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Tauopathies and cognition

Progressive supranuclear palsy

PSP is an adult-onset neurodegenerative disorder characterized by an atypical akinetic-rigid syndrome that is usually non-responsive to levodopa, early postural instability, and vertical supranuclear-gaze palsy. Recent epidemiological studies have shown that the disorder is more common

Table 19.1 Spectrum of major neurodegenerative disorders causing dementia and Parkinsonism

Tauopathies:

Progressive supranuclear palsy (PSP)

Corticobasal degeneration (CBD)

Frontotemporal lobar degeneration (FTLD):

Pick's disease

Frontotemporal dementia with parkinsonism (FTDP)

Multiple system tauopathy with pre-senile dementia (MSTD)

a-Synucleinopathies:

Lewy body disease:

Parkinson's disease

Dementia with Lewy bodies

Multiple system atrophy (MSA)

Tardopathies [TAR-DNA-binding protein-43 (TDP-43) proteinopathies]:

Frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U)

Frontotemporal lobar degeneration with motor-neuron disease (FTLD-MND)

Frontotemporal lobar degeneration with motor-neuron disease associated with repeat expansions in the C9ORF72 gene [12]

Amyloidopathies:

Alzheimer's disease

Alzheimer's disease associated with mutations in the genes encoding amyloid precursor protein (APP), presenilin 1 (PSEN1), or presenilin 2 (PSEN2)

Miscellaneous:

Fragile X-associated tremor/ataxia syndrome (FXTAS)

Spinocerebellar ataxias (SCA type 2, 17, 21)

Fahr's syndrome (bilateral striopallidodentate calcification)

Huntington's disease

than previously recognized, with an average annual incidence for ages 50-99 years of around 5.3 cases per 100,000 population [13].

Although in their seminal paper Steele et al. [14] reported cognitive impairment in seven out of the nine patients they evaluated, and indeed the characteristic pattern of neuropsychological deficits observed in PSP gave rise to the term ‘subcortical dementia’ [3], traditionally more attention was paid to the motor and oculomotor abnormalities that aid in the differentiation of PSP from PD than to the cognitive and behavioural disturbances associated with it.

Behavioural and cognitive changes occur in 50 to 90% of patients with PSP, often within the first year of the disease [15, 16]. In cross-sectional studies, frequency of dementia in PSP is about 55% [17].

Cognitive changes were initially reported by Albert et al. [3] and described as a prototypical ‘subcortical dementia’. The pattern of deficits could be differentiated from that seen in patients with ‘cortical dementia, who usually present with aphasia, apraxia, and/or agnosia, and it was suggested that the symptoms found in PSP were similar to those which had previously been described in patients with frontal lobe lesions [11, 18]. The ‘subcortical dementia’ described by Albert et al. [3] was characterized by a cluster of neuropsychological deficits including forgetfulness, slowing of thought processes, emotional or personality changes (apathy, depression, irritability), and impaired ability to manipulate acquired knowledge. The neuropsychological basis for all these deficits seems to be the slowing in performance of cognitive functions rather than primary dysfunction of the cortical systems responsible for each cognitive domain, so that cognitive functions may be strikingly preserved if the patient is given sufficient time to respond. As PSP was thought to almost exclusively affect subcortical nuclei (including the pallidum and caudate nucleus, red nucleus, subthalamic nucleus, and substantia nigra), the authors proposed that cognitive impairment in PSP was due to bilateral frontal-subcortical dysfunction [3]. In keeping with this suggestion, neuroimaging studies have shown PSP to affect both the pre-synaptic and post-synaptic aspects of the dopaminergic and cholinergic neurotransmitter systems that project their efferent connections to the prefrontal cortex, and lead to early and clinically relevant cognitive dysfunction [19, 20-22].

PSP patients have a dramatically slowed speed of information processing, early and severe executive dysfunction with problems in orienting attentional resources, difficulty in planning and shifting conceptual sets, and prominent recall deficits with moderate forgetfulness [23, 24]. These cognitive deficits can also be found in PD patients and other akinetic-rigid syndromes, but patients with PSP show a greater decline in attention, processing speed, set-shifting, and categorization abilities than PD or MSA patients [25, 26]. Slowed speed of information processing and execution of responses is particularly altered in PSP. In order to disentangle whether this slowness is directly related to cognitive dysfunction or to bradykinesia, Dubois et al. [27] measured reaction times using tasks with different levels of cognitive complexity but the same motor demands. They found that central processing time in PSP is significantly increased when performing complex tasks compared with both a PD and a control group, while cognitive speed in the PD group was similar to controls. These results have been further replicated in studies using event-related potentials showing dramatically increased response latencies in complex attentional tasks in PSP that have not been observed in other dementias or parkinsonian syndromes [28].

Executive function is clearly altered in PSP, with impairment in most tests sensitive to frontal lobe dysfunction [24]. In particular, PSP patients show impairment in tasks of working memory, reasoning, problem-solving, conceptualization, planning, and social cognition [29, 30]. Characteristically, PSP patients also show perseverative errors during the performance of executive tasks, as well as deficits of response inhibition that seem not to be so frequent in other parkinsonian syndromes such as PD or MSA [29]. Similar to patients with focal prefrontal lesions, PSP patients show decreased ability to inhibit previously learned cognitive responses, while PD patients show more evident deficits in the maintenance of new cognitive programmes [31]. This cognitive dissociation has been linked to differential involvement of the medial prefrontal cortex (associated with impaired response inhibition) [32], and dysfunction of circuits connecting the striatum with the dorsolateral prefrontal cortex (associated with impairment in set maintenance) [33]. Recently, the inability to inhibit cognitive or motor responses has been claimed as a useful clinical marker that can help to discriminate PSP from PD [34]. The applause sign—the inability to stop clapping the hands after three times—was observed in 71% of PSP patients but in none of the PD patients [34]. Perseverative behaviours, due to the inability to stop an automatic activity once it has been released, have been related to dysfunction of the medial aspects of the prefrontal cortex and the caudate nucleus [35].

