has also been called “temporal variant FTD,” accounts for 20% of FTLD cases.

Symptoms
Language difficulty, the predominant complaint of people with SD, is due to the disease damaging the left temporal lobe, an area critical for assigning meaning to words. The language deficit is not in producing speech but is a loss of the meaning, or semantics, of words. At first, you might notice someone substituting a word like "thingy" for more unusual words, but eventually a person with svPPA will lose the meaning of more common words as well. Names of people, even good friends, can become quite difficult for people with svPPA. Like the behavioral variant, memory, an understanding of where they are, and sense of day and time tend to function as before. Muscle control for daily life and activities tends to remain good until late in the disease. Some of these skills may seem worse than they actually are because of the language difficulty people with svPPA have when they try to express themselves.

When svPPA starts in the right temporal lobe, people in the early stages have more trouble remembering the faces of friends and familiar people. Additionally, these people show profound deficits in understanding the emotions of others. The loss of empathy is an early, and often initial, symptom of patients with this right-sided form of svPPA. Eventually people with right-sided onset progress to the left side and then develop the classical language features of svPPA. Similarly, left-sided cases progress to involve the right temporal lobe and then the person experiences difficulty recognizing faces, foods, animals and emotion. svPPA patients eventually develop classical bvFTD behaviors including disinhibition, apathy, loss of empathy and diminished insight. The time from diagnosis to the end is longer than for those with bvFTD, typically taking about six years.

svPPA

Diagnosis
The diagnosis of svPPA is made by reviewing the data from a neurological exam, neuropsychological and language testing, laboratory tests, and neuroimaging studies.

Treatment
As of yet, there are no medications available to cure or delay the progression of svPPA, but there are a number of medications that alleviate the symptoms. Medical management includes treatment of concomitant medical conditions such as infections, parkinsonian symptoms, seizures, pain and improving nutritional status. All medications the patient is taking should be fully reassessed for optimal response at the dose prescribed, and the patient should only be on necessary medications that are effective in treating the underlying conditions.

Nonfluent/agrammatic variant primary progressive aphasia (nfvPPA) accounts for only about 20% of all people with FTLD.

Symptoms
Unlike svPPA where the person maintains the ability to speak but loses the meaning of the word, people with nfvPPA have difficulty producing language fluently even though they still know the meaning of the words they are trying to say. The person may talk slowly or have trouble saying words, using the telephone, talking within groups of people, or understanding complex sentences. In recent years it has become apparent that many patients with nfvPPA go on to develop severe parkinsonian symptoms that overlap with progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) such as an inability to move the eyes side-to-side, muscle rigidity in the arms and legs, falls, and weakness in the muscles around the throat.

nfvPPA

Diagnosis
The diagnosis of nfvPPA is made by reviewing the data from a neurological exam, neuropsychological and language testing, laboratory tests, and neuroimaging studies.

Treatment
As of yet, there are no medications available to cure or delay the progression of nfvPPA, but there are a number of medications that alleviate the symptoms. Medical management includes treatment of concomitant medical conditions such as infections, parkinsonian symptoms, seizures, pain and improving nutritional status. All medications the patient is taking should be fully reassessed for optimal response at the dose prescribed, and the patient should only be on necessary medications that are effective in treating the underlying conditions.

Corticobasal degeneration (CBD) is considered to be part of the “Pick complex” of neurodegenerative diseases because it is clinically, genetically and pathologically similar to frontotemporal dementia (FTD). It is characterized by nerve cell loss in multiple areas of the brain including the cerebral cortex and the basal ganglia.

CBD typically occurs in patients aged 45–70. Rarely, there is a family history of dementia, psychiatric problems or a movement disorder. The current estimates of 2000–3000 people affected by CBD in the US likely underestimates the frequency of this disorder.

 

Symptoms
Patients with CBD usually present with either a movement disorder or cognitive deficits. As the disease progresses, most patients will develop both types of symptoms, often with a delay of 2–3 years.

The movement problems can look like Parkinson’s disease (PD). Unlike PD however, CBD patients typically do not typically improve with PD medicines, such as carbidopa-levodopa, and many symptoms of CBD are not found in PD patients. A characteristic feature of movement symptoms in CBD is rigidity, although tremor is less common. Frequently symptoms begin insidiously in one hand, arm or leg.

Many patients will complain initially of a subtle change in sensation or an inability to make the affected limb follow commands. This latter deficit is called apraxia and may be confused for clumsiness or weakness. There may be difficulties in completing specific tasks, such as opening a door or brushing one’s teeth or using tools, like a can opener. When a leg is affected initially, a patient may have problems with complex movements such as dancing; or when more severe, a patient may begin to trip and fall. Some patients will experience an involuntary stiffening, twisting or contraction of the affected limb called dystonia. There may be uncontrolled jumping of the limb when it is tapped gently or when the patient is startled, called myoclonus.

