Accurate diagnosis of these Parkinson-plus syndromes is improved when precise diagnostic criteria are used. Since diagnosis of individual Parkinson-plus syndromes is difficult, the prognosis is often poor. Proper diagnosis of these neurodegenerative disorders is important as individual treatments vary depending on the condition. The nuclear medicine SPECT procedure using I-IBZM, is an effective tool in the establishment of the differential diagnosis between patients with PD and Parkinson-plus syndromes.

Computed tomography (CT) scans of people with PD usually appear normal. MRI has become more accurate in diagnosis of the disease over time, specifically through iron-sensitive T2* and SWI sequences at a magnetic field strength of at least 3T, both of which can demonstrate absence of the characteristic 'swallow tail' imaging pattern in the dorsolateral substantia nigra. In a meta-analysis, absence of this pattern was 98% sensitive and 95% specific for the disease. Diffusion MRI has shown potential in distinguishing between PD and Parkinson plus syndromes, though its diagnostic value is still under investigation. CT and MRI are also used to rule out other diseases that can be secondary causes of parkinsonism, most commonly encephalitis and chronic ischemic insults, as well as less frequent entities such as basal ganglia tumors and hydrocephalus.

Dopamine-related activity in the basal ganglia can be directly measured with PET and SPECT scans. A finding of reduced dopamine-related activity in the basal ganglia can rule out drug-induced parkinsonism, but reduced basal ganglia dopamine-related activity is seen in both PD and the Parkinson-plus disorders so these scans are not reliable in distinguishing PD from other neurodegenerative causes of parkinsonism.

MJD can be diagnosed by recognizing the symptoms of the disease and by taking a family history. Physicians ask patients questions about the kind of symptoms relatives with the disease had, the progression and harshness of symptoms, and the ages of onset in family members.

Presymptomatic diagnosis of MJD can be made with a genetic test. The direct detection of the genetic mutation responsible for MJD has been available since 1995. Genetic testing looks at the number of CAG repeats within the coding region of the MJD/ATXN3 gene on chromosome 14. The test will show positive for MJD if this region contains 61-87 repeats, as opposed to the 12-44 repeats found in healthy individuals. A limitation to this test is that if the number of CAG repeats in an individual being tested falls between the healthy and pathogenic ranges (45-60 repeats), then the test cannot predict whether an individual will have MJD symptoms.

The types of imaging techniques that are most prominently utilized when studying and/or diagnosing CBD are:

- 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. FDOPA PET is used to study the efficacy of the dopamine pathway.

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.

A physician will initially assess for Parkinson's disease with a careful medical history and neurological examination. People may be given levodopa, with any resulting improvement in motor impairment helping to confirm the PD diagnosis. The finding of Lewy bodies in the midbrain on autopsy is usually considered final proof that the person had PD. The clinical course of the illness over time may reveal it is not Parkinson's disease, requiring that the clinical presentation be periodically reviewed to confirm accuracy of the diagnosis.

Other causes that can secondarily produce parkinsonism are stroke and drugs. Parkinson plus syndromes such as progressive supranuclear palsy and multiple system atrophy must be ruled out. Anti-Parkinson's medications are typically less effective at controlling symptoms in Parkinson plus syndromes. Faster progression rates, early cognitive dysfunction or postural instability, minimal tremor or symmetry at onset may indicate a Parkinson plus disease rather than PD itself. Genetic forms with an autosomal dominant or recessive pattern of inheritance are sometimes referred to as familial Parkinson's disease or familial parkinsonism.

Medical organizations have created diagnostic criteria to ease and standardize the diagnostic process, especially in the early stages of the disease. The most widely known criteria come from the UK Queen Square Brain Bank for Neurological Disorders and the U.S. National Institute of Neurological Disorders and Stroke. The Queen Square Brain Bank criteria require slowness of movement (bradykinesia) plus either rigidity, resting tremor, or postural instability. Other possible causes of these symptoms need to be ruled out. Finally, three or more of the following supportive features are required during onset or evolution: unilateral onset, tremor at rest, progression in time, asymmetry of motor symptoms, response to levodopa for at least five years, clinical course of at least ten years and appearance of dyskinesias induced by the intake of excessive levodopa.

