**6. Functional neuroimaging in other neurodegenerative diseases like dementia, Parkinson's disease, and Huntington's disease**

### **6.1 Functional neuroimaging in dementia**

26 Neuroimaging for Clinicians – Combining Research and Practice

Auditory processing underlying stimulus detection measured by MEG and subsequent memory-based comparison processes were abnormal in ten ALS patients with bulbar signs (Pekkonen et al., 2004), and a reduced response to auditory and visual stimuli was observed in ALS patients compared to healthy controls using EEG (Münte et al., 1998; Vieregge et al., 1999). This finding may indicate a changed sensory processing capacity as well as reduced attention capacity (Pinkhardt et al., 2008), an ability assigned to the frontal cortex known to

The association of functional cortical changes and cognitive deficits has been confirmed by an fMRI paradigm of letter fluency and confrontation naming in 28 non-demented ALS patients compared to 18 healthy controls (Abrahams et al., 2004) and had been demonstrated previously by other functional imaging techniques (Ludolph et al., 1992; Kew et al., 1993b; Abrahams et al., 2004). There is increasing evidence that not only do 2–5% of ALS patients present an ALS/dementia complex but also that patients with classical ALS without obvious clinical evidence of cognitive deficits may have subtle changes in frontal cortical function (Ludolph et al., 1992; Kew et al., 1993b; Lulé et al., 2005; Lomen-Hoerth et al., 2002). The cognitive impairment has been reported as more pronounced in ALS patients with a bulbar onset compared to patients with spinal onset (Abrahams et al., 1997; Strong et al., 1999; Lomen-Hoerth et al., 2002; Schreiber et al., 2005) and is also evident in patients with primary lateral sclerosis (PLS; Piquard et al., 2006). Longitudinal investigation of ALS patients (up to 18 months) revealed that cognitive dysfunction in ALS occurred early in the disease course and that the cognitive deficits may not progress in synchrony with motor decline, but distinctly more slowly (Schreiber et al., 2005). Functional imaging studies confirm hypoperfusion in the resting state in the frontal cortex in ALS with or without cognitive deficits (Ludolph et al., 1992; Anzai et al., 1990; Tanaka et al., 1993). Apart from the local hypometabolism, there is also evidence for decreased activity in different cortical areas during the performance of different tasks. Findings from fMRI studies support the association of reduced frontal executive function and reduced activity in fronto-parietal areas, and confirm findings from studies using other imaging techniques (Kew et al., 1993b; Abrahams et al., 1996). In non-demented ALS patients, a correlation between reduced verbal fluency and reduced activity in middle and inferior frontal gyrus, anterior cingulate cortex, and parietal and temporal lobe have been observed in an fMRI study by Abrahams et al. which included 22 non-demented ALS patients compared with 18 healthy controls (Abrahams et al., 2004). There is no evidence of additional recruitment in other areas to compensate the functional loss in the frontal cortex, as has been shown for the motor system. Cognitive functions of frontal areas do not exhibit redundancy of motor pathways, and compensation is therefore not possible. Further longitudinal fMRI studies of different cognitive functions in ALS might improve our understanding of subclinical cognitive

Further differences in cortical pattern activation were observed in ALS patients without significant cognitive impairments during processing of socio-emotional stimuli. Pictures of persons in emotional situations were presented to 13 ALS patients and 15 healthy controls at an initial measurement and to 10 of these ALS patients and 14 healthy controls at a second measurement after six months. ALS patients presented an increased activity in the rightsided supramarginal area (BA 40), which is part of the social-information processing network. This difference in social-information processing pattern increased over the course of six months (Lulé et al., 2007b). The increased activity in the social information-processing

be involved in ALS (Ludolph et al., 1992; Kew et al., 1993b).

deficits in ALS.

There is the described overlap of dementia and motor neuron diseases, however, contrary to the above described prominent role in MND, the role of imaging in dementia has traditionally been directed at ruling out treatable and reversible aetiologies (Tartaglia et al., 2011). Contrary to motor neuron diseases it was rarely used to better understand the pathophysiology of the different dementias.

