Cognitive features of DLB

Impairment in attention/concentration, executive function, and visuospatial function, with relative preservation in confrontation naming and verbal memory, can be considered the prototypical neuropsychological profile of impairment in DLB [34]. Memory impairment tends to be mild, but it can be severe in some [35]. In fact, some patients with DLB can have prominent memory deficits, and these presentations likely reflect concurrent Alzheimer’s pathology [29]. Many patients describe the tendency to lose one’s train of thought in the middle of a sentence, which some have termed “verbal blocking.” Geographic disorientation can lead to getting lost while driving, or even struggling to locate the bathroom in one’s own home. Visuospatial impairment is often easily demonstrated in the office (e.g., intersecting pentagons, Necker cube). Misidentification errors involving people can occur and are particularly upsetting when patients fail to recognize their own spouse or children. Some believe their own reflection in mirrors is someone other than themselves, sometimes leading to conversations or arguments with the perceived individual. Trouble using the telephone, television remote, microwave, and household appliances is a common complaint. Bradyphrenia, distractibility, and difficulties with multitasking and performing sequential tasks are very common. There is usually no demonstrable apraxia of speech or aphasia early in the course of the disease.

There can be considerable variability on formal testing even when the tests are performed hours, weeks or months apart, likely due to the prominent fluctuations in cognition and attention seen in this disease [21]. Patients and their caregivers often describe forgetfulness for upcoming appointments and social engagements, losing details of recent events and conversations, and tendency to repeat questions, yet on office testing these individuals typically perform better than expected on the delayed recall portions of screening mental status examinations. In mildly affected patients, a discrepancy between a person’s functional abilities (poor performance) and his/her findings on neuropsychological testing (good performance) can be striking, sometimes leading the clinician to a strong suspicion of depression, anxiety, stress or other factors as the underlying cause of their cognitive symptoms.

One observation that many clinicians now appreciate is the relative lack of anosagnosia: these patients are typically bothered by their cognitive symptoms and are seeking treatment on how to improve it, whereas patients with AD typically are not overly bothered by their memory impairment or overtly argue with family members that “my memory is fine!”

Early cognitive features of DLB: The concept of mild cognitive impairment (MCI) is founded on the idea of a transitional state between normal aging and dementia; in other words, one does not evolve from a normal cognitive state on one day to a demented state the next, but rather this likely evolves over months or years. Numerous analyses have supported the concept and utility of the MCI transitional state from normal aging to AD [36], and there are growing data supporting the same concept from normal aging to MCI to DLB [37]. Both amnestic and non-amnestic cognitive impairment can precede DLB, but presentations that include non-memory domains are more likely to develop DLB [38].

Behavioral/psychiatric features of DLB

The presence of visual hallucinations is a defining feature of DLB [39]. These hallucinations are often vivid and well-formed false perceptions of insects, animals or people. The hallucinations can be in black and white or in color, and at times they are frightening. Some patients talk to the perceived people or animals. Many patients recognize that the visual experiences are in fact hallucinations and are not actually present; these patients manage to carry out their daily activities relatively undisrupted. Some describe a tendency to blink hard, or look away for a few seconds and then redirect their gaze back, and the image disappears. Other patients believe that the hallucinations are real, and arguments often ensue when family members attempt to convince these patients that the images are not actually there. Others describe them as comical or even consider them as “friends” of sorts. These hallucinations can limit the use of levodopa to treat motor impairment, since psychotic symptoms are often worsened with dopaminergic medications in this patient group [40]. The use of neuroleptics to treat psychosis in DLB is also limited, given that these patients typically have significant neuroleptic sensitivity, with marked worsening of parkinsonism and confusion/agitation with this class of medications. In fact, this neuroleptic sensitivity is so distinctive, that it is considered a suggestive diagnostic feature of the disease [21]. Cholinesterase inhibitors have been shown to improve both DLB-associated psychosis and cognitive deficits in randomized clinical trials, and therefore can be considered as the first-line treatment for DLB-associated psychosis [41, 42].

