Diagnostics

Symptoms of PSP typically present in the sixth to seventh decade of life and consist of postural instability with falls, vertical supranuclear gaze palsy, dysarthria, dysphagia, and cognitive and behavioral disturbances. Typical presentation (onset with falls, gaze palsy and cognitive dysfunction) of PSP is referred to as “Richardson’s syndrome”, whereas the commonest of atypical variants (asymmetric onset, tremor, and levodopa response) is termed as “PSP-Parkinsonism” (Williams et al., 2005). Atypical presentations are difficult to diagnose ante-mortem.

International consensus criteria (see below) are available and differentiate between possible, probable and definite PSP, of which the latter requires neuropathological confirmation (Litvan et al., 1996). According to neuropathological criteria for PSP a high density of neurofibrillary tangles and neuropil threads is required in at least three of the following areas: pallidum, subthalamic nucleus, substantia nigra or pons, together with the involvement of at least three of the following areas: striatum, oculomotor complex, medulla or dentate nucleus (Litvan et al., 1996).

International consensus criteria for PSP

(Litvan et al, 1996)

Possible PSP

• Gradually progressive disorder, onset age 40 or later
• Either vertical supranuclear palsy or slowing of vertical saccades and postural instability with falls in the first year of disease onset
• No evidence of other diseases that could explain the symptoms

Probable PSP

• Gradual progressive disorder, onset age 40 or later
• Vertical supranuclear gaze palsy and postural instability with falls in the first year of disease onset
• No evidence of other diseases that could explain the symptoms

Definite PSP

• Clinical possible or probable PSP and histopathological confirmation

Supportive criteria

• Symmetric akinesia or rigidity, proximal more than distal
• Abnormal neck posture, especially retrocollis
• Poor or absent response to levodopa therapy
• Early presence of dysarthria and dysphagia
• Early onset of cognitive impairment with at least two out of the following features: apathy, impaired abstract reasoning, decreased verbal fluency, utilization or imitation behaviour, frontal symptoms

The clinical diagnosis of Parkinson’s disease is based on the presence of motor symptoms. The clinical features include slowness of movements, compromise of balance, muscle rigidity and tremor. Non-motor manifestations, such as autonomic disturbances, sleep problems and psychiatric problems, are common and may antedate the motor symptoms in Parkinson’s disease (Langston, 2006). Dementia with Lewy bodies starts with cognitive decline with fluctuating attention and hallucinations before the emergence of parkinsonism. Parkinson’s disease with dementia and Dementia with Lewy bodies share many clinical and pathological features and are often considered to be part of the same disease spectrum.

Pathologically, Parkinson’s disease is characterized by a selective loss of neurons in the brainstem that produce the neurotransmitters dopamine and noradrenaline. Microscopically, Lewy bodies and Lewy neurites composed of abnormal aggregated proteins, primarily abnormal a-synuclein, are visible inside the affected nerve cells. A recent staging procedure for Lewy body pathology in the brain proposes that Parkinson’s disease begins in the lower brainstem and olfactory bulb (stage 1-2). The pathology progresses from the brainstem to the midbrain and forebrain in stages 3-4. In the end-stages 5-6, the pathological process reaches the neocortex (Braak et al., 2003). Moreover, Lewy body pathology is not only found in the central nervous system but also in the peripheral and enteric systems. The pathology outside the nigrostriatal system may account for non-motor, non-dopaminergic manifestations of Parkinson’s disease. In Dementia with Lewy bodies, the Lewy bodies are found throughout the brain and concomitant Alzheimer’s disease pathology is not uncommon.

