Progressive Supranuclear Palsy (PSP) is a brain disorder that affects movement, vision, speech, and thinking ability (cognition). The signs and symptoms of this disorder usually become apparent in mid- to late adulthood, most often in a person's 60s. Most people with progressive supranuclear palsy survive 5 to 9 years after the disease first appears, although a few affected individuals have lived for more than a decade.

Loss of balance and frequent falls are the most common early signs of progressive supranuclear palsy. Affected individuals have problems with walking, including poor coordination and an unsteady, lurching gait. Other movement abnormalities develop as the disease progresses, including unusually slow movements (bradykinesia), clumsiness, and stiffness of the trunk muscles. These problems worsen with time, and most affected people ultimately require wheelchair assistance.

Progressive supranuclear palsy is also characterized by abnormal eye movements, which typically develop several years after the other movement problems first appear. Restricted up-and-down eye movement (vertical gaze palsy) is a hallmark of this disease. Other eye movement problems include difficulty opening and closing the eyelids, infrequent blinking, and pulling back (retraction) of the eyelids. These abnormalities can lead to blurred vision, an increased sensitivity to light (photophobia), and a staring gaze.

Additional features of progressive supranuclear palsy include slow and slurred speech (dysarthria) and trouble swallowing (dysphagia). Most affected individuals also experience changes in personality and behavior, such as a general loss of interest and enthusiasm (apathy). They develop problems with cognition, including difficulties with attention, planning, and problem solving. As the cognitive and behavioral problems worsen, affected individuals increasingly require help with personal care and other activities of daily living.

Estimates vary, but only about three to six in every 100,000 people worldwide, or approximately 20,000 Americans, have PSP—making it much less common than Parkinson's disease (another movement disorder in which an estimated 50,000 Americans are diagnosed each year). 

PSP was first described as a distinct disorder in 1964, when three scientists published a paper that distinguished the condition from Parkinson's disease. It was sometimes referred to as Steele-Richardson-Olszewski syndrome, reflecting the combined names of the scientists who defined the disorder.

Currently there is no effective treatment for PSP, but some symptoms can be managed with medication or other interventions.

Quick Facts of PSP:

• Progressive supranuclear palsy (PSP) is a neurodegenerative disorder that has no known cause or cure
• It affects brain cells that control balance, walking, coordination, eye movement, speech, swallowing, and thinking
• Five to six people in 100,000 have PSP
• Symptoms begin, on average, when an individual is in the early 60’s, but may start as early as in the 40’s
• PSP is slightly more common in men than women, but it has no known geographical, occupational, or racial preference

Symptoms of PSP include:

• Loss of balance
• Changes in personality
• Weakness of eye movements, especially in the downward direction
• Weakened movements of the mouth, tongue, and throat
• Slurred speech
• Difficulty swallowing

Progressive supranuclear palsy (PSP) is a late-onset degenerative disease involving the gradual deterioration and death of specific volumes of the brain.[1][2] The condition leads to symptoms including loss of balance, slowing of movement, difficulty moving the eyes, and dementia.[1] PSP may be mistaken for other neurodegenerative diseases such as Parkinson's and Alzheimer's. The cause of the condition is uncertain, but involves accumulation of tau protein within the brain. Medications such as levodopa and amantadine may be useful in some cases.[1]

PSP affects about six people per 100,000.[1] The first symptoms typically occur in persons aged 60–70 years. Males are slightly more likely to be affected than females.[1] No association has been found between PSP and any particular race, location, or occupation.[1]

Signs and symptoms
The initial symptoms in two-thirds of cases are loss of balance, lunging forward when mobilizing, fast walking, bumping into objects or people, and falls.[3][citation needed] Dementia symptoms are also initially seen in about one in five cases.[4]

Other common early symptoms are changes in personality, general slowing of movement, and visual symptoms. The most common behavioral symptoms in patients with PSP include apathy, disinhibition, anxiety, and dysphoria.[4]

Later symptoms and signs are dementia (typically including loss of inhibition and ability to organize information), slurring of speech, difficulty swallowing, and difficulty moving the eyes, particularly in the vertical direction. The latter accounts for some of the falls experienced by these patients, as they are unable to look up or down.

Some of the other signs are poor eyelid function, contracture of the facial muscles, a backward tilt of the head with stiffening of the neck muscles, sleep disruption, urinary incontinence, and constipation.

The visual symptoms are of particular importance in the diagnosis of this disorder. Patients typically complain of difficulty reading due to the inability to look down well. Notably, the ophthalmoparesis experienced by these patients mainly concerns voluntary eye movement and the inability to make vertical saccades, which is often worse with downward saccades. Patients tend to have difficulty looking down (a downgaze palsy) followed by the addition of an up gaze palsy. This vertical gaze paresis will correct when the examiner passively rolls the patient's head up and down as part of a test for the oculocephalic reflex. Involuntary eye movement, as elicited by Bell's phenomenon, for instance, may be closer to normal. On close inspection, eye movements called "square-wave jerks" may be visible when the patient fixes at distance. These are fine movements, that can be mistaken for nystagmus, except that they are saccadic in nature, with no smooth phase. Although healthy individuals also make square-wave jerk movements, PSP patients make slower square-wave jerk movements, with smaller vertical components.[5] Assessment of these square-wave jerks and diminished vertical saccades is especially useful for diagnosing progressive supranuclear palsy, because these movements set PSP patients apart from other parkinsonian patients.[5] Difficulties with convergence (convergence insufficiency), where the eyes come closer together while focusing on something near, like the pages of a book, is typical. Because the eyes have trouble coming together to focus at short distances, the patient may complain of diplopia (double vision) when reading.