Visual illusions, in which objects are perceived as something different than they actually are, can also occur in DLB. Some typical examples include perceiving chairs, lamps or mailboxes as people or animals. Delusions are also frequent and typically have a paranoid quality. Common examples include believing that one’s belongings have been stolen or that other people are invading or living in the home (i.e., phantom boarder) [43]. One particular delusion can evolve around misidentification errors, in which a person believes that his or her spouse has been replaced by an identical-appearing imposter (i.e., Capgras syndrome) [44]. Visual hallucinations, including extracampine hallucinations, have been found to be more common in patients with DLB who have a ¹⁸F-FDG PET scan with an AD-like hypometabolic pattern [45]. Auditory, tactile or olfactory hallucinations are uncommon.

A REM sleep/wakefulness dysregulation has been proposed as a mechanism underlying visual hallucinations, based on polysomnographic monitoring in patients with PD and psychosis, in which the dream imagery of REM sleep may be invading into wakefulness [46]. A similar mechanism has been proposed to underlie hallucinations associated with DLB [47, 48]. If further studies substantiate this mechanism, treatments already known to be efficacious in the management of narcolepsy may prove useful in the management of hallucinations, hypersomnolence, and similar phenomena associated with DLB. Another proposed pathophysiological basis for visual hallucinations in DLB includes a deficit in choline acetyltransferase activity (ChAT) and cholinergic neurons in the basal forebrain [39, 49]. A greater deficit of ChAT in areas of the temporal lobe is associated with a greater risk of hallucinations.

Apathy, depression, and anxiety are also all very common in DLB [39, 49]. Mood disorders in this disease are likely due to the accumulation of Lewy bodies in the dorsal raphe serotonergic nucleus. Agitation or aggressive behavior tends to occur late in the illness, if at all.

Early behavioral/psychiatric features of DLB: Visual hallucinations, delusions, depression, anxiety or apathy in the absence of other neurologic features could be early manifestations of DLB. Isolated visual hallucinations or visual illusions may be particularly concerning for evolving DLB [50, 51].

Motor/extrapyramidal features of DLB

Spontaneous parkinsonism (i.e., unrelated to dopamine antagonist exposure) is a defining characteristic of DLB [11]. The degree of parkinsonism seen in DLB patients may be related to regional patterns of Lewy body pathology [52]. Rigidity and bradykinesia tend to be symmetric [21, 53]. While some patients have an asymmetric or unilateral rest tremor with a pill-rolling quality typical of PD, a tremor that is symmetric and more prominent with posture is more typical of DLB [9, 11, 54]. Prominent postural instability with frequent falls is a supportive feature. Myoclonus occurs in some patients, which can complicate differentiation from Creutzfeldt–Jakob disease if progression occurs over a short period of time [55]. Carbidopa/levodopa can be beneficial for patients with DLB, but the response is significantly less robust than in typical PD [56], and the therapeutic dose often needs to be reduced due to levodopa-induced psychosis [39]. The use of dopamine agonists (such as pramipexole, ropinirole, and rotigotine patch) and anticholinergic anti-parkinsonian medications (such as trihexyphenidyl) is contraindicated due to their tendency to exacerbate delusions and hallucinations, and worsen cognition.

Early motor/extrapyramidal features of DLB: Subtle parkinsonism, even when asymptomatic, is an early sign of DLB. The characteristics of parkinsonism in DLB can help to distinguish it from PD early in the disease course. This includes the more symmetric rigidity, bradykinesia, and postural tremor seen in DLB, as well as the typical absence of an asymmetric pill-rolling rest tremor, and the prominent early gait impairment characterized by postural instability and frequent falls [9].

Sleep features associated of DLB

REM sleep–behavior disorder (RBD) is common in DLB [32, 57]. In RBD, there is an absence of atonia that is normally seen in REM sleep, and patients subsequently appear to “act out their dreams” in which they yell, scream, swear, punch, kick, swing, jump out of bed, and so on. The dreams often have a chasing or attacking theme, with the patient attempting to protect himself or herself. When the patient is awakened, the description of the dream tends to match the behaviors that were exhibited. Injuries to patients and their bed partners can occur [11]. Dysfunction in brainstem neuronal networks is believed to underlie RBD [32].

