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= Applause Sign = The applause sign is a behavioural indicator referring to a patient’s ability to execute the same number of hand claps as demonstrated by an examiner.

Background
The applause sign was first described by Dubois and colleagues in 1995, as “a simple test of motor control that helps to differentiate Progressive supranuclear palsy (PSP) from frontal or striatofrontal degenerative diseases” ,but has since appeared in various neurodegenerative conditions also involving frontal lobe dysfunction.

The applause sign is identified by response to the three-clap test (TCT), where the patient is asked ‘to clap three times as quickly as possible after demonstration’. The subject shows the applause sign when they clap more than three times. PSP patients are most common displayers of the sign, with occasional appearances in individuals showing Corticobasal degeneration, Parkinson's disease, Amyotrophic Lateral Sclerosis, Frontotemporal dementia and Alzheimer's.

Frontal Lobe Dysfunction
The applause sign can indicate frontal lobe dysfunction because deliberate movement functions are localised to the frontal lobe. Hence, when the frontal lobe functions abnormally, an inability to execute movement according to intention results.

In particular, the ability to stop actions as and when intended is a process to which voluntary movement control is integral. The inferior frontal gyrus of the frontal lobe is responsible for generating stop processes. Hence, when a patient experiences frontal lobe dysfunction, this results in movement perseveration (an abnormal prolongation of current activity), and appearance of the applause sign.

Higher frequency of the applause sign in clinically severe than mild and moderate Alzheimer's evidences this mechanism, with prominent frontal lobe dysfunction only shown in severe cases. FMRI studies in healthy participants also show increased activity in the frontal lobe during “stop-signal tasks”.

Basal Ganglia Dysfunction
The applause sign can also reflects dysfunction of the subthalamic nucleus (STN) and pallidum, two subcortical structures involved in basal ganglia function.

Normal function of the STN prevents unwanted movement through its influence in the indirect pathway of the basal ganglia. By increasing its glutaminergic output to the pallidum, it stimulates the pallidum's GABAergic neurons. This then decreases excitation of the thalamus and, as a result, decreases movement. Hence, when the STN is dysfunctional, unwanted movements such as additional claps go unprevented, and we see appearance of the applause sign.

Lower volume of the palladium and ventral diencephalon (where STN is housed) have been found in patients with an applause sign, evidencing this mechanism, supported by significant correlation between TCT scores and UPDRS part III scores , an indicator of basal ganglia dysfunction.

Combined Mechanism (Frontalstriatal disconnection syndrome)
One study proposes a combined mechanism, involving both basal ganglia input and the inferior frontal gyrus.

When there is disruption in basal ganglia pathways, mirror neurons of the inferior frontal gyrus and cortical frontal motor preparation areas, stop receiving basal ganglia input. These areas are important in imitation behaviour, so this results in an uninhibited response from this imitation processing circuitry. Hence, we observe an inability to stop imitation of claps when desired during TCTs.

This mechanism may reflect the elevated prevalence of this sign in PSP patients, since PSP is associated with lesions in the frontal lobe and subcortical structures simultaneously, as well as explain why conditions display the sign regardless of if they are predominantly frontal or predominantly subcortical.

List of Conditions Associated With Frequent Appearance

 * Progressive supranuclear palsy
 * Parkinson's Disease
 * Cortico-Basal Degeneration and Syndrome
 * Alzheimer's Disease
 * Frontotemporal Dementia
 * Amyotrophic Lateral Sclerosis

As a test for abnormal neurodegeneration
The Applause Sign has been able to identify patients with neurodegenerative conditions from healthy controls at 100% success rate.

When identifying PSP
Separating PSP patients and healthy controls using the sign had a mean success rate of 64.7% across 4 known studies, effectiveness as high as 85% in one.

Appearance of the sign, when used in conjunction with classical oculomtor findings, the presence of a dysexecutive syndrome, parkinsonian features and delayed verbal responses enables highly accurate PSP diagnosis.

When identifying FTD
One study reported the sign as present in 80% of patients with the disinhibited subtype of the behavioral variant of FTD (bvFTD).

As a test of executive function
TCT scores show correlation with Stroop Test scores and performance on the Initiation/Preservation task of the Dementia rating scale results, which are both common measures of executive function.

As part of a combined test of cognitive impairment
A Rapid Cognitive Screen Test (RCS-T) combined with a triple test of the applause and two other signs appears effective in identifying specific cognitive impairment.

Lacking specificity
The applause sign is detectable in any condition impacting the frontal lobe, so it cannot discriminate between neurodegenerative conditions, including PSP from Parkisnonian disorders, and CBD from MSA. The applause sign is also present in 72% of patients with any form of cognitive impairment, regardless of whether this is mild cognitive impairment (MCI) or dementia.

Additionally, it may also reflect only certain condition subtypes, rather than all forms: in one study, prevalence of applause sign was 63% in atypical parkinsonism and only 29% in typical PD. Another reported the occurrence of the sign in cortical dementias patients as 10%, but a much higher 39% in cortico-subcortical dementia patients.

The applause sign also fails to discriminate between individuals who clap more and individuals who clap less than 3 times. Which of these response categories a person falls into changes the dysfunctional motor initiative responsible, which has particular implication for understanding of behavioural FTD of the apathetic subtype, as many patients display propensity to clap less than three times.

The applause sign's non-specificity may make it more appropriate as part of wider diagnostic framework, or as an observational clue, similar to glabellar, masseter, and palmomental signs in Parkinsonian disorders.

Contradictory evidence from Alzheimer's research
One study finds no correlation between results of the Luria motor sequence test of motor behaviour and the applause sign. If the applause sign demonstrates motor disruption as theorised, then this presents significant opposition to that claim.

This criticism has been disregarded by some on the basis that the applause sign exclusively reflects motor perseveration and therefore not expected to be associated to performance in motor planning and execution tests.

Lack of published research
22 distinct studies exist on the applause sign and its effectiveness. Within this, only 129 PSP patients have been examined across 6 studies, including one sample of only 5. Relation to CBD is based on 2 studies sampling 2 and 9 participants. Further studies about the diagnostic properties of the applause sign must come forward to clarify its practical value and specific role as a sign of frontostriatal disconnection.