A characteristic facial appearance known as “procerus sign”, with a wide-eye stare, furrowing of forehead with a frowning expression and deepening of other facial creases is diagnostic of PSP.[6]

Cardinal manifestations:

*Supranuclear ophthalmoplegia
*Neck dystonia
*Parkinsonism
*Pseudobulbar palsy
*Behavioral and cognitive impairment
*Imbalance and walking difficulty
*Frequent falls

Cause
The cause of PSP is unknown. Fewer than 1% of those with PSP have a family member with the same disorder. A variant in the gene for tau protein called the H1 haplotype, located on chromosome 17 (rs1800547), has been linked to PSP.[7] Nearly all people with PSP received a copy of that variant from each parent, but this is true of about two-thirds of the general population. Therefore, the H1 haplotype appears to be necessary but not sufficient to cause PSP. Other genes, as well as environmental toxins, are being investigated as other possible contributors to the cause of PSP.

Additionally, the H2 haplotype, combined with vascular dysfunction, seems to be a factor of progressive supranuclear palsy.[8]

Besides tauopathy, mitochondrial dysfunction seems to be a factor involved in PSP. Especially, mitochondrial complex I inhibitors (such as acerogenin's and quinolines contained in Annonaceae, as well as rotenoids) are implicated in PSP-like brain injuries.[9]

Pathophysiology
The affected brain cells are both neurons and glial cells. The neurons display neurofibrillary tangles (NFTs), which are clumps of tau protein, a normal part of a brain cell's internal structural skeleton. These tangles are often different from those seen in Alzheimer's disease, but may be structurally similar when they occur in the cerebral cortex.[10] Their chemical composition is usually different, however, and is similar to that of tangles seen in corticobasal degeneration.[11] Tufts of tau protein in astrocytes, or tufted astrocytes, are also considered diagnostic. Unlike globose NFTs, they may be more widespread in the cortex.[12] Lewy bodies are seen in some cases, but whether this is a variant or an independent co-existing process is not clear, and in some cases, PSP can coexist with corticobasal degeneration, Parkinson's, and/or Alzheimer's disease, particularly with older patients.[13][14][15][16][17]

The principal areas of the brain affected are the:

*Basal ganglia, particularly the subthalamic nucleus, substantia nigra, and globus pallidus
*brainstem, particularly the portion of the midbrain where "supranuclear" eye movement resides, as well as dopaminergic nuclei.
*cerebral cortex, particularly that of the frontal lobes and the limbic system (similarly to frontotemporal degeneration)
*dentate nucleus of the cerebellum
*spinal cord, particularly the area where some control of the bladder and bowel resides

Some consider PSP, corticobasal degeneration, and frontotemporal dementia to be variations of the same disease.[18][19] Others consider them separate diseases.[20][21][22] PSP has been shown occasionally to co-exist with Pick's disease.[23]

Diagnosis

Person with progressive dementia, ataxia, and incontinence. A clinical diagnosis of normal-pressure hydrocephalus was entertained. Imaging did not support this, however, and on formal testing, abnormal nystagmus and eye movements were detected. A sagittal view of the CT/MRI scan shows atrophy of the midbrain, with preservation of the volume of the pons. This appearance has been called the "hummingbird sign" or "penguin sign". Also, atrophy of the tectum is seen, particularly the superior colliculi. These findings suggest the diagnosis of progressive supranuclear palsy.[24]
MRI is often done to diagnose PSP. MRI may show atrophy in the midbrain with preservation of the pons giving a "hummingbird" sign appearance and Mickey Mouse sign.[25]

Types
Based on the pathological findings in confirmed cases of PSP, it is divided into the following categories:

*classical Richardson syndrome (PSP-RS)
*PSP-parkinsonism (PSP-P), PSP-pure akinesia with gait freezing (PSP-PAGF)
*frontal PSP, PSP-corticobasal syndrome (PSP-CBS), PSP-behavioural variant of frontotemporal dementia (PSP-bvFTD) and PSP-progressive non-fluent aphasia (PSP-PNFA)[26]
*PSP-C
*PSP induced by Annonaceae[27]

Richardson syndrome is characterized by the typical features of PSP. In PSP-P features of Parkinson’s Disease overlap with the clinical presentation of PSP and follows a more benign course. In both PSP-P and PSP- PAGF distribution of abnormal tau is relatively restricted to the brain stem. Frontal PSP initially presents with behavioral and cognitive symptoms, with or without ophthalmoparesis and then evolve into typical PSP.[6] The phenotypes of PSP-P and PSP-PAGF are sometimes referred as the ‘brain stem’ variants of PSP, as opposed to the ‘cortical’ variants which present with predominant cortical features including PSP-CBS, PSP-bvFTD, and PSP-PNFA.[28] Cerebellar ataxia as the predominant early presenting feature is increasingly recognized as a very rare subtype of PSP (PSP-C) which is associated with severe neuronal loss with gliosis and higher densities of coiled bodies in the cerebellar dentate nucleus.[29]