When PD diagnoses are checked by autopsy, movement disorders experts are found on average to be 79.6% accurate at initial assessment and 83.9% accurate after they have refined their diagnosis at a follow-up examination. When clinical diagnoses performed mainly by nonexperts are checked by autopsy, average accuracy is 73.8%. Overall, 80.6% of PD diagnoses are accurate, and 82.7% of diagnoses using the Brain Bank criteria are accurate.

A task force of the International Parkinson and Movement Disorder Society (MDS) has proposed diagnostic criteria for Parkinson’s disease as well as research criteria for the diagnosis of prodromal disease, but these will require validation against the more established criteria.

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. 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.

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.

The confirmatory diagnosis is made via brain biopsy, however, other tests can be used to help such as MRI, EEG, CT, as well as the physical exam and history

Diagnosis of MSA can be challenging because there is no test that can definitively make or confirm the diagnosis in a living patient. Clinical diagnostic criteria were defined in 1998 and updated in 2007. Certain signs and symptoms of MSA also occur with other disorders, such as Parkinson's disease, making the diagnosis more difficult.

Both MRI and CT scanning frequently show a decrease in the size of the cerebellum and pons in those with cerebellar features. The putamen is hypodense on T2-weighted MRI and may show an increased deposition of iron in Parkinsonian form. In cerebellar form, a "hot cross" sign has been emphasized; it reflects atrophy of the pontocereballar fibers that manifest in T2 signal intensity in atrophic pons.

A definitive diagnosis can only be made pathologically on finding abundant glial cytoplasmic inclusions in the central nervous system.

Genetic testing can confirm a neuroferritinopathy diagnosis. A diagnosis can be made by analyzing the protein sequences of affected individuals and comparing them to known neuroferritinopathy sequences.

Parkinson-plus syndromes are usually more rapidly progressive and less likely to respond to antiparkinsonian medication than PD. However, the additional features of the diseases may respond to medications not used in PD.

Current therapy for Parkinson-plus syndromes is centered around a multidisciplinary treatment of symptoms.

These disorders have been linked to pesticide exposure.

A neurological examination would show evidence of muscle rigidity; weakness; and abnormal postures, movements, and tremors. If other family members are also affected, this may help determine the diagnosis. Genetic tests can confirm an abnormal gene causing the disease. However, this test is not yet widely available. Other movement disorders and diseases must be ruled out. Individuals exhibiting any of the above listed symptoms are often tested using MRI (Magnetic Resonance Imaging) for a number of neuro-related disorders. As PKAN is a disease prominently evident in the brain, MRIs are very useful in making a sound diagnosis. An MRI usually shows iron deposits in the basal ganglia. Development of diagnostic criteria continues in the hope of further separating PKAN from other forms of neurodegenerative diseases featuring NBIA.

Blood tests usually come back normal in affected individuals, so they do not serve as a reliable means of diagnosis. Blood tests can show low serum ferritin levels. However, this is unreliable as method of diagnosis, as some patients show typical serum ferritin levels even at the latest stages of neuroferritinopathy. Cerebral spinal fluid tests also are typically normal.

Ferritin found in the skin, liver, kidney, and muscle tissues may help in diagnosing neuroferritinopathy. More cytochrome c oxidase-negative fibers are also often found in the muscle biopsies of affected individuals.