Finally, CBD patients often complain that the affected limb feels like it is not a part of their body, a sensation called alien limb. Sometimes an alien limb will move on its own, in an uncontrollable way. For example, an alien hand will rise to touch the patient’s face. Alien limb phenomenon was dramatized by the actor Peter Sellers in the film Dr. Strangelove.

Patients with CBD who present with cognitive difficulties are often initially diagnosed with frontotemporal dementia or Alzheimer's disease. It is only after they develop movement symptoms that the diagnosis of CBD is considered. Occasionally, a diagnosis of CBD is not apparent until a patient’s brain is examined at autopsy and shows "ballooned" neurons, protein aggregations (neuronal inclusions) and other abnormalities resulting from abnormal accumulation of the tau protein.

Progressive difficulty with language is a common cognitive complaint in CBD. This most commonly involves difficulty with expression of language, such as word finding difficulty or naming problems. Reading, writing and simple mathematical calculations may also be impaired.

Personality changes, inappropriate behavior, repetitive and/or compulsive activities similar to those seen in FTD are also common in CBD. Short-term memory problems, such as repeating questions or misplacing objects are less common.

Increasingly it has become evident that CBD presents in a wide-variety of ways, with the majority of patients beginning with either apathy, trouble with speaking or motor rigidity without tremor.

SeeleyStains

Diagnosis
The diagnosis of CBD is made by reviewing the data from a neurological exam, neuropsychological testing, laboratory tests, and neuroimaging studies.

Treatment and Prognosis
At this time, there is no specific treatment for CBD. Instead individual symptoms are targeted with specific medications. For example, rigidity and difficulty walking may partially respond to treatments for Parkinson’s disease. Dystonia and myoclonus may respond to muscle relaxants or anti-seizure medications. Memory and behavior problems may or may not respond to treatments, such as donepezil, for Alzheimer's disease. Depression and/or anxiety can be treated with an antidepressant, such as sertraline, citalopram or escitalopram.

Physical therapy and stretching exercises may relieve rigidity, prevent contractions and deformities, and maintain muscle strength. Assistive devices like canes or walkers can be helpful. Speech, physical and occupational therapy may be beneficial.

1yr_PSP_bvFTD
Brain atrophy over one year in two FTLD syndromes. FTLD is a group of progressive brain diseases that lead to severe damage and loss of neurons in specific brain networks that control behavior, cognition and motor control. The damage can be measured on successive brain MRI scans. This image shows the areas of most severe brain tissue loss measured on MRI scans taken one year apart in two types of FTLD. The relative severity of brain tissue loss over one year in a group of patients with behavioral variant Frontotemporal Dementia (bvFTD) is represented in red-yellow, whereas the severity of annual tissue loss in patients with Progressive Supranuclear Palsy (PSP) is shown in yellow, orange and blue. The image is a slice approximately in the center of the brain, parallel to the nose. All colored images are superimposed on a MRI scan of a healthy adult brain. The images were generated as part of the NIH-supported Frontotemporal Lobar Degeneration Neuroimaging Initiative (R01AG032306) and Four Repeat Tauopathy Neuroimaging Initiative (R01AG038791) projects on which many of the FTLD CRC procedures are based. (Credit: S. Dutt, H. Rosen, A. Boxer)

Progressive supranuclear palsy (PSP) is a degenerative brain disease leading to difficulties with walking and balance, problems with eye movements, changes in behavior, difficulty with speech and swallowing, and dementia.

PSP occurs primarily in middle-aged adults and the elderly, with slightly more males being affected than females. Approximately 1.39–6.4 in every 100,000 individuals are estimated to have PSP, but because the disorder is difficult to diagnose, this is thought to be considerably underestimated. In part because it is relatively rare, PSP is frequently misdiagnosed as Parkinson’s disease (PD). However, its treatment response and clinical symptoms are different, making an accurate diagnosis important for patient management.

Most known forms of PSP are sporadic, but there have been some cases of a genetic relationship, following an autosomal dominant inheritance pattern with reduced penetrance.

PSP, corticobasal degeneration (CBD) and frontotemporal dementia (FTD) are not associated with amyloid plaques in the brain, such as those seen in Alzheimer's disease, but are associated with the abnormal accumulation of a protein called tau. Some researchers have chosen to group PSP along with CBD and FTD under a single term called Pick-complex disorders or primary tauopathies. It is likely that whether one presents with PSP, CBD or FTD depends in part on the location in the brain of these microscopic changes, although individual differences may play an important role as well.

