**2. Synucleinopathies: Dementia with lewy bodies**

Synucleinopathies comprise a diverse groups of neurodegenerative proteinopathies that share common pathological lesions composed of aggregates of conformational and posttranslational modifications of alpha-synuclein in selected populations of neurons and glia. Abnormal filamentous aggregates of misfolded alpha-synuclein protein are the major components of LB, dystrophic (Lewy) neurites and the Papp–Lantos filaments in oligodendroglia and neurons linked to degeneration of affected brain regions. The synucleinopathies (see table 1) include Lewy Body disease (Parkinson Disease (PD), DLB, Multiple System Atrophy (MSA)) and neurodegeneration with brain iron accumulation type I, (NBIIA), formerly Hallervorden–Spatz disease. The pathological diagnosis of Lewy body disease is established by validated consensus criteria based on semi-quantitative assessment of subcortical and cortical LB as their common hallmarks. They are accompanied by subcortical multisystem degeneration with neuronal loss and gliosis with or without AD pathologic features. LB deposition also occur in numerous other disorders, including pure autonomic failure, neuroaxonal dystrophies and their presence is also evident in various amyloidoses and tauopathies. MSA, a sporadic, adult-onset degenerative movement disorder of unknown cause, is characterized by alpha-synuclein–positive glial cytoplasmic and rare neuronal inclusions throughout the central nervous system associated with striatonigral degeneration, olivopontocerebellar atrophy and involvement of medullar and spinal autonomic nuclei. In NBIIA alpha-synuclein is present in axonal spheroids and glial and neuronal inclusions. While the identity of the major components of LB suggests that a pathway leading from normal soluble to abnormal misfolded filamentous proteins is central for their pathogenesis, regardless of the primary disorder, there are conformational differences in alpha-synuclein between neuronal and glial aggregates, showing no uniform mapping for its epitopes. Despite several cellular and transgenic models, it is not clear whether inclusion body formation is an adaptive/neuroprotective or a pathogenic reaction process generated in response to different, mostly undetermined, functional triggers linked to neurodegeneration. From a clinicopathological point of view, recognizable differences appear along the spectrum of the synucleinopathies. In fact PD is characterized by subcortical and rare cortical LB associated with degeneration of the dopaminergic nigrostriatal and other subcortical systems while more extensively distributed LB accompanied by striatonigral degeneration and variable extents of AD pathologic states typify DLB which, depending on the severity and extent of neuritic AD pathologic conditions, can be divided into two subgroups: "pure" DLB and DLB variant of AD. Finally, LB may also occur in AD, which is defined by the presence of neocortical neuritic pathologic findings ( amyloid plaques and neurofibrillary tangles). Among the synucleinophaties DLB represents the second most frequent cause of dementia in the elderly after AD [3].

We contributed to several studies on this argument along the years, and in the present chapter we discuss the role of clinical neurophysiological studies in DLB in comparison with other disorders. The essential background of our original studies laid in the fact that most historical studies were performed when the DLB clinical entity was unknown and therefore some of the past results were marred by absent recognition of this clinical

Synucleinopathies comprise a diverse groups of neurodegenerative proteinopathies that share common pathological lesions composed of aggregates of conformational and posttranslational modifications of alpha-synuclein in selected populations of neurons and glia. Abnormal filamentous aggregates of misfolded alpha-synuclein protein are the major components of LB, dystrophic (Lewy) neurites and the Papp–Lantos filaments in oligodendroglia and neurons linked to degeneration of affected brain regions. The synucleinopathies (see table 1) include Lewy Body disease (Parkinson Disease (PD), DLB, Multiple System Atrophy (MSA)) and neurodegeneration with brain iron accumulation type I, (NBIIA), formerly Hallervorden–Spatz disease. The pathological diagnosis of Lewy body disease is established by validated consensus criteria based on semi-quantitative assessment of subcortical and cortical LB as their common hallmarks. They are accompanied by subcortical multisystem degeneration with neuronal loss and gliosis with or without AD pathologic features. LB deposition also occur in numerous other disorders, including pure autonomic failure, neuroaxonal dystrophies and their presence is also evident in various amyloidoses and tauopathies. MSA, a sporadic, adult-onset degenerative movement disorder of unknown cause, is characterized by alpha-synuclein–positive glial cytoplasmic and rare neuronal inclusions throughout the central nervous system associated with striatonigral degeneration, olivopontocerebellar atrophy and involvement of medullar and spinal autonomic nuclei. In NBIIA alpha-synuclein is present in axonal spheroids and glial and neuronal inclusions. While the identity of the major components of LB suggests that a pathway leading from normal soluble to abnormal misfolded filamentous proteins is central for their pathogenesis, regardless of the primary disorder, there are conformational differences in alpha-synuclein between neuronal and glial aggregates, showing no uniform mapping for its epitopes. Despite several cellular and transgenic models, it is not clear whether inclusion body formation is an adaptive/neuroprotective or a pathogenic reaction process generated in response to different, mostly undetermined, functional triggers linked to neurodegeneration. From a clinicopathological point of view, recognizable differences appear along the spectrum of the synucleinopathies. In fact PD is characterized by subcortical and rare cortical LB associated with degeneration of the dopaminergic nigrostriatal and other subcortical systems while more extensively distributed LB accompanied by striatonigral degeneration and variable extents of AD pathologic states typify DLB which, depending on the severity and extent of neuritic AD pathologic conditions, can be divided into two subgroups: "pure" DLB and DLB variant of AD. Finally, LB may also occur in AD, which is defined by the presence of neocortical neuritic pathologic findings ( amyloid plaques and neurofibrillary tangles). Among the synucleinophaties DLB

represents the second most frequent cause of dementia in the elderly after AD [3].