Batten disease is rare, so may result in misdiagnosis, which in turn causes increased medical expenses, family stress, and the chance of using incorrect forms of treatment. Nevertheless, Batten disease can be diagnosed if properly detected. Vision impairment is the most common observable symptom to detect the disease. Children are more prevalent, and should be suspected more for juvenile Batten disease. Children or someone suspected to have Batten disease should initially be seen by an optometrist or ophthalmologist. A fundus eye examination that aids in the detection of common vision impairment abnormalities, such as granularity of the retinal pigment epithelium in the central macula will be performed. Though it is also seen in a variety of other diseases, a loss of ocular cells should be a warning sign of Batten disease. If Batten disease is the suspected diagnosis, a variety of tests is conducted to help accurately confirm the diagnosis, including:

- Blood or urine tests can help detect abnormalities that may indicate Batten disease. For example, elevated levels of dolichol in urine have been found in many individuals with NCL. The presence of vacuolated lymphocytes—white blood cells that contain holes or cavities (observed by microscopic analysis of blood smears)—when combined with other findings that indicate NCL, is suggestive for the juvenile form caused by "CLN3" mutations.

- Skin or tissue sampling is performed by extracting a small piece of tissue, which then is examined under an electron microscope. This can allow physicians to detect typical NCL deposits. These deposits are common in tissues such as skin, muscle, conjunctiva, and rectum. This diagnostic technique is useful, but other invasive tests are more reliable for diagnosing Batten disease.

- Electroencephalogram (EEG) is a technique that uses special probes attached on to the individual's scalp. It records electrical currents/signals, which allow medical experts to analylze electrical pattern activity in the brain. EEG assists in observing if the patient has seizures.

- Electrical studies of the eyes are used, because as mentioned, vision loss is the most common characteristic of Batten disease. Visual-evoked responses and electroretinograms are effective tests for detecting various eye conditions common in childhood NCLs.

- Computed tomography (CT) or magnetic resonance imaging (MRI) are diagnostic imaging tests which allow physicians to better visualize the appearance of the brain. MRI imaging test uses magnetic fields and radio waves to help create images of the brain. CT scan uses x-rays and computers to create a detailed image of the brain's tissues and structures. Both diagnostic imaging test can help reveal brain areas that are decaying, or atrophic, in persons with NCL.

- Measurement of enzyme activity specific to Batten disease may help confirm certain diagnoses caused by different mutations. Elevated levels of palmitoyl-protein thioesterase is involved in "CLN1". Acid protease is involved in "CLN2". Cathepsin D is involved in "CLN10".

- DNA analysis can be used to help confirm the diagnosis of Batten disease. When the mutation is known, DNA analysis can also be used to detect unaffected carriers of this condition for genetic counseling. If a family mutation has not previously been identified or if the common mutations are not present, recent molecular advances have made it possible to sequence all of the known NCL genes, increasing the chances of finding the responsible mutation(s).

There are five sub-types of MJD that are characterized by the age of onset and range of symptoms.

The sub-types illustrate a wide variety of symptoms that patients can experience. However, assigning individuals to a specific sub-type of the disease is of limited clinical significance.

- Type I is distinguished by arrival between the ages of 10 and 30 and represents approximately 13% of individuals. It usually has fast development and severe rigidity and dystonia.

- Type II is the most common sub-type (approximately 57% of individuals with MJD ) and typically begins between 20 and 50 years of age . It has an intermediate progression and causes symptoms that include spasticity, exaggerated reflex responses and spastic gait, ataxia and upper motor neuron signs.

- Type III MJD has a slow progression. Patients typically have an onset between the ages of 40 and 70 and represent approximately 30% of MJD patients. Symptoms include muscle twitching, tingling, cramps, unpleasant sensations such as numbness, pain in the feet, hands and limbs and muscle atrophy. Nearly all patients experience a decline in their vision such as blurred vision, double vision, inability to control eye movements, and loss of capability to distinguish color. Some patients also experience Parkinsonian symptoms.

- Type IV is distinguished by Parkinsonian symptoms that respond particularly well to levodopa treatment.

- Type V appears to resemble Hereditary Spastic Paraplegia; however, more research is needed to conclude the relationship between Type V MJD and hereditary spastic paraplegia.

Microscopic features of PKAN include:

- Iron granules

- Spheroid bodies

- Lewy bodies within neurons

MRI is often done to diagnose PSP. MRI may show atrophy in the midbrain with preservation of the pons giving a "hummingbird" sign appearance.