Staging and characterization of post mortem MS lesions (van der Valk and De Groot, 2000) and (Bö et al., 2006):

0. Normal appearing white matter (hardly any HLA reactivity, no demyelination)
1. Reactive (groups of HLA-positive microglial cells, no demyelination)
2. Active lesion (demyelination, HLA positive microglial cells throughout the lesion)
   Sub score 1-3 reflects degree of activation of HLA positive microglial cells: ramified appearance = 1 up to big rounded foamy morphology = 3
3. Chronic active lesion (hypocelular gliotic centre, active border with HLA-positive macrophages/microglial cells)
   Sub score 1-3 reflects degree of activation of HLA positive microglial cells: ramified appearance = 1 up to big rounded foamy morphology = 3
4. Gliotic inactive hypocellular lesion, with some HLA-positive microgliosis
5. Grey matter lesion (for cortex not for spinal cord):
   Type I = mixed grey-white matter lesion
   Type II = grey matter lesion
   Type III = subpial demyelination
   Type IV = grey matter lesion that stops exactly at the border with white matter
6. Shadow plaque

Frontotemporal dementia (FTD) is the second most common presenile dementia and is clinically characterized by behavioural changes, language difficulties and executive dysfunction (1. The Lund and Manchester Criteria, 1994). The clinical spectrum of FTD includes the behavioural variant FTD (bvFTD), and two language variants; semantic dementia (SD), and progressive non-fluent aphasia (PNFA). FTD is accompanied by motor neuron disease in 5 – 15 % of the cases.

The estimated prevalence of FTD in the Netherlands is 9.4 per 100,000 in the age group of 60 – 69 years (2. Rosso et al, 2003). The onset age is between 50 – 65 years in most cases, with a mean disease duration of 8 – 10 years (range 2 – 20 years), whereas patients with FTD and motor neuron disease have shorter disease duration (three years).

Family history is positive in approximately 40 percent of all cases, whereas the other 60 percent is sporadic (3. Seelaar et al, 2008). Two genetic defects are found in familial FTD; mutations in the microtubule associated protein tau (MAPT) and mutations in the Progranulin (GRN) genes. Mutations in these two genes account for approximately half of the familial cases. The genetic defect(s) of the other familial cases has not been discovered to date.

Neuropathogical examination is necessary for the definite diagnosis FTD. The frontal and temporal are typically severely affected in most FTD cases, but the hippocampus, basal ganglia and substantia nigra are also involved. FTD is part of the clinicopathological spectrum frontotemporal lobar degeneration (FTLD). Three specific protein accumulations have been recognized in FTLD: tau, TDP-43 and FUS. The most recent neuropathological criteria were published by (4) MacKenzie et al, 2010.

References

1. The Lund and Manchester Criteria:Clinical and neuropathological criteria for frontotemporal dementia. Journal of neurology, neurosurgery, and psychiatry. 1994 Apr;57(4):416-8
2. Rosso et al. Frontotemporal dementia in The Netherlands: patient characteristics and prevalence estimates from a population-based study. Brain. 2003;126(Pt 9):2016-22. Epub 03 Jul 22
3. Seelaar et al. Distinct genetic forms of frontotemporal dementia. Neurology. 2008 Oct 14;71(16):1220-6
4. Mackenzie et al. Nomenclature and nosology for neuropathological subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathologica. 2010 Jan; 119(1):1-4

A clinical diagnosis of AD is based on the clinical criteria of probable AD (McKhann G et al., 1984 and updated by Dubois B et al. in 2007). These criteria require that the presence of cognitive impairment and a suspected dementia syndrome be confirmed by neuropsychological testing for a clinical diagnosis of possible or probable AD. A histopathological confirmation by autopsy is required for a definitive diagnosis.

Individuals suffering from AD develop pathological changes of the brain. Most conspicuous is the occurrence of extracellular amyloid and intracellular neurofibrillary changes. To establish a diagnosis of AD, six stages of disease propagation can be distinguished with respect to the location of the tangle-bearing neurons and the severity of changes. The first two stages are characterized by either a mild or a severe alteration of the transentorhinal layer Pre-alpha (transentorhinal stages I-II: clinically silent). The two forms of limbic stages (stages III-IV: incipient Alzheimer’s disease) are marked by a conspicuous affection of layer Pre-alpha in both the transentorhinal region and the entorhinal cortex proper. In addition, there is mild involvement of the first Ammon’s horn sector. The hallmark of the two isocortical stages (stages V-VI: fully developed Alzheimer’s disease) is the destruction of virtually all isocortical association areas (Braak H and Braak E, 1991 and Braak H and Braak E, 1995).