Structural CT and MRI scans are mainly used to assess volumetric changes in dementias with decreases in gyral and increases in sulcal size secondary to decrease in synaptic density, neuronal loss, and cell shrinkage (Tartaglia et al., 2010). The medial temporal lobes, especially the hippocampus and entorhinal cortex (ERC), are among the earliest sites of pathologic involvement in AD (Braak & Braak, 1991), and studies have repeatedly shown decreased hippocampal and ERC volumes in patients with AD compared with age-matched controls (Appel et al., 2009). Other severely affected areas include the lateral parietal and posterior superior temporal regions and medial posterior portion of the cingulate gyrus (Jones et al., 2006), but atrophy is also evident in the frontal, temporal, and occipital lobes (Rusinek et al., 1991). Recent neuropathological data provide evidence that disease pathology starts in locus coeruleus and propagates into transentorhinal region and other cerebral regions (Braak & Del Tredici, 2011a). MRI of hippocampal and cortical regions in the parietal and lateral temporal regions has been successfully used as prognostic marker in patients with mild cognitive impairment (MCI) to develop AD (Du et al., 2003; Schott et al., 2003). High field MRI provided evidence for a sensitivity of the thickness of CA1 to distinguish subjects with AD from normal controls (Kerchner et al., 2010). Like in ALS, white matter (WM) pathology was long not in focus of research. However, recent work provides evidence for WM changes in AD and MCI in association with cognitive changes (Zhang et al., 2007; Sexton et al., 2010). It might even be useful to distinguish different forms of dementia (Firbank et al., 2007; Zhang et al., 2009). NAA spectroscopy has been used as a possible diagnostic marker in dementia. NAA is consistently reported as being lower in the parietal gray matter and hippocampus of patients with AD than in cognitively normal elderly subjects (Schuff et al., 2002).

On the functional level of the brain, evidence for a reduced function of frontal areas in FTD compared to AD was seen using fMRI (Rombouts et al., 2003). Furthermore, alterations in the default mode network (areas active during rest and idling of the brain) in resting state have been found for AD and MCI patients (Tartaglia et al., 2011). In the future, the application of neuroimaging in dementia will increase, as there will be extended evidence for prognostic and clinical marker for different forms of dementia.

Degeneration of the Human Nervous System and Magnetic Resonance Neuroimaging 29

setting due to low patient load. Spectroscopy and resting state analysis will extend our understanding of molecular and functional changes of cortical structures and networks. MRI neuroimaging has the potential to fill the gap between pathogenesis and clinical

Brain computer interfaces (BCIs) are a technique, which transfers and translates brain signals to technical devices for communication, control of environment (e.g. light switches) or prosthetic devices. BCIs are the only applicable means for communication in patients with advanced neurodegenerative diseases and no voluntary muscle control like in complete locked-in patients (CLIS) at end stage of ALS. There has been the unsolved question why patients in CLIS are unable to control EEG BCIs (Kübler & Birbaumer, 2008). With the means of functional neuroimaging, the question of activity of the idling brain of CLIS patients might be solved. Neuroimaging provide essential insight into the brains of patients with neurodegenerative diseases who are unable to communicate due to the loss of

MRI based neuroimaging has been extensively applied in diagnosis of neurodegenerative diseases. Low patient load and high applicability are in favour for this technique. Availability of MRI scanner in many clinics has already made neuroimaging an essential key in diagnosis of neurodegenerative diseases. The value of neuroimaging techniques for biomarker is still subject to ongoing debate; yet, there is a strong need for easy to apply biomarkers. In most neurodegenerative diseases, loss and death of motor neurons occur long before onset of clinical symptoms. Diagnosis is usually based on clinical symptoms when the majority of target cells are already affected. Braak and colleagues in Alzheimer's disease have provided evidence for this. Tau tangles are found up to 30-50 years prior to onset of clinical symptoms (Braak & Braak, 1991; Braak & Del Tredici, 2011b). Effective therapeutic trials, however, ask for application as early as possible. Emergence of several disease-modifying drugs in neurodegenerative diseases has particularly highlighted the need for biomarkers of therapeutic response. Unwanted drug effects has brought additional requirement for effective biomarkers for optimal initial patient selection and timing of discontinuation (Turner et al., 2011). In the future, in search for robust biomarkes, MRI