It is possible to detect the signs of Alexander disease with magnetic resonance imaging (MRI), which looks for specific changes in the brain that may be tell-tale signs for the disease. It is even possible to detect adult-onset Alexander disease with MRI. Alexander disease may also be revealed by genetic testing for the known cause of Alexander disease. A rough diagnosis may also be made through revealing of clinical symptoms including, enlarged head size, along with radiological studies, and negative tests for other leukodystrophies.

There is no cure or treatment for GSS. It can, however, be identified through genetic testing. GSS is the slowest to progress among human prion diseases. Duration of illness can range from 3 months to 13 years, with an average duration of 5 or 6 years.

PSP is frequently misdiagnosed as Parkinson's disease because of the slowed movements and gait difficulty, or as Alzheimer's disease because of the behavioral changes. It is one of a number of diseases collectively referred to as Parkinson plus syndromes. A poor response to levodopa along with symmetrical onset can help differentiate this disease from PD. Also, patients with the Richardson variant tend to have an upright or arched-back posture as opposed to the stooped-forward posture of other Parkinsonian disorders, although PSP-Parkinsonism (see below) may show the stooped posture. Early falls are characteristic, especially with Richardson-syndrome.

The symptoms of DLB overlap clinically with those of Alzheimer's disease and Parkinson's disease, but are associated more commonly with the latter. Because of this overlap, early DLB is often misdiagnosed. The overlap of neuropathological and presenting symptoms (cognitive, emotional, and motor) may make an accurate differential diagnosis difficult. In fact, DLB often is confused in its early stages with Alzheimer's disease and/or vascular dementia (multi-infarct dementia). However, while Alzheimer’s disease usually begins gradually, DLB frequently has a rapid or acute onset, with an especially rapid cognitive and physical decline in the first few months. Thus, DLB tends to progress more rapidly than Alzheimer’s disease. Despite the difficulty, a prompt diagnosis is important because of the risks of sensitivity to certain neuroleptic (antipsychotic) medications and because appropriate treatment of symptoms may improve life for both the person with DLB and the person's caregivers.

Dementia with Lewy bodies is distinguished from the dementia that sometimes occurs in Parkinson's disease by the time frame in which dementia symptoms appear relative to Parkinson symptoms. Parkinson's disease with dementia (PDD) would be the diagnosis when the onset of dementia is more than a year after the onset of Parkinsonian symptoms. DLB is diagnosed when cognitive symptoms begin at the same time or within a year of Parkinson symptoms.

MSA usually progresses more quickly than Parkinson's disease. There is no remission from the disease. The average remaining lifespan after the onset of symptoms in patients with MSA is 7.9 years. Almost 80% of patients are disabled within five years of onset of the motor symptoms, and only 20% survive past 12 years. Rate of progression differs in every case and speed of decline may vary widely in individual patients.

O’Sullivan and colleagues (2008) identified early autonomic dysfunction to be the most important early clinical prognostic feature regarding survival in MSA. Patients with concomitant motor and autonomic dysfunction within three years of symptom onset had a shorter survival duration, in addition to becoming wheelchair dependent and bed-ridden at an earlier stage than those who developed these symptoms after three years from symptom onset. Their study also showed that when patients with early autonomic dysfunction develop frequent falling, or wheelchair dependence, or severe dysphagia, or require residential care, there is a shorter interval from this point to death.

There is no cure for GSS, nor is there any known treatment to slow the progression of the disease. However, therapies and medication are aimed at treating or slowing down the effects of the symptoms. Their goal is to try to improve the patient's quality of life as much as possible. Despite there being no cure for GSS, it is possible to undergo testing for the presence of the underlying genetic mutation. Testing for GSS involves a blood and DNA examination in order to attempt to detect the mutated gene at certain codons. If the genetic mutation is present, the patient will eventually be afflicted by GSS, and, due to the genetic nature of the disease, the offspring of the patient are predisposed to a higher risk of inheriting the mutation.