**2. Synucleinopathies: Dementia with lewy bodies** 

entity.


Table 1. Sinucleinophaties and LB location.

The central clinical feature of DLB is progressive dementia prominently characterized, in the early phases of the disease, by deficits in attention, executive function and visuospatial ability, at difference with AD where memory impairment is the main early feature of dementia. Fluctuations in attention and alertness, recurrent complex visual hallucinations and parkinsonism represent the core features for the diagnosis. Suggestive clinical features are REM sleep behavior disorder, severe sensitivity to neuroleptics and low dopamine transporter uptake in the basal ganglia demonstrated by single photon emission computerized tomography (SPECT) or Positron Emission Tomography (PET) imaging. Supportive features are often present and are represented by repeated falls and syncopes, transient and unexplained loss of consciousness, severe autonomic dysfunction (e.g., orthostatic hypotension, urinary incontinence), hallucinations in other modalities than visual, systematized delusions, depression, relative preservation of medial temporal lobe structures on CT or MRI scans, generalized low uptake on SPECT/PET perfusion scans with low occipital activity, abnormally low uptake on 123I-metaiodobenzilguanidine (123I-MIBG) myocardial scintigraphy [2].

In this last revision of criteria for the diagnosis of DLB, electroencephalography (EEG) abnormalities with transient slow waves or sharp waves were also reported as supportive features for the diagnosis[2,4].

We performed a prospective study evaluating the incidence and characteristics of EEG abnormalities in patients affected by AD, DLB and PD with Dementia at their first

Is There a Place for Clinical Neurophysiology Assessments in Synucleinopathies? 303

Recent epidemiological studies have shown an association between visual impairments and visual hallucinations in patients with PD [9]. Neuropsychological studies have revealed visuoperceptual impairments in PDD and DLB patients with visual hallucinations [10]. Additionally, recent radiological studies have demonstrated decreased blood flow in the posterior temporal and occipital regions in hallucinatory PD and DLB patients [11]. Taking these findings together, it is possible to speculate that visual information processing

Impairment of achromatic as well as chromatic vision in PD has been extensively proven using clinical, psychophysiological and electrophysiological methods (ERGs and VEPs) and

Some studies demonstrated a significant difference between PD patients and well matched control subjects in the amplitude of VEP, of flash (ERG) and pattern electroretinogram (PERG: retinal response evoked by viewing an alternating checkerboard or grating) [12]. The VEP, PERG and flash ERG originate from different parts of the retina and central nervous system and reflect different physiological processes. The changes in these potentials in PD may reflect the widespread nature of the biochemical disorder affecting both retina and central nervous system. Indeed PD patients have also been shown to have abnormal auditory evoked potentials [13]. Abnormal VEPs were described in patients with PD: the percentage of VEP delays and the amount of latency increments detected in PD patients are dependent on the spatial frequency (that is a parameter of the stimulating pattern). The VEP latency increases as a function of increasing spatial frequency [14] in normal subjects, and our results [15] show that this latency increase is enhanced in PD and also when dopamine blockers are administered. Delayed responses, consisting of increased latencies of the P100 component evoked by patterned stimuli of degree to 7.5' elements (spatial frequency of 0.5 to 4 cycles per degree) were observed in PD patients and the delays disappeared together with clinical symptoms when L-Dopa was administered [15,16,17]. The evidence of VEP delays in PD were concomitant with the identification of dopaminergic cells (amacrine and horizontal cells) in the retina, both evidences reciprocally supporting the idea that the cause of delays was dependent on retinal dopamine cell deficiencies. In these studies retinal and occipital visual evoked potentials and event-related potentials (P300) have been recorded in normal human subjects before and after the administration of the dopaminergic receptor antagonist, haloperidol, and/or the dopaminergic precursor L-DOPA. The data show that either retinal or occipital visual potentials and P300 are delayed by haloperidol. These findings are consistent with the hypothesis that haloperidol in healthy subjects mimics the electrophysiological abnormalities observed in PD. On the other hand, L-Dopa does not generally modify these latencies in controls, while it is known to decrease the same parameters in PD patients. This is in accord with the involvement of a specific mechanism in the recovery observed in PD patients during L-Dopa therapy. Data confirm that the alterations of visual and cognitive potentials observed in PD are closely related to the impairment of dopaminergic transmission. The results of our study [15] on haloperidol administration in non-PD patients showed that this dopamine receptor blocking drug increased the latency of VEPs obtained with 2 and 4 cpd stimuli, while the effect on 0.5 cpd and 1 cpd VEPs was less consistent. This finding supports the hypothesis that dopamine modifies the processing of VEPs by acting at the synaptic level. The specific sensitivity of VEP changes to the spatial frequency of stimulation in PD and haloperidol treated subjects, which is evident in our results, might suggest that the VEP abnormalities found in our study

functions are selectively impaired in DLB and PDD.

attributed to dopaminergic deficiency at the retina level.

presentation in a tertiary clinic, not later than 1 year from the onset of dementia [5]. Supportive elements for the diagnosis came from Clinical Assessment of Fluctuations (CAF) scale, polysomnography (PSG) and Mayo Sleep Questionnaire for the assessment of REM sleep Behaviour Disorder (RBD). CAF is a neuropsychological test [6] able to evidence, on the basis of patient and caregivers interviews, the presence of fluctuating consciousness. The questionnaires are able to discriminate 85% of DLB patients, as confirmed by autopsy [7]. Cognitive fluctuations are considered a clinical feature typical of DLB, described in 70-80% of these patients, only in 14-20% of AD patients and in 15-30% of VaD subjects [8].