Many patients with DLB also have excessive daytime somnolence, in which they will struggle to stay awake during the day [58]. Other sleep disorders in DLB include prolonged sleep latency, sleep fragmentation, and early-morning awakenings [59].

The importance of recognizing these sleep disorders cannot be over-emphasized. We have evaluated hundreds of patients with DLB over the past several years, and we have yet to meet a single patient who does not have one or more primary sleep disorders. Many have three or four sleep disorders and yet none has been diagnosed and treated. All of these sleep disorders are treatable, and maximal improvement in patient symptomatology tends not to happen until all sleep disorders are adequately treated.

Early sleep features of DLB: The onset of RBD often occurs years or even decades before any cognitive or motor symptoms develop, and likely represents a prodromal phase of a Lewy body disorder (e.g., DLB, PD, PDD or multiple system atrophy)[32, 47, 60]. The longest and most comprehensive prospective study of idiopathic RBD followed patients for a median of 10.5 years and found that 70% developed an alpha-synucleinopathy (16 PD, 14 DLB, and 1 MSA out of 44 patients), with an additional five patients developing MCI, both amnestic and non-amnestic subtypes. The four patients who were free of a diagnosable neurodegenerative disorder and were available for testing had decreased striatal dopamine transporter imaging uptake. In addition, individuals with RBD without parkinsonism have been found to have prominent visuospatial impairment, which is a major feature of cognitive deficits seen in DLB [61]. Hypersomnolence has been reported as another early symptom of DLB and has been correlated with reduced hypocretin levels [62].

Autonomic features of DLB

Orthostatic hypotension, thermal dysregulation, impotence, urinary incontinence, sialorrhea, and constipation are common autonomic features of DLB [63–65]. Orthostatic hypotension can be severe and may limit the use of levodopa to treat motor impairment. Abnormal sudomotor dysfunction is evidenced by severely reduced sympathetic sweat responses and a lower skin vasomotor reflex compared with healthy controls [63]. The degree of autonomic dysfunction in DLB appears to be intermediate between PD (relatively mild, at least early in the illness) and multiple system atrophy (relatively severe) [66]. Lewy bodies have been found in the intermediolateral column of the spinal cord, and in the neurons/plexi of the heart and gut, reflecting the rather widespread nature of Lewy body pathology in the peripheral and central nervous system in DLB [67].

Early autonomic features of DLB: There is now suspicion that the peripheral nervous system may be affected by Lewy bodies prior to involvement of the central nervous system [68]. For example, there is substantial cardiac sympathetic denervation in DLB as evidenced by reduced cardiac (123)I-MIBG uptake [69, 70], helping to explain the reduced coefficient of variation of the R-R intervals in DLB patients compared with PDD, PD, and healthy controls.^.

Sensory features of DLB

Olfactory dysfunction is present in a significant proportion of DLB patients, which is likely due to prominent involvement of the olfactory bulb in Lewy body disorders [38, 71]. As a result, bedside olfactory testing has been shown to help distinguish DLB from AD [38, 72]. Furthermore, the cytoskeletal organization of the cones and the pattern of synuclein expression present in the retina in those with DLB were found to be abnormal [73], helping to explain the involvement of the visual system in DLB [74].

Early sensory features of DLB: Hyposmia/anosmia are prodromal symptoms of DLB that can predate the cognitive and/or motor impairment seen in this disease by several years [38, 45, 75].

Ocular features of DLB

Visual symptoms include impaired saccades, convergence insufficiency, and reduced blink rate leading to dry eyes [76, 77].

Early ocular features of DLB: Impaired color vision can be a prodromal symptom of DLB, recognized several years prior to motor or cognitive impairment [38, 45, 75].

Other clinical features of DLB

Fluctuations are considered a defining feature of DLB [21]. This phenomenon refers to periods of time when cognition and arousal are near normal, contrasting with other periods characterized by marked confusion and/or hypersomnolence. Transient loss of consciousness can be observed and is a supportive diagnostic feature of DLB. The etiology of these fluctuations remains unclear; it is possible that they are due to abnormalities in cognition or sleep, which are so prevalent in DLB, or a combination of these and other processes. Although fluctuations have been difficult to operationalize and measure, tools now exist that differentiate fluctuations associated with DLB from those that can occur in other disorders [78–81]. However, the methods for measuring fluctuations have not made their way into routine clinical practice.