The prognosis is generally poor. With early onset, death usually occurs within 10 years from the onset of symptoms. Individuals with the infantile form usually die before the age of 7. Usually, the later the disease occurs, the slower its course is.

Currently, there is no cure for FTD. Treatments are available to manage the behavioral symptoms. Disinhibition and compulsive behaviors can be controlled by selective serotonin reuptake inhibitors (SSRIs). Although Alzheimer's and FTD share certain symptoms, they cannot be treated with the same pharmacological agents because the cholinergic systems are not affected in FTD.

Because FTD often occurs in younger people (i.e. in their 40's or 50's), it can severely affect families. Patients often still have children living in the home. Financially, it can be devastating as the disease strikes at the time of life that often includes the top wage-earning years.

Personality changes in individuals with FTD are involuntary. Managing the disease is unique to each individual, as different patients with FTD will display different symptoms, sometimes of rebellious nature.

The progression of the degeneration caused by bvFTD may follow a predictable course. The degeneration begins in the orbitofrontal cortex and medial aspects such as ventromedial cortex. In later stages, it gradually expands its area to the dorsolateral cortex and the temporal lobe. Thus, the detection of dysfunction of the orbitofrontal cortex and ventromedial cortex is important in the detection of early stage bvFTD. As stated above, a behavioural change may occur before the appearance of any atrophy in the brain in the course of the disease. Because of that, image scanning such as MRI can be insensitive to the early degeneration and it is difficult to detect early-stage bvFTD.

In neuropsychology, there is an increasing interest in using neuropsychological tests such as the Iowa gambling task or Faux Pas Recognition test as an alternative to imaging for the diagnosis of bvFTD. Both the Iowa gambling task and the Faux Pas test are known to be sensitive to dysfunction of the orbitofrontal cortex.

Faux Pas Recognition test is intended to measure one’s ability to detect faux pas types of social blunders (accidentally make a statement or an action that offends others). It is suggested that people with orbitofrontal cortex dysfunction show a tendency to make social blunders due to a deficit in self-monitoring. Self-monitoring is the ability of individuals to evaluate their behaviour to make sure that their behaviour is appropriate in particular situations. The impairment in self-monitoring leads to a lack of social emotion signals. The social emotions such as embarrassment are important in the way that they signal the individual to adapt social behaviour in an appropriate manner to maintain relationships with others. Though patients with damage to the OFC retain intact knowledge of social norms, they fail to apply it to actual behaviour because they fail to generate social emotions that promote adaptive social behaviour.

The other test, the Iowa gambling task, is a psychological test intended to simulate real-life decision making. The underlying concept of this test is the somatic marker hypothesis. This hypothesis argues that when people have to make complex uncertain decisions, they employ both cognitive and emotional processes to assess the values of the choices available to them. Each time a person makes a decision, both physiological signals and evoked emotion (somatic marker) are associated with their outcomes and it accumulates as experience. People tend to choose the choice which might produce the outcome reinforced with positive stimuli, thus it biases decision-making towards certain behaviours while avoiding others. It is thought that somatic marker is processed in orbitofrontal cortex.

The symptoms observed in bvFTD are caused by dysfunction of the orbitofrontal cortex, thus these two neuropsychological tests might be useful in detecting the early stage bvFTD. However, as self-monitoring and somatic marker processes are so complex, it likely involves other brain regions. Therefore, neuropsychological tests are sensitive to the dysfunction of orbitofrontal cortex, yet not specific to it. The weakness of these tests is that they do not necessarily show dysfunction of the orbitofrontal cortex.

In order to solve this problem, some researchers combined neuropsychological tests which detect the dysfunction of orbitofrontal cortex into one so that it increases its specificity to the degeneration of the frontal lobe in order to detect the early-stage bvFTD. They invented the Executive and Social Cognition Battery which comprises five neuropsychological tests.

- Iowa gambling task

- Faux Pas test

- Hotel task

- Mind in the Eyes

- Multiple Errands Task

The result has shown that this combined test is more sensitive in detecting the deficits in early bvFTD.