Thus, in PSP there seems to be a more diffuse impairment of prefrontal-based cognitive functions compared with PD. In fact, performance in a simple phonemic fluency test—which represents a reliable marker of prefrontal function—is able to separate PSP patients from those with PD. In patients with parkinsonian syndromes in the early stages (PD versus PSP versus CBD with 1-4 years of disease duration), performance on a phonemic fluency task producing seven or fewer words in a minute recently yielded high positive (81%) and negative (95%) predictive value for the diagnosis of PSP [36]. Recent data have shown direct neocortical degeneration in the prefrontal cortex beyond the well-established degeneration of subcortical nuclei [16]. It is known that clinical heterogeneity and atypical presentations result in frequent clinical misdiagnosis in the early stages of PSP [37]. In 2005, Williams et al. [38] identified two clinical phenotypes in pathologically proven PSP patients. Patients assigned to the Richardson’s syndrome (RS) group (54% of all cases) developed the classical syndrome associated with PSP, with early onset of postural instability and falls, supranuclear vertical-gaze palsy, and a more severe cognitive dysfunction. By contrast, patients in the PSP-parkinsonism (PSP-P) group (32% of all cases) were characterized by asymmetric onset, tremor, and a moderate initial therapeutic response to levodopa, and were frequently confused with PD. More recently, a third type of presentation has been described [16]. In a prospective study of 152 patients with a clinical diagnosis of PSP given after a disease duration of 5 years, 20% of the subjects had predominant cognitive dysfunction and behavioural changes at disease onset associated with mild instability problems and absent or mild oculomotor disturbances. The most common initial misdiagnosis in this group was dementia, in particular FTD (35%). Volumetric magnetic resonance imaging (MRI) studies have shown that PSP patients have a greater loss of grey matter volume in both the medial and lateral aspects of the prefrontal cortex than with MSA and PD patients, which correlates with the degree of executive dysfunction but not with motor dysfunction [39]. When measuring loss of grey and white matter volume in PSP subgroups, patients with predominant cognitive versus parkinsonian symptoms have been found to have bilateral specific and higher atrophy in the prefrontal lobe [40], which reinforces the hypothesis that cognitive impairment in PSP is a direct consequence of the degeneration of the prefrontal cortex along with degeneration of subcortical nuclei.

In summary, all these findings characterize PSP as a heterogeneous clinical entity spanning a broad clinical spectrum of symptoms that may manifest as either a predominant motor disorder resembling PD, an atypical parkinsonism with postural instability, oculomotor disturbances, and cognitive impairment, or as a predominant dementing disease with prominent and early behavioural disturbances resembling FTD. Recently, clinical and pathological studies have shown that PSP can present as progressive non-fluent aphasia, with subsequent development of the parkinsonian symptoms and oculomotor disturbances of typical PSP after a delay of 3-8 years [41-43]. Such patients are more likely to progress to mutism, and to develop limb-kinetic apraxia, but progression to dementia is slower. PSP patients with progressive non-fluent aphasia have less prominent midbrain atrophy but more marked prefrontal atrophy compared with typical PSP [44].

Behavioural changes are also a frequent and characteristic feature in PSP [45]. In the first descriptive study of neuropsychiatric symptoms in PSP, almost all patients suffered from moderate to severe apathy (91%), and 36% exhibited disinhibition. Depression (18%), anxiety (18%), and irritability (9%) were infrequent, and hallucinations or delusions were not reported [46]. Apathy was significantly associated with executive dysfunction, suggesting that both cognitive dysfunction and apathy in PSP are mediated by degeneration in similar prefrontal areas or by dysfunction of similar frontal-subcortical connections [46, 47]. The impact of apathy in PSP is further stressed by the fact that PSP can be discriminated from PD and AD by more severe apathy and less depression [48, 49]. A consistent relationship of apathy with disinhibition is further evidence of the important role of the dysfunction of the orbitofrontal and medial frontal circuits in the behavioural disturbances of PSP [48], which has been replicated in recent studies showing that frontal atrophy in volumetric MRI studies correlates with behavioural changes in PSP [50]. Although hallucinations have been infrequently reported, they can be present in 9 to 16% of PSP patients [51, 52]. More detailed descriptions of behavioural disorders in PSP patients have shown the occurrence of behaviours typically ascribed to patients with FTD. In a large series of patients meeting the criteria for clinically probable PSP, disinhibition was found in 32% of the sample and eating disorders appeared in up to 40% of patients [53]. Abnormal eating behaviours, one of the core and more specific features of FTD, have been described in PSP in the form of ‘greed for food’, following an impulsive behaviour in which patients eat ‘voraciously’ and ‘without biting enough before swallowing’, which seems related to a need or urge to eat ‘faster and faster’, but without the features of hyperphagia or hyperorality [54]. In a comparative MRI study of PSP and FTD, a very similar pattern of frontal cortical atrophy was seen in the two groups, with PSP patients displaying significant atrophy in the frontal rectal gyrus, anterior temporal lobes, and thalamus [55].

 
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