Other early clinical features of DLB: Fluctuations in cognition, arousal, and motor functioning could theoretically be an early clinical feature in PD, PDD, and DLB, but the lack of operationalization of the concept of “fluctuations” and lack of good measurement tools will make this difficult to study. Using one simple and easy-to-use tool, the frequency of fluctuations was high in DLB, low in AD, and almost absent in cognitively normal subjects [78–81].

Cognitive features of PDD

As noted above, the lack of “Alzheimerization” in the brains of most patients with PDD likely explains the relative preservation of anterograde memory functioning and benefit from cuing on memory measures in those with PDD compared with those with DLB [14]. Otherwise, the profile of impairment in attention/concentration, executive functioning, and visuospatial functioning is similar between PDD and DLB. It is important to keep in mind that dementia in PD typically occurs more than a decade after the onset of parkinsonian motor symptoms [12–15], differentiating it from DLB, in which dementia should occur either before, concurrently or within 1 year of the onset of parkinsonism. Levodopa therapy complicates cognition in PD and PDD because it enhances some cognitive functions, while worsening others, based on the specific cortical–striatal circuitry involved in the specific task [83, 84].

Early cognitive features of PD: There is growing data supporting a transition from normal cognition in PD to MCI-PD to PDD [85–88]. Non-amnestic single-domain impairment is the most common MCI subtype in PD patients [86]. The development of MCI-PD is associated with increasing age, longer disease duration, and worsening disease severity. Significant cognitive deficits can even occur within the first few years of PD diagnosis, even without prior suspicion of any cognitive impairment. One recent study showed more than one-third of PD patients met criteria for PD-MCI within 3 years after diagnosis, and 50% met criteria after 5 years [89, 90]. Patients with tremor as the predominant motor symptom have a lower risk of developing PD-MCI.

Behavioral/psychiatric features of PDD

Depression is the most common psychiatric disorder among patients with PD [91], with suicide-specific mortality 5.3 times higher than expected [92]. Recurrent and fully formed visual hallucinations, delusions (often with paranoia or phantom boarder themes), apathy, and anxiety are also common psychiatric symptoms in PDD, and can significantly impair quality of life [14]. Pseudobulbar affect has been observed in 7% of PD patients, leading to unpredictable and involuntary episodes of laughing or crying [93].

Early behavioral/psychiatric features of PD: Depression and anxiety are significantly more common in early PD compared with healthy controls [94], and remain under-treated [95]. In one study of de novo, untreated PD patients, two-thirds of those who screened positive for depression were not taking an antidepressant. Apathy was also found to be significantly more common in early PD compared with healthy controls, and worsened over time. Presence and passage hallucinations can occur in the first few years after PD diagnosis, and typically precede frank visual hallucinations [96].

Motor/extrapyramidal features of PDD

The motor features of typical PD – a 4 to 6 Hz unilateral or asymmetric rest tremor with a “pill-rolling” and/or “wrist pronation–supination” quality [97] – along with asymmetric bradykinesia/rigidity, and postural instability are typically present for at least 10 years prior to the onset of dementia [12, 14, 15]. The tremor is most prominent at rest, but can also be present with action, although the postural tremor seen in PD is different from that seen in essential tremor, as it is a re-emergent tremor [98]. This entails a latency during which there is initially no observable tremor despite the arms being outstretched. Chin, lip, jaw tremor is common in PD and uncommon in essential tremor, which tends to affect the head and voice [76]. Bradykinesia is a diagnostic requirement of the Queen Square Brain Bank criteria for PD, but criteria published by Gelb et al. do not require bradykinesia to be present as long as there is a characteristic PD tremor [99]. There is typically a robust response to levodopa, with 70–100% resolution in PD motor symptoms [82] (with the caveat that tremor and/or postural instability can be refractory to dopaminergic medication in some patients) [100, 101]. Motor fluctuations impair quality of life for those with PD, requiring patients to take more frequent and higher doses of dopaminergic medications, yet limiting their use due to peak dose dyskinesias [102]. Postural deformities in PD are also common, and can include camptocormia, antecollis, and Pisa syndrome [103]. Myopathy and axial dystonia have both been implicated in the etiology of these deformities. Gait is impaired due to asymmetric rigidity and bradykinesia, in addition to shortened stride length (shuffling), freezing (difficulty initiating gait), and/or festination (involuntary acceleration). Patients can report mild imbalance initially, but falls due to postural instability usually occur later in the disease course [76].

