corticobasal degeneration ( cbd ) is an uncommon , sporadic , neurodegenerative disease described for the first time by rebeiz et al . .
it can be associated with an extraordinary variety of motor , sensory , behavioural , and cognitive symptoms .
it is an asymmetrical parkinsonism affecting a limb , typically an arm : rigidity is the most common manifestation of the parkinsonian syndrome followed by bradykinesia , gait disorder ( postural instability and falls ) , and tremor ; asymmetrical limb dystonia is common as well .
other cardinal signs include higher cortical dysfunctions such as apraxia ( limb more common than orofacial , eyelid - opening ) .
dementia , progressive nonfluent aphasia , speech apraxia , progressive - supranuclear - palsy- ( psp- ) like syndrome and posterior cortical atrophy syndrome are other presentations of cbd [ 3 , 4 ] .
cbd is a tauopathy ( characterised by abnormal deposition of the microtubule - associated protein tau ) , similar to frontotemporal dementia and progressive supranuclear palsy ( psp ) .  
the typical pathological findings in cbd include focal asymmetric cortical atrophy , nigral degeneration , taupositive neuronal , and glial lesions in both gray and white matters . to achieve more accurate clinical diagnosis , neuropsychological , electrophysiological , and imaging methods
could be applied to differentiate this disease from the other parkinsonism syndromes [ 3 , 4 ] .   in comparison with other neurological diseases ,
the symptoms of cbd are particularly difficult to understand and the patients have considerable difficulties in describing their experience
. a better understanding of the disease may help clinicians to make diagnosis , providing patients with comprehensive information about prognosis and difficulties they will encounter during the course of the disease , improving their quality of life as well as their careers .
a 71-year - old woman , primary school graduate , formerly farmhand , was referred to our department of neurology with left rigid - akinetic syndrome and cognitive dysfunction .
she had no previous medical or family neurological history ; she just reported in the previous months frequent falls and postural instability .  
cognitive symptoms included impairment of spoken - language production and attention / concentration deficits .  
her main complaint was difficulty in using her left arm and hand , which gradually progressed .
the limb became severely rigid and adopted a dystonic posture associated with pain and functional disability .  
her clinical features slowly deteriorated and , 1 year later , involved also the left lower limb with gait disorder associated to postural instability and falls .
subsequently , the patient underwent brain mri and 18f - fluorodeoxyglucose - positron emission tomography ( pet ) .
she has been previously diagnosed as parkinson 's disease but with no response to levodopa or dopaminergic medications .
her clinical symptoms gradually progressed and , four months later , blepharospasm and mild dysphagia appeared .    when she was admitted to our neurological centre ,
the neurological examination revealed : blepharospasm ; hypomimia and asmmetric bradykinesia ; left upper - arm - fixed - dystonia ; spasticity in left lower limb and pyramidal signs ( babinski , hoffmann , and grasp reflex ) ; moderate disturbance of gait   with short steps , tendency to drag her left leg , bradykinesia , and propulsion requiring assistance .  
the other tests revealed impairment in visuospatial abilities , severe visuospatial neglect ( figure 1 ) , constructional and ideomotor apraxia , poor word fluency with mild visual confrontation anomia , and nonverbal oral apraxia .  
brain mri showed asymmetric cortical atrophy in the right frontotemporal cortex ( figure 2 ) .
no abnormalities were found on eeg examination , even if , a deeper analysis showed a focal slow wave activity in the right parietotemporal area .
the diagnosis was based on the gradual onset of a parkinsonian disorder associated with cortical dysfunctions and other supportive features such as cognitive dysfunction , asymmetric atrophy on mri imaging , and asymmetric hypoperfusion on pet .
clinically cbd begins in the sixth , seventh , or eighth decade , with slight predilection for women [ 8 , 9 ] .
typically the primary symptoms develop in a profoundly asymmetric way , affecting either one arm or , less frequently , a leg , which appears to be rigid , dystonic , akinetic , or apraxic .