Volker Diekmann, Hans-Peter Müller, Jan Kassubek and Alexander Unrath (all University of Ulm) are thankfully acknowledged for their help in the course of the fMRI and DTI experiments and data analyses. Special thanks to Sonja Fuchs and Sandra Pauli (University of Ulm) for technical assistance in MRI measurements and Johanna Heimrath for her help with the manuscript. We would like to thank Corinna Hendrich, Regina Gastl and Anne Sperfeld (all University of Ulm) for supporting us in the recruitment of patients. Special

thanks to the patients and healthy subjects who participated in our studies.

**8. Future advances of neuroimaging in neurodegeneration** 

motor control like in ALS or cognitive ability like in dementia.

based neuroimaging techniques are a promising candidate.

outcome of neurodegenerative diseases.

**8.1 Brain-computer interfaces** 

**8.2 Clinical implications** 

**9. Acknowledgement** 

#### **6.2 Functional neuroimaging in Parkinson's disease**

Like in most neurodegenerative diseases, neuroimaging in Parkinson's disease has been challenging because the majorities of neurons are affected before clinical symptoms evolve and diagnosis is made. The clinical symptoms of PD appear when approximately 50-80% of the nigral dopamine (DA) neurons have been lost already. Consequently, structural imaging has in general been unrewarding, although some newer MRI techniques, such as diffusion tensor imaging or shape analysis, are somewhat more promising and provided evidence for a reduced volume and changed connectivity of substantia nigra (Stössl, 2011). Functional neuroimaging is a promising candidate to detect specific changes in PD. Functional connectivity measured with resting state MRI provided evidence for changed pattern in motor network (Wu et al., 2009; Helmich et al., 2010) and in the default network (Palmer et al., 2010). MRI spectroscopy may be useful in differentiating between PD and atypical parkinsonian syndromes (Firbank et al., 2002). Functional MRI in PD has been widely used and proven to be sensitive to e.g. polymorphism of catechol-O-metyltransferase (COMT) in PD. Different activation patterns in fronto-parietal areas in an fMRI task provided a clear link to genotype, dopaminergic medication and cognitive performance in PD patients (Williams-Gray et al., 2007, 2008). In the future, functional neuroimaging may be used to get a fast and objective means of functional and genetic status in advanced stage PD patients.

#### **6.3 Functional neuroimaging in Huntington's disease**

Among neurodegenerative disorders, HD is unique in that individuals destined to develop symptoms can be identified through genetic testing before clinical signs of the disease begin. This raises the possibility of developing therapies to prevent or delay the onset of clinical manifestations in HD gene carriers. Therefore, substantial effort has been dedicated to the characterization of quantitative descriptors of disease progression in premanifest individuals (Eidelberg & Surmeier, 2011). Neuroimaging may be used to clarify diagnosis in the pre-symptomatic stage. The idea of imaging as a preclinical marker in HD was supported by findings in a prospective observational study (Tabrizi et al., 2011).

The vast number of neuroimaging studies in HD traditionally was on single brain regions like structural and functional studies on the striatum. Several PET studies revealed association of striatal and cortical dysfunction in association with genetic alterations and cognitive function. However, with the evolvement of MRI volumetric studies with low patient load, better insight on striatal function was found in a faster and easier way. However, even with this technique, systems-level changes might not be detectable. Connectivity studies like in resting state MRI might be more susceptible and applicable in the future.

### **7. Conclusion**

Despite different aetiology of neurodegenerative diseases, similar approaches have been used in diseases of the central and peripheral nervous system. MRI based neuroimaging has extended our understanding of involvement of cortical structures which by far outreach the usually described clinical changes. Different neuroimaging techniques provide limitations that can be compensated by other techniques. Structural and functional MRI has taken over radio nucleotide dependent measurements in clinical setting due to low patient load. Spectroscopy and resting state analysis will extend our understanding of molecular and functional changes of cortical structures and networks. MRI neuroimaging has the potential to fill the gap between pathogenesis and clinical outcome of neurodegenerative diseases.
