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Tau

Tau is a 68-kDa microtubule-associated protein important for cell stability and axonal transport in neurons [5]. Tau exists in several isoforms and may be phosphorylated at numerous sites. Tangles characteristic of AD are composed of hyperphosphorylated tau [5]. Concentrations of total tau (t-tau) as well as phosphorylated tau (p-tau) can be measured in CSF. Levels of t-tau in CSF are increased about three-fold in AD compared with normal controls [5]. However, similar elevations in CSF t-tau concentrations may be seen after stroke and traumatic brain injury [57], and even

Table 11.1 C ross-sectional and longitudinal studies assessing the associations of CSF biomarkers with neuropsychological performance or dementia risk in PD patients

Authors

n

Setting

aSyn

A042

Tau/p-tau

Comments

Cross-sectional studies:

Compta et al. [42]

20

Clinic-based

NA

Phonemic fluency

0/0

Increased t-tau and p-tau values associated with impaired verbal learning and naming in PD-D

Alves et al. [47]

109

Population- based, de novo

NA

verbal memory

0/0

verbal memory also correlated with A040 and AP38 levels

Leverenz et al. [50]

22

Clinic-based

NA

Processing speed

0/0

Correlation lost after adjustment for age

Kang et al. [27]

63

Clinic-based, de novo

0

0

0/0

First results from Parkinson's Progression Markers Initiative

Yarnall et al. [30]

67

Clinic-based,

incident

0

visual memory

0/0

AP42 correlated with Montreal Cognitive Assessment Score; lower AP42 and AP40 in PD-MCI than PD with normal cognition

Longitudinal studies:

Siderowf et al. [54]

45

Clinic-based, 19

months'

follow-up

NA

T cognitive decline (DRS-2)

0/0

Largest effect size for decline in attention subscale of DRS-2; no

association between CSF markers and baseline DRS-2 scores; low baseline AP42 levels in APOE e4 carriers

Compta et al. [55]

27

Clinic-based, 18

months'

follow-up

NA

T PD-D risk

0/0

Low baseline A042 predicted limbic and posterior-cortical neuropsychological decline as well as frontal, limbic and posterior-cortical thinning on MRI

Table 11.1 (continued) Cross-sectional and longitudinal studies assessing the associations of CSF biomarkers with neuropsychological performance or dementia risk in PD patients

Authors

n

Setting

aSyn

A|t42

Tau/p-tau

Comments

Alves et al. [56]

104

Population- based, incident cohort, 60 months' follow-up

NA

T PDD risk

0/0

Baseline A042 levels measured by two analytic methods and at two different laboratories; low AP42 levels predicted PD-D at high sensitivity (>85%) and independently of age and cognitive status at baseline; no association of baseline A040 or AP38 levels with PD-D risk

PD-D, Parkinson's disease dementia; PD-MCI, Parkinson's disease with mild cognitive impairment; NA, not assessed; 0, no significant correlation with cognitive measures (cross-sectional studies) or association with PD-D risk (longitudinal studies); DRS-2, Mattis Dementia Rating Scale.

higher values are found in rapidly progressing neurodegenerative disorders such as Creutzfeld- Jakob disease [58]. Hence, t-tau is considered as a rather non-specific CSF marker of neuronal cell loss. Increased CSF p-tau levels, in contrast, appear to be more closely related to tangle pathology and are therefore a more specific marker for AD.

Neuronal loss and tangle pathology may be found in the brains of patients with PD-D and DLB but are usually less extensive and severe than in AD [13]. In agreement with this, CSF tau proteins have been shown to be valuable in distinguishing AD from the synucleinopathies, particularly in combination with other CSF markers [29, 45, 59].

In PD, the association of CSF tau protein levels with cognition has been investigated extensively, mainly by cross-sectional studies. Most of these studies show normal or even decreased levels of CSF tau in patients without dementia, including individuals with de novo PD and PD-MCI [27, 30, 47]. Results are more inconsistent in patients with PD-D, although several groups reported mild to moderately increased t-tau levels in PD-D relative to PD without dementia and normal controls [40-42]. In PD-D, but not in PD without dementia, CSF levels of t-tau and p-tau have been shown to correlate with neuropsychological deficits indicating dysfunction of the posterior cortex [42]. Combined, these findings could indicate that tau levels—at least in some patients—may increase with progressive cognitive decline in PD; however, these changes appear to occur later than those observed for CSF Ap. Indeed, while A^42 predicted PD-D in the few longitudinal studies conducted so far this was not the case for tau proteins [54-56]. Longitudinal studies with repeated CSF measures would be valuable to clarify the trajectories of CSF tau proteins in relation to cognitive changes in PD.

 
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