clinical features include a series of motor , cognitive and neuropsychiatric symptoms , that can be explained by impairment of the cortical and subcortical structures .
motor symptoms include progressive asymmetric rigid - akinetic parkinsonism usually involving the upper limbs , without resting tremor , focal stimulus - sensitive or action myoclonus [ 4 , 11 ] , blepharospasm , speech abnormalities , gait disorder with postural instability and falls , and asymmetric limb dystonia , generally of the upper limbs , sometimes evolving towards the development of a dystonic clenched fist [ 3 , 12 ] .
eye movements are usually preserved , although a delay in the initiation of saccades may occur , in absence of pursuit and optokinetic nystagmus impairment [ 13 , 14 ] .
involvement of higher cortical functions results in often symmetric ideomotor apraxia , firstly affecting the limb , then , as the disease progresses , eyelid - opening , tongue , lips .
the alien - limb phenomenon , that is seen in 50% of the cases , can be defined as  a circumstance in which one of the patient 's hands behaves in a way which the patient finds foreign , alien or at least uncooperative 
; it commonly co - occurs with cortical sensory loss [ 11 , 16 ] .
cognitive decline is a common feature of the disorder , occasionally the presenting feature of the disease .
the prominent characteristics are impairment of spoken - language production ( typically nonfluent aphasia ) , frontal executive impairment , calculation and visuospatial skills impairment , whereas semantic and episodic memory may be spared .
neuropsychiatric symptoms may include depression , apathy , anxiety , irritability , disinhibition , delusions , and obsessive compulsive disorder .
abnormalities on magnetoencephalography , an exaggerated electromyographic - electromyographic ( emg - emg ) coherence , and an alteration in cortical excitability evaluated by means of transcranial magnetic stimulation ( tms )   were noted in patients with cbd . on the other hand , conventional electroencephalography ( eeg )
may be normal when the first clinical symptoms appear , and often remains unchanged as the disease progresses .
nevertheless , an unilateral slowing may be evident in some patients , which may occasionally generalise to the whole cortex as the disease evolves [ 24 , 25 ] . in a study involving six patients , vion - dury and coworkers , using a quantitative standard
eeg ( eegq ) with spectral analysis , found indeed the occurrence of several eeg abnormalities ( generally enhanced by hyperventilation or intermittent photic stimulation ) , such as an increase of slow rhythms ( delta or theta frequency range ) and occasionally the occurrence of sharp waves .
these abnormalities were lateralised in five patients ( more often after hyperventilation ) and were bilateral in one , confirming the asymmetrical features of cbd .
moreover , huang et al . showed that the eeg recordings with jerk - locked back average do not present any jerk - locked cortical potentials .   in cbd ,
the cortical sensory evoked potentials ( seps ) are not enlarged as in cortical reflex myoclonus , and backaveraged cortical potentials do not precede each myoclonic jerk [ 2628 ] .
clinical and imaging evidence suggests that the localized parietal cortical damage is a pivotal factor for the absence of a giant sep in these patients .
an asymmetric alternation of inhibitory and excitatory balance at the level of cortical neurons leading to a particularly enhanced cortical excitability may moreover play an important role in the generation of myoclonus [ 27 , 28 ] .
the loss of the inhibitory input from the somatosensory cortex to the relatively intact motor cortex , which results from the prominent asymmetric parietal atrophy , may give rise to the asymmetric hyperexcitable motor cortex without giant sep [ 30 , 31 ] , even - though the existence of an alternative hyper - excitable thalamo - cortical pathway can not be excluded .
in effect , motor cortex disinhibition has been clearly demonstrated in cbd by means of tms applied in several paradigms in different neurophysiological studies [ 3234 ] . by applying single pulse - tms , lu and
coworkers discovered a relatively higher motor evoked potential ( mep ) amplitude and a significantly shorter cortical silent period in the affected hand of cbd patients .