Differential diagnosis
PSP is frequently misdiagnosed as Parkinson's disease because they both involve slowed movements and gait difficulty, with PSP being one of a collection of diseases referred to as Parkinson plus syndromes. Both Parkinson's and PSP have an onset in late middle age and involve slowing and rigidity of movement. However, several distinguishing features exist. Tremor is very common with Parkinson's, but rare with PSP. Speech and swallowing difficulties are more common and severe with PSP and the abnormal eye movements of PSP are essentially absent with PD.[30] A poor response to levodopa along with symmetrical onset can also help differentiate PSP from PD.[31] Patients with the Richardson variant of PSP tend to have an upright posture or arched back, as opposed to the stooped-forward posture of other Parkinsonian disorders, although PSP-Parkinsonism (see below) can demonstrate a stooped posture.[32] Early falls are also more common with PSP, especially with Richardson syndrome.[33]

PSP can also be misdiagnosed as Alzheimer's disease because of the behavioral changes.[34]

Chronic traumatic encephalopathy shows many similarities with PSP.[citation needed]

Current management- Supportive therapies

No cure for PSP is known, and management is primarily supportive. PSP cases are often split into two subgroups, PSP-Richardson, the classic type, and PSP-Parkinsonism, where a short-term response to levodopa can be obtained.[35] Dyskinesia is an occasional but rare complication of treatment.[36] Amantadine is also sometimes helpful.[37] After a few years the Parkinsonian variant tends to take on Richardson features.[38] Other variants have been described.[39][40][41][42] Botox can be used to treat neck dystonia and blepharospasm, but this can aggravate dysphagia.[43]

Two studies have suggested that rivastigmine may help with cognitive aspects, but the authors of both studies have suggested a larger sampling be used.[44][45] There is some evidence that the hypnotic zolpidem may improve motor function and eye movements, but only from small-scale studies.[46][47]

Rehabilitation
Patients with PSP usually seek or are referred to occupational therapy, speech-language pathology for motor speech changes typically a spastic-ataxic dysarthria, and physical therapy for balance and gait problems with reports of frequent falls.[48] Evidence-based approaches to rehabilitation in PSP are lacking and, currently, the majority of research on the subject consists of case reports involving only a small number of patients.

Case reports of rehabilitation programs for patients with PSP generally include limb-coordination activities, tilt-board balancing, gait training, strength training with progressive resistive exercises, and isokinetic exercises and stretching of the neck muscles.[48] While some case reports suggest that physiotherapy can offer improvements in balance and gait of patients with PSP, the results cannot be generalized across all PSP patients, as each case report only followed one or two patients.[48] The observations made from these case studies can be useful, however, in helping to guide future research concerning the effectiveness of balance and gait training programs in the management of PSP.

Individuals with PSP are often referred to occupational therapists to help manage their condition and to help enhance their independence. This may include being taught to use mobility aids.[49][50] Due to their tendency to fall backwards, the use of a walker, particularly one that can be weighted in the front, is recommended over a cane.[49] The use of an appropriate mobility aid helps to decrease the individual’s risk of falls and makes them safer to ambulate independently in the community.[50] Due to their balance problems and irregular movements, individuals need to spend time learning how to safely transfer in their homes and in the community.[49] This may include rising from and sitting in chairs safely.[50]

Due to the progressive nature of this disease, all individuals eventually lose their ability to walk and will need to progress to using a wheelchair.[49] Severe dysphagia often follows, and at this point death is often a matter of months.[35]

Experimental treatments
Drugs targeting the tau protein offer a promising avenue for therapeutic intervention. The growth factor davunetide was recently trialed in patients to prevent hyperphosphorylated, insoluble forms of tau, however it was unable to show efficacy possibly due insufficient CNS penetration.[51] Antisense therapy has shown efficacy in several other human neurodegenerative disorders and has recently been shown to substantially extend lifespan in animals with PSP.[52] Biogen and Ionis Pharmaceuticals currently are investigating a tau-lowering antisense therapy for Alzheimer's disease and frontotemporal dementia which could also have applicability to PSP.[53]

Prognosis
Currently, no effective treatment or cure has been found for PSP, although some of the symptoms can respond to nonspecific measures. The poor prognosis is predominantly attributed to the serious impact this condition has on the quality of life.[3] The average age at symptoms onset is 63 and survival from onset averages 7 years with a wide variance.[54] Pneumonia is a frequent cause of death.[55]

History
In 1877, Dr. Charcot described a 40-year-old woman who had rigid-akinetic parkinsonism, neck dystonia, dysarthria, and eye-movement problems. Chavany and others reported the clinical and pathologic features of a 50-year-old man with a rigid and akinetic form of parkinsonism with postural instability, neck dystonia, dysarthria, and staring gaze in 1951. Progressive supranuclear palsy was first described as a distinct disorder by neurologists John Steele, John Richardson, and Jerzy Olszewski in 1963.[1][56][57][58] They recognized the same clinical syndrome in 8 patients and described the autopsy findings in 6 of them in 1963.

Progressive supranuclear palsy was not a “new” disease in 1963, as 22 well-documented case reports had been identified in the neurologic literature between 1877 and 1963.[59] The unique frontal lobe cognitive changes of progressive supranuclear palsy (apathy, loss of spontaneity, slowing of thought processes, and loss of executive functions) were first described by Albert and colleagues in 1974.[60]

Societies
There are several organizations around the world that support PSP patients and the research into PSP and related diseases, such as corticobasal degeneration (CBD) and multiple system atrophy (MSA).

Canada: PSP Society of Canada, a federally registered non-profit organization which serves patients and families dealing with PSP, CBD and MSA, set up in 2017 through the help of CurePSP in the USA[61]
France: Association PSP France, a nonprofit patient association set up in 1996 through the help of PSPA in the UK. It also gives support to French speaking patients in Quebec, Morocco, Algeria, Belgium and Lebanon[62]
UK: PSPA, a national charity for information, patient support and research of PSP and CBD, set up in 1995[63]
Ireland: PSPAI, a body which aims to get PSP better known[64]
US: CurePSP, a nonprofit organization for promoting awareness, care and research of PSP, CBD, MSA "and other prime of life neurodegenerative diseases"[65]

In popular culture
In the 2020 American musical comedy-drama television series, Zoey's Extraordinary Playlist, the title character's father (Mitch Clarke, played by Peter Gallagher) has PSP and dies in the final episode of the first season.[66]

American singer Linda Ronstadt was diagnosed with PSP in 2019, subsequent to an initial diagnosis of Parkinson's disease in 2014.[67]

References

 

Multiple System Atrophy (MSA) causes movement symptoms and affects the network of nerves — the autonomic nervous system — that controls blood pressure, digestion and other involuntary processes.

Symptoms of MSA include:

• Slowness, stiffness, and walking and balance problems
• Clumsiness and incoordination
• Slurred speech
• Low blood pressure, constipation and bladder problems
• Difficulty controlling emotions (laughing or crying at inappropriate times)
• Acting out dreams (REM sleep behavior disorder)
• Breathing problems, especially at night

Corticobasal Degeneration (CBD) causes movement, memory and thinking (cognitive), and behavioral symptoms. Movement symptoms typically start in one hand, arm or leg and later may involve other parts of the body.

In CBD, a protein called tau builds up in certain brain cells. Exactly why this protein accumulates and cells die isn't understood, but researchers are examining these mechanisms to understand the disease and find ways to target it.

Symptoms of CBD include:

• Slowness and stiffness
• Dystonia (muscle contractions causing abnormal postures)
• Myoclonus (rapid muscle jerks)
• Difficulty paying attention or concentrating, or other cognitive changes
• Language problems; trouble finding words or speaking in full sentences
• Behavioral changes, such as acting or speaking crudely

When the arm is involved, a person may be unable to control it, even though they know what they want to do and have the muscle strength to do so. For example, they may have trouble combing their hair or turning a key in a lock. Sometimes the arm may even move on its own; this is called "alien limb syndrome." CBD also may eventually lead to walking and balance problems.

Corticobasal degeneration (CBD) is a rare neurodegenerative disease involving the cerebral cortex and the basal ganglia.[1] CBD symptoms typically begin in people from 50 to 70 years of age, and the average disease duration is six years. It is characterized by marked disorders in movement and cognition, and is classified as one of the Parkinson plus syndromes. Diagnosis is difficult, as symptoms are often similar to those of other disorders, such as Parkinson's disease, progressive supranuclear palsy, and dementia with Lewy bodies, and a definitive diagnosis of CBD can only be made upon neuropathologic examination.

Signs and symptoms

Because CBD is progressive, a standard set of diagnostic criteria can be used, which is centered on the disease's evolution. Included in these fundamental features are problems with cortical processing, dysfunction of the basal ganglia, and a sudden and detrimental onset.[2] Psychiatric and cognitive dysfunctions, although present in CBD, are much less prevalent and lack establishment as common indicators of the presence of the disease.[3]

Although corticobasal degeneration has a plethora of symptoms, some are more prevalent than others. In a study of 147 patients with CBD, it was found that all of them had at least one Parkinsonian sign, 95% having two and 93% had some higher order dysfunction (cognitive impairments like acalculia, sensory loss, dementia, neglect, etc.). In a separate study of 14 patients recorded 3 years after the onset of symptoms, many patients had high numbers of motor symptoms. 71% had bradykinesia (slow movements), 64% showed apraxia, 43% reported limb dystonia, and although more cognitive 36% had dementia. In another study of 36, over half had a useless/alien arm and 27% had a gait impediment[21]. From this we can see why CBD is hard to diagnose. Even if it can be distinguished as different from one of the other similar diseases, the varying combinations of symptoms creates a difficult path to diagnosis.[citation needed]

Motor and associated cortical dysfunctions-
Some of the most prevalent symptom types in people exhibiting CBD pertain to identifiable movement disorders and problems with cortical processing. These symptoms are initial indicators of the presence of the disease. Each of the associated movement complications typically appear asymmetrically and the symptoms are not observed uniformly throughout the body. For example, a person exhibiting an alien hand syndrome (explained later) in one hand, will not correspondingly display the same symptom in the other hand. Predominant movement disorders and cortical dysfunctions associated with CBD include:

*Parkinsonism
*Alien hand syndrome
*Apraxia (ideomotor apraxia and limb-kinetic apraxia)
*Aphasia[3]

Parkinsonism
The presence of parkinsonism as a clinical symptom of CBD is largely responsible for complications in developing unique diagnostic criteria for the disease.[4] Other such diseases in which parkinsonism forms an integral diagnostic characteristic are Parkinson's disease (PD) and progressive supranuclear palsy (PSP). Parkinsonism in CBD is largely present in an extremity such as the arm, and is always asymmetric. It has been suggested that non-dominant arm is involved more often.[5] Common associated movement dysfunctions that comprise parkinsonism are rigidity, bradykinesia, and gait disorder, with limb rigidity forming the most typical manifestation of parkinsonism in CBD. Despite being relatively indistinct, this rigidity can lead to disturbances in gait and correlated movements. Bradykinesia in CBD occurs when there is notable slowing in the completion of certain movements in the limbs. In an associated study, it was determined that, three years following first diagnosis, 71% of persons with CBD demonstrate the presence of bradykinesia.[3]

Alien hand syndrome
Alien hand syndrome has been shown to be prevalent in roughly 60% of those people diagnosed with CBD.[6] This disorder involves the failure of an individual to control the movements of their hand, which results from the sensation that the limb is "foreign".[2] The movements of the alien limb are a reaction to external stimuli and do not occur sporadically or without stimulation. The presence of an alien limb has a distinct appearance in CBD, in which the diagnosed individual may have a "tactile mitgehen". This mitgehen (German, meaning "to go with") is relatively specific to CBD, and involves the active following of an experimenter's hand by the subject's hand when both hands are in direct contact. Another, rarer form of alien hand syndrome has been noted in CBD, in which an individual's hand displays an avoidance response to external stimuli. Additionally, sensory impairment, revealed through limb numbness or the sensation of prickling, may also concurrently arise with alien hand syndrome, as both symptoms are indicative of cortical dysfunction. Like most of the movement disorders, alien hand syndrome also presents asymmetrically in those diagnosed with CBD.[7]

Apraxia
Ideomotor apraxia (IMA), although clearly present in CBD, often manifests atypically due to the additional presence of bradykinesia and rigidity in those individuals exhibiting the disorders. The IMA symptom in CBD is characterized by the inability to repeat or mimic particular movements (whether significant or random) both with or without the implementation of objects. This form of IMA is present in the hands and arms, while IMA in the lower extremities may cause problems with walking. Those with CBD that exhibit IMA may appear to have trouble initiating walking, as the foot may appear to be fixed to floor. This can cause stumbling and difficulties in maintaining balance.[3] IMA is associated with deterioration in the premotor cortex, parietal association areas, connecting white matter tracts, thalamus, and basal ganglia. Some individuals with CBD exhibit limb-kinetic apraxia, which involves dysfunction of more fine motor movements often performed by the hands and fingers.[6]

Aphasia
Aphasia in CBD is revealed through the inability to speak or a difficulty in initiating spoken dialogue and falls under the non-fluent (as opposed to fluent or flowing) subtype of the disorder. This may be related to speech impairment such as dysarthria, and thus is not a true aphasia, as aphasia is related to a change in language function, such as difficulty retrieving words or putting words together to form meaningful sentences. The speech and/or language impairments in CBD result in disconnected speech patterns and the omission of words. Individuals with this symptom of CBD often lose the ability to speak as the disease progresses.[3]

Psychiatric and cognitive disorders
Psychiatric problems associated with CBD often present as a result of the debilitating symptoms of the disease. Prominent psychiatric and cognitive conditions cited in individuals with CBD include dementia, depression, and irritability, with dementia forming a key feature that sometimes leads to the misdiagnosis of CBD as another cognitive disorder such as Alzheimer's disease (AD). Frontotemporal dementia can be an early feature.[8]

Molecular features
Neuropathological findings associated with CBD include the presence of astrocytic abnormalities within the brain and improper accumulation of the protein tau (referred to as tauopathy).[9]

Astroglial inclusions
Postmortem histological examination of the brains of individuals diagnosed with CBD reveal unique characteristics involving the astrocytes in localized regions.[10] The typical procedure used in the identification of these astroglial inclusions is the Gallyas-Braak staining method.[11] This process involves exposing tissue samples to a silver staining material which marks for abnormalities in the tau protein and astroglial inclusions.[12] Astroglial inclusions in CBD are identified as astrocytic plaques, which present as annularly displays of blurry outgrowths from the astrocyte. A recent study indicated that produces a high density of astrocytic plaques in the anterior portion of the frontal lobe and in the premotor area of the cerebral cortex.[13]

Tauopathy
The protein tau is an important microtubule-associated protein (MAP), and is typically found in neuronal axons. However, malfunctioning of the development of the protein can result in unnatural, high-level expression in astrocytes and glial cells. As a consequence, this is often responsible for the astrocytic plaques prominently noted in histological CBD examinations. Although they are understood to play a significant role in neurodegenerative diseases such as CBD, their precise effect remains a mystery.[12]

In recent years Corticobasal Degeneration is seen to be a tauopathy[22]. This is believed due to the most common indicator of CBD being a faulty tau protein. Tau proteins are integral in keeping microtubules stable and these defective cells create 4 microtubule-binding repeats[23]. These 4 binding repeats have increased affinity in binding with microtubules[25]. Because of this increased affinity, they form insoluble fibers (also called "paired helical filaments). Microtubules themselves keep the cell and cytoskeletal structure stable[24]. Thus, when Tau proteins create unnatural configurations, microtubules become unstable, and eventually leads to cell death.[citation needed]

Diagnosis
New diagnostic criteria known as the Armstrong criteria were proposed in 2013, although the accuracy of these is limited and further research is needed.[14]

Criteria-
Insidious onset and gradual progression
Lasts 1 year or more
Meets one of the four subtypes:
*Possible CBS
*FBS or NAV
*PSPS plus at least one CBS feature other than limb rigidity or akinesia
No exclusion criteria present
More likely if onset is after age 50
More likely if no family history (2 or more relatives)
More likely if no genetic mutation affecting T[clarification needed] (e.g., MAPT)[15]

Possible corticobasal syndrome subtype
Symptoms may be symmetric or asymmetric.

One or more of:
limb rigidity or akinesia
limb dystonia
limb myoclonus, plus one of:
orobuccal or limb apraxia
cortical sensory deficit
alien limb phenomena (more than simple levitation)
More likely (probable sporadic CBS) if:[citation needed]

Asymmetric presentation
Onset after age 50
No family history (2 or more relatives)
No genetic mutation affecting T (e.g. MAPT)
plus two of:
limb rigidity or akinesia
limb dystonia
limb myoclonus
plus two of:
orobuccal or limb apraxia,
cortical sensory deficit
alien limb phenomena (more than simple levitation)[15]
Frontal behavioural-spatial syndrome subtype
Two of:[citation needed]

executive dysfunction
behavioural or personality changes
visuospatial deficits
NAV of primary progressive aphasia subtype
Effortful, agrammatic speech plus at least one of:[citation needed]

impaired grammar/sentence comprehension with relatively preserved single word comprehension or
groping, distorted speech production (apraxia of speech)
Progressive supranuclear palsy syndrome subtype
Three of:[citation needed]

axial or symmetric limb rigidity or akinesia
postural instability or falls
urinary incontinence
behavioural changes
supranuclear vertical gaze palsy or decreased vertical saccade velocity
Exclusion criteria
These apply to all types of CBD.

Evidence of Lewy body disease
multiple system atrophy
Alzheimer's disease
ALS
semantic or logopenic variant primary progressive aphasia
structural lesion suggestive of focal cause
granulin mutation or reduced plasma progranulin levels
TDP-43 or fused in sarcoma (FUS) mutations[15]
The diagnostic criteria for clinical use may result in a misdiagnosis of other tau-based diseases.[14]

The probable criteria are proposed for clinical research.[14]

Clinical vs. postmortem
One of the most significant problems associated with CBD is the inability to perform a definitive diagnosis while an individual exhibiting the symptoms associated with CBD is still alive. A clinical diagnosis of CBD is performed based upon the specified diagnostic criteria, which focus mainly on the symptoms correlated with the disease. However, this often results in complications as these symptoms often overlap with numerous other neurodegenerative diseases.[16] Frequently, a differential diagnosis for CBD is performed, in which other diseases are eliminated based on specific symptoms that do not overlap. However, some of the symptoms of CBD used in this process are rare to the disease, and thus the differential diagnosis cannot always be used.[3]

Postmortem diagnosis provides the only true indication of the presence of CBD. Most of these diagnoses utilize the Gallyas-Braak staining method, which is effective in identifying the presence of astroglial inclusions and coincidental tauopathy.[citation needed]

Overlap with other diseases
Progressive supranuclear palsy (PSP) is frequently the disease most often confused with CBD. Both PSP and CBD result in similar symptoms, and both display tauopathies upon histological inspection.[17] However, it has been noted that tauopathy in PSP results in tuft-shaped astrocytes in contrast with the ring-shaped astrocytic plaques found as a result of CBD.[13]

Individuals diagnosed with PD often exhibit similar movement dysfunction as those diagnosed with CBD, which adds complexity to its diagnosis. Some other neurodegenerative diseases including Alzheimer's disease (AD), dementia with Lewy bodies (DLB), chronic traumatic encephalopathy (CTE) and frontotemporal dementia (FTD) also show commonalities with CBD.[3][18][8]

Neuroimaging
The types of imaging techniques that are most prominently utilized when studying and/or diagnosing CBD are:[citation needed]

magnetic resonance imaging (MRI)
single-photon emission computed tomography (SPECT)
fluorodopa positron emission tomography (FDOPA PET)
Developments or improvements in imaging techniques provide the future possibility for definitive clinical diagnosis prior to death. However, despite their benefits, information learned from MRI and SPECT during the beginning of CBD progression tend to show no irregularities that would indicate the presence of such a neurodegenerative disease.[3] FDOPA PET is used to study the efficacy of the dopamine pathway.[19]

Despite the undoubted presence of cortical atrophy (as determined through MRI and SPECT) in individuals experiencing the symptoms of CBD, this is not an exclusive indicator for the disease. Thus, the utilization of this factor in the diagnosis of CBD should be used only in combination with other clinically present dysfunctions.[4]

MRI
MRI images are useful in displaying atrophied portions of neuroanatomical positions within the brain. As a result, it is especially effective in identifying regions within different areas of the brain that have been negatively affected due to the complications associated with CBD. To be specific, MRI of CBD typically shows posterior parietal and frontal cortical atrophy with unequal representation in corresponding sides. In addition, atrophy has been noted in the corpus callosum.[19]

Functional MRI (fMRI) has been used to evaluate the activation patterns in various regions of the brain of individuals affected with CBD. Upon the performance of simple finger motor tasks, subjects with CBD experienced lower levels of activity in the parietal cortex, sensorimotor cortex, and supplementary motor cortex than those individuals tested in a control group.[19]

SPECT
SPECT is currently being used to try to detect CBD. With many patients of CBD, there are areas in the basal ganglia which have difficulties receiving dopamine, typically asymmetrically. Specifically affected, are dopamine transporters which are presynaptic on the nigrostriatal cells. SPECT is used to detect these abnormalities in Dopamine transporters. Given that many patients have asymmetrical loss of function and metabolism this can help differentiate patients with CBD and those with Alzheimer's.[citation needed]

SPECT studies of individuals diagnosed with CBD involve perfusion analysis throughout the parts of the brain. SPECT evaluation through perfusion observation consists of monitoring blood release into different locations in tissue or organ regions, which, in the case of CBD, pertains to localized areas within the brain. Tissue can be characterized as experiencing overperfusion, underperfusion, hypoperfusion, or hyperperfusion. Overperfusion and underperfusion relate to a comparison with the overall perfusion levels within the entire body, whereas hypoperfusion and hyperperfusion are calculated in comparison to the blood flow requirements of the tissue in question. In general, the measurements taken for CBD using SPECT are referred to as regional cerebral blood flow (rCBF).[19]

In general, SPECT reveals hypoperfusion within both the posterior regions of the frontal and parietal lobes. As in images gathered through MRI, SPECT images indicated asymmetry in the presentation of abnormalities throughout the brain.[4] Additional studies have revealed the presence of perfusion anomalies in the thalamus, temporal cortex, basal ganglia, and pontocerebellar (from the pons to the cerebellum) locations within subjects' brains.[19]

FDOPA PET
Research has suggested that the integrity of the dopamine system in the striatum has been damaged as an effect of CBD. Current studies employing the use of FDOPA PET scanning (FDOPA PET) as a possible method for identifying CBD have focused on analyzing the efficiency of neurons in the striatum that utilize the neurotransmitter dopamine. These studies have concluded that, in general, dopamine uptake was diminished in the caudate and the putamen. This characteristic also has the potential to be useful in distinguishing CBD from the similar PD, as individuals having been diagnosed with PD were more likely to have a lower uptake of dopamine than in individuals with CBD.[19]

Other clinical tests or procedures that monitor the presence of dopamine within the brain (β-CIT SPECT and IBZM SPECT) have shown similar findings. β-CIT serves as an indicator for presynaptic dopaminergic neurons, whereas IBZM is a tracer that shows an affinity for the postsynaptic neurons of the same type. Despite agreement with other imaging studies, these two SPECT methods suffer some scrutiny due to better accuracy in other imaging methods. However, β-CIT SPECT has proven to be helpful in distinguishing CBD from PSP and multiple system atrophy (MSA).[19]

Corticobasal syndrome-
All of the disorders and dysfunctions associated with CBD can often be categorized into a class of symptoms that present with the disease of CBD. These symptoms that aid in clinical diagnosis are collectively referred to as corticobasal syndrome (CBS) or corticobasal degeneration syndrome (CBDS). Alzheimer's disease, Pick's disease, FTDP-17 and progressive supranuclear palsy can display a corticobasal syndrome.[20][21] It has been suggested that the nomenclature of corticobasal degeneration only be used for naming the disease after it has received verification through postmortem analysis of the neuropathology.[4] CBS patients with greater temporoparietal degeneration are more likely to have AD pathology as opposed to frontotemporal lobar degeneration.[22]

Treatment
Because the exact cause of CBD is unknown, there exists no formal treatment for the disease. Instead, treatments focus on minimizing the appearance or effect of the symptoms resulting from CBD. The most easily treatable symptom of CBD is parkinsonism, and the most common form of treatment for this symptom is the application of dopaminergic drugs. However, in general only moderate improvement is seen and the relief from the symptom is not long-lasting. In addition, palliative therapies, including the implementation of wheelchairs, speech therapy, and feeding techniques, are often used to alleviate many of the symptoms that show no improvement with drug administration.[23]

There is no consensus on what causes CBD and so most of the treatment goes in helping symptoms. Unfortunately, many treatments are typically low in their success rates or have not been tested thoroughly or produced frequently. For example, in relation to the motor aspect of disability, CBD has a high resistance against treatments to help the dopamine intake like levodopa. A number of studies have reported no real levels of improvement based with the use of similar drugs/dopaminergic agonists. Because of the brains levels of inhibition, some medications have focused on creating an inhibition that would negate the effect. Many of these relaxants and anticonvulsants have some success but also have unwanted side effects[21]. Cognitive and associative effects of CBD are also hard to treat as we are still unsure of many of the treatments for the symptomatic diseases that ensue like dementia, aphasia, neglect, apraxia and others.[citation needed]

Epidemiology
Clinical presentation of CBD usually does not occur until age 60, with the earliest recorded diagnosis and subsequent postmortem verification being age 28.[19] Although men and women present with the disease, some analysis has shown a predominant appearance of CBD in women. Current calculations suggest that the prevalence of CBD is approximately 4.9 to 7.3 per 100,000 people. The prognosis for an individual diagnosed with CBD is death within approximately eight years, although some patients have been diagnosed over 17 years ago (2017) and are still in relatively good standing, but with serious debilitation such as dysphagia, and overall limb rigidity. The partial (or total) use of a feeding tube may be necessary and will help prevent aspiration pneumonia, primary cause of death in CBD. Incontinence is common, as patients often can't express their need to go, due to eventual loss of speech. Therefore, proper hygiene is mandatory to prevent urinary tract infections.[3]

CBD research has been limited by the rarity of the disease and the lack of research criteria. It is estimated to affect 0.6-0.9 per 100,000 per year.[citation needed]

Progressive supranuclear palsy (PSP) without CBD is estimated to be ten times more common. CBD represents roughly 4–6% of patients with Parkinsonism. Average age at disease onset is about 64, with the youngest confirmed onset being at age 43. There may be a slight female predominance.[24]

History
Corticobasal syndrome was first recognized in 1967 when Rebeiz, Kolodny, and Richardson Jr described three people with a progressive asymmetric akinetic-rigid syndrome combined with apraxia, which they named corticodentatonigral degeneration with neuronal achromasia.[24][25] The condition was "mostly forgotten" until 1989, when Marsden et al. used the name corticobasal degeneration.[24] In 1989 Gibb and colleagues provided detailed clinical and pathological descriptions in a further three cases adopting the name corticobasal degeneration,[26] after which various other names included "corticonigral degeneration with nuclear achromasia" and "cortical basal ganglionic degeneration".[2] Although the underlying cause of CBD is unknown, the disease occurs as a result of damage to the basal ganglia, specifically marked by neuronal degeneration or depigmentation (loss of melanin in a neuron) in the substantia nigra.[17] Additional distinguishing neurological features of those diagnosed with CBD consist of asymmetric atrophy of the frontal and parietal cortical regions of the brain.[2] Postmortem studies of patients diagnosed with CBD indicate that histological attributes often involve ballooning of neurons, gliosis, and tauopathy.[17] Much of the pioneering advancements and research performed on CBD has been completed within the past decade or so, due to the relatively recent formal recognition of the disease.[citation needed]

The Office of Rare Diseases in the United States created the first criteria in 2002, and the Armstrong clinical diagnostic criteria were created in 2013.[24]

Society and culture
The Salt Path by Raynor Winn is an inspiring account of walking England's 630 mile South West Coast Path with her husband who had corticobasal degeneration.[27]

 

References

• Boeve BF (2011). "The multiple phenotypes of corticobasal syndrome and corticobasal degeneration: Implications for further study". Journal of Molecular Neuroscience. 45 (3): 350–3. doi:10.1007/s12031-011-9624-1. PMID 21853287. S2CID 30307394.
• Hassan A, Whitwell JL, Josephs KA (2011). "The corticobasal syndrome-alzheimer's disease conundrum". Expert Review of Neurotherapeutics. 11 (11): 1569–78. doi:10.1586/ern.11.153. PMC 3232678. PMID 22014136.
• Goode BL, Chau M, Denis PE, Feinstein SC (2000). "Structural and Functional Differences between 3-Repeat and 4-Repeat Tau Isoforms". Journal of Biological Chemistry. 275 (49): 38182–38189. doi:10.1074/jbc.m007489200. PMID 10984497. S2CID 30896096.
• Mahapatra RK, Edwards MJ, Schott JM, Bhatia KP (2004). "Corticobasal degeneration". The Lancet Neurology. 3 (12): 736–43. doi:10.1016/s1474-4422(04)00936-6. PMID 15556806. S2CID 15324889. ProQuest 201513368.
• Avila J (1992). "Microtubule functions". Life Sci. 50 (5): 327–334. doi:10.1016/0024-3205(92)90433-p. PMID 1732704.