A clinical evaluation by a neurologist is important in the diagnosis of PSP, as it is often misdiagnosed and difficult to diagnose early. This involves an interview with the patient and a partner, such as a spouse, relative or close friend, to provide examples of behavior and daily functional activities, a physical exam to assess mobility and vision, and a neuropsychological evaluation for evaluation of cognition.

Symptoms
The clinical features used to diagnose PSP are:

  • Progressive difficulty with walking (gait) and balance resulting in frequent falls
  • Progressive loss of voluntary control of eye movements (gives the disorder its name)
  • Progressive changes in behavior and/or cognition

The motor symptoms observed in PSP include a combination of slowed movement and stiffness in the neck and trunk, in addition to the imbalance and falls. Visual symptoms are quite prominent and characteristic of PSP. The earliest of these are slowing of vertical saccades (the quick eye movements we use in redirecting our vision), causing difficulty with changing to a new visual target. Other difficulties with eye movement include difficulty opening and closing the eyes and decreased blinking. The decreased blinking, along with a constant raised-eyebrows facial expression, gives the face a fixed stare, characteristic of the disease. The gaze difficulties can lead to problems such as difficulty in making eye contact, difficulty in reading (because of inability to scan lines on a page), and difficulty with eating (because of inability to look down at their food).

Dysarthria (slow or slurred speech) is a very common symptom in PSP. Patients often find it difficult to carry conversations with others because of the delay of their responses and their difficulties with speech pronunciation. Eventually, difficulties with control of oral movements can progress to the point where swallowing food, and particularly liquids, can be poorly coordinated, leading to the leakage of food into the windpipe (dysphagia). This can result in pneumonia, the most common cause of death in PSP. Some warning signs caregivers should look for are drooling, food collecting in the mouth, increased effort in swallowing, chest congestion, trouble talking, and weight loss.

PSP patients also experience cognitive and behavioral changes suggesting abnormal function in the frontal lobes. Cognitive changes consist of a decline in frontal lobe functioning, such as slow information processing and retrieval, concrete thinking, impaired reasoning, difficulty planning and shifting between tasks. Behaviorally, patients often exhibit apathy including decreased motivation and withdrawal, impulsivity and perseveration, an inability to switch tasks or change topic. Depression is also common.

In contrast with PSP, PD patients don’t experience severe balance dysfunction until later in the course of their disease. They also experience tremors that are uncharacteristic of PSP. In PSP, the posture is stiff and upright with a tendency to fall backwards, as opposed to the stooped posture seen in PD.

Diagnosis
The diagnosis of PSP is made by reviewing the data from a neurological exam, neuropsychological testing, laboratory tests, and neuroimaging studies.

Treatment
Currently, there are no effective treatments for PSP. There are medications, however, that may relieve some of the symptoms. Mostly, these are medications used for typical PD. People with PSP do not respond to these agents as well as a person with typical PD.

Lifestyle changes may help alleviate some of the problems associated with PSP. These include use of a walking aid with a heavy front to prevent falling backwards, eating more solid foods and less thin liquids, and physical therapy or exercise programs to improve mobility.

If swallowing problems become more severe, insertion of a feeding tube directly into the stomach can significantly decrease the risk of pneumonia.

The first steps to treating someone with FTLD are an accurate diagnosis and non-pharmacologic intervention. These steps should be followed by a review of all medications (prescribed, OTC, herbal, etc.) to look for contraindications, interactions, inappropriate prescription or inappropriate dosage. As of yet, there are no medications available to cure or delay the progression of FTLD, but there are a number of medications that alleviate the symptoms. Medical management includes treatment of concomitant medical conditions such as infections, parkinsonian symptoms, seizures, pain and improving nutritional status. All medications the patient is taking should be fully reassessed for optimal response at the dose prescribed, and the patient should only be on necessary medications that are effective in treating the underlying conditions.

Of the reversible dementias, medication use is the most common cause. Furthermore, adverse drug events (ADEs) occur in 15 to 35% of older people, with 29% of those events requiring health care services. An inappropriate or contraindicated medication can cause greater harm than good to the patient due to impaired liver metabolism, decreased renal function, increased body fat or increased sensitivity to CNS medications which can produce impaired memory and delayed psychomotor performance. While each individual varies in their sensitivity and precise condition, these general guidelines should be considered before prescribing certain medications.

For more details, please see http://memory.ucsf.edu/ftd/medical/treatment.