they therefore supposed that the relatively enlarged mep may be explained postulating that an increased number of motorneurons are being recruited by the descending volleys from the motor cortex , while the shorter silent periods may reflect mainly defective inhibitory processes . the result from paired pulse - tms studies
also supported the last hypothesis [ 22 , 23 , 35 ] ; for example , frasson et al .   showed that , in patients with cbd , paired magnetic stimuli delivered at short ( inhibitory ) interstimulus intervals ( isis ) invariably elicited enlarged meps ; moreover , asymmetric corticocortical disinhibition [ 22 , 36 ] , as well as asymmetric tms maps organization [ 32 , 37 ] , has been observed in patients with cbd . in conclusion
, several mechanisms could explain this abnormal motor cortical excitability , namely , loss of inhibitory neurons in the cortex or thalamus , effect of morphological changes in cortical neurons mainly in the somatosensory cortices , disruption of some neuronal circuits , or the existence of alternative cortical - subcortical pathways [ 33 , 38 ] .
morphologic imaging of the brain , although normal in the early phases of the disease , may demonstrate asymmetrical cortical atrophy , in particular of the frontal and parietal lobe , more evident contralaterally to the side most severely clinically affected [ 39 , 40 ] .
asimmetrical atrophy in the basal ganglia , corpus callosum , lateral ventricles , and cerebral peduncles may be present .
functional imaging studies might be useful in the differential diagnosis of patients with suspected cbd , showing asymmetrical hypoperfusion on spect and asymmetrical hypometabolism on pet involving the parietal - frontal cortex and basal ganglia .
all criteria stress the combination of an akinetic - rigid syndrome with apraxia , alien limb syndrome , and cortical sensory deficits .
a universally recognized feature is the asymmetry of clinical presentation , further corroborated by a contralateral asymmetrical atrophy on the structural and hypometabolism on the functional neuroimaging .
neuropathologically cbd presents as asymmetrical focal atrophy of the cerebral cortex focused on the peri - rolandic posterior frontal and parietal cortex , especially the motor and sensory areas .
there is a relative sparing of temporal and occipital cortex , except in some forms presenting with dementia or primary progressive aphasia , which are characterised by a more symmetric and more severe involvement of the frontal and temporal lobes .
basal ganglia are also involved with substantial atrophy in the lateral two - thirds of the substantia nigra , and , to a lesser extent , of putamen , pallidum , thalamus , and hypothalamus .
histologically cbd is characterised by large pale ballooned neurons ( neuronal achromasia ) , with tau - positive cytoplasmatic inclusions and astrocytic plaques ( annular clusters of tau - positive deposits within the distal processes of astrocytes ) , typically distributed in atrophic cortices [ 5 , 6 , 42 ] .
molecularly cbd is a taupathy , characterised by accumulation of abnormal filamentous inclusions of hyperphosphorylated tau - protein in neurons and glia , similarly to progressive supranuclear palsy ( psp ) , and some forms of frontotemporal dementia with parkinsonism ( ftd ) [ 5 , 44 ] .
this molecular overlap , especially with psp is very argued , and whether they are the extremities of the spectrum of a single disorder or two different disorders with a similar genetic predisposition is not clear [ 3 , 18 ] .
the symptoms can be gathered in four categories : natural history and presentation , motor , sensory motor , and cognitive symptoms .
the first three categories include characteristics which have been taken into account in almost all the previous diagnostic criteria .
up to 1994 , dementia was an exclusion criterion of cbd ; from 2003 , on the base of new criteria , cognitive impairments support diagnosis , so the inclusion of the cognitive criteria reflects the growing recognition of the importance of cognitive assessment in the diagnosis of cbd [ 3 , 45 ] .  