Early motor/extrapyramidal features of PD: Shoulder disturbances, including a frozen shoulder, are often the first symptom of PD, and are likely secondary to severe asymmetric proximal upper extremity rigidity and bradykinesia [104]. In addition, family and friends may notice that an arm on one side is not swinging as well, or the patient may notice a change in handwriting, or decreased dexterity on one side as an initial symptom. Gait impairment can initially present as a feeling of dragging or catching of the leg on one side [76]. It is also useful to characterize early features of the tremor seen in PD, which typically affects the distal parts of the extremity first, and may initially only involve the fingers, or even the thumb alone [105].

Sleep features of PDD

As in DLB, RBD tends to precede the onset of motor, cognitive, and neuropsychiatric features of PD and PDD by many years [48, 60, 106]. RBD can be severe and may endanger the patient and his/her bed partner. Hypersomnolence is also common in PDD; in fact, the new Consensus Criteria for PDD include excessive day-time somnolence as a behavioral feature of the disorder [14, 107]. Neuropathologic analyses have revealed hypocretin cell loss in the lateral hypothalamus in patients with PD [108, 109], providing a mechanism of how hypersomnolence could be a manifestation of LBD pathology. Sleep fragmentation, reversal of the sleep–wake cycle, and insomnia can also occur in PD and PDD [58, 110, 111]. A link between restless leg syndrome (RLS) and PD remains controversial [112].

Early sleep features of PD: The occurrence of RBD in the absence of any coexisting neurologic symptoms is termed “idiopathic RBD.” There now exist considerable data suggesting that idiopathic RBD is an early feature of a synucleinopathy in many individuals, often manifesting years or decades prior to the onset of cognitive or motor changes [32, 48, 57, 60, 75, 113, 114]. Recent studies have demonstrated changes on electroencephalography [115, 116], single-photon emission computed tomography (SPECT) [117–119], positron emission tomography (PET) [120], neuropsychological testing [121], smell testing [122], color discrimination [75], cardiac autonomic activity [123], and more subtle abnormalities on measures of autonomic, motor, and gait functioning in patients with RBD [124], suggesting that a more widespread multisystem neurologic disorder is present: most likely PD, given that it is the most common synucleinopathy. In addition, hypersomnia has recently been associated with an increased risk of PD [125], and thus also likely PDD.

Autonomic features of PDD

The autonomic features in PDD are similar to those in DLB, and likely reflect Lewy body pathology in the interomediolateral spinal cord and peripheral autonomic ganglia. Autonomic symptoms, such as erectile dysfunction, orthostatic hypotension, urinary incontinence, sudomotor dysfunction, gastroparesis, seborrhea, and constipation, can significantly impair quality of life [126, 127]. Defects in thermoregulation can cause episodes of diaphoresis, facial flushing, and hyperthermia [128]. Management of orthostatic hypotension can be quite challenging to manage, particularly if aggressive dosing of levodopa is required to minimize parkinsonism, as dopaminergic medications can worsen orthostasis. PD is also associated with seborrheic dermatitis due to an increase in sebum excretion.

Early autonomic features of PD: Braak and coworkers have proposed that Lewy body pathology begins in the peripheral nervous system and subsequently involves the olfactory bulbs and lower brainstem, with Lewy bodies then spreading to more rostral structures as PD becomes more advanced [68, 129, 130]. As a result, neurons in the locus ceruleus are affected earlier than neurons in the substantia nigra pars compacta, indicating that a norepinephrine deficit is more severe than a dopaminergic deficit. Given the Braak hypothesis, one would predict that the autonomic features would precede the cognitive and motor features of LBD, and in fact