the core features of disease are insidious onset and progressive course , no identifiable cause ( tumor , infarct ) of symptomatology , cortical dysfunction includes at east one of the following : ( i ) focal or asymmetric ideomotor apraxia , ( ii ) alien - limb phenomena , ( iii ) cortical sensory loss , ( iv ) visual or sensory hemineglect , constructional apraxia , ( v ) focal or asymmetric myoclonus , ( vi ) apraxia of speech / nonfluent aphasia : extrapyramidal dysfunction as reflected by one of the following : ( i ) focal or asymmetrical appendicular rigidity lacking prominent and sustained l - dopa response , ( ii ) focal or asymmetrical appendicular dystonia .  
the supportive investigations are variable degrees of focal or lateralized cognitive dysfunction , with relative preservation of learning and memory , on neuropsychometric testing , focal or asymmetric atrophy on computed tomography or magnetic resonance imaging , typically maximal in parietofrontal cortex , focal or asymmetric hypoperfusion on single - photon emission computed tomography and positron emission tomography , typically maximal in parietofrontal cortex / basal ganglia / thalamus .
predominant parkinsonian features might not be easy to distinguish from idiopathic pd and atypical parkinsonian syndromes ( e.g. , psp and multiple system atrophy , msa ) .
akinetic - rigid syndrome , early inbalance and poor response to dopaminergic treatment are typical symptoms for cbp , psp , and msa , in contrast with pd .
psp is clinically and pathologically   related to cbd , but with differences in symmetrical versus asymmetrical parkinsonism , and in the pattern of rigidity , which tends to be more nuchal / axial in psp and more limb - accentuated in cbd .
also , while the superanuclear gaze palsy can occur in both conditions , in cbd it tends to affect the horizontal more than the vertical gaze and the saccade latency ( delay in initiating saccades ) more than saccade velocity ( the speed of saccades ) .   in patients with cognitive presentation ,
the diagnosis depends on the specific case : pronounced visuoperceptual deficits related to dementia with lewy bodies ( dlb ) , language involvement to primary progressive aphasia ( ppa ) , and prominent behavioral features to frontotemporal dementia ( ftd ) .
it is important to explain the nature of the motor as well as the cognitive deficits to the patients as well as to all people involved in their care . as a motor disorder
, cbd has been recognized for over 30 years . however , more recent findings suggest that there is a neuropsychological syndrome associated with cbd . the most prominent neuropsychological features of cbd include limb apraxia , ideomotor and ideational apraxias .
executive function and language impairments are also reported .   the characterization of the natural history of patients with the cbd ( clinical , laboratory , neuropsychological , radiological features ) is important to improve the accuracy of diagnosis .
 corticobasal degeneration ( cbd ) is an uncommon , sporadic , neurodegenerative disorder of mid- to late - adult life . 
 we describe a further example of the pathologic heterogeneity of this condition . 
 a 71-year - old woman initially presented dysarthria , clumsiness , progressive asymmetric bradykinesia , and rigidity in left arm . 
 rigidity gradually involved ipsilateral leg ; postural instability with falls , blepharospasm , and dysphagia subsequently developed . 
 
 she has been previously diagnosed as unresponsive parkinson 's disease . at our clinical examination , 
 she presented left upper - arm - fixed - dystonia , spasticity in left lower limb and pyramidal signs ( babinski and hoffmann ) . 
 brain mri showed asymmetric cortical atrophy in the right frontotemporal cortex . 
 neuropsychological examination showed an impairment in visuospatial functioning , frontal - executive dysfunction , and hemineglect . 
 
 this case demonstrates that association of asymmetrical focal cortical and subcortical features remains the clinical hallmark of this condition . 
 there are no absolute markers for the clinical diagnosis that   is complicated by the variability of presentation involving also cognitive symptoms that are reviewed in the paper . despite the difficulty of diagnosing cbd , somatosensory evoked potentials , motor evoked potentials , long latency reflexes , and correlations between results on electroencephalography ( eeg ) and electromyography ( emg ) provide further support for a cbd diagnosis . 
 these techniques are also used to identify neurophysiological correlates of the neurological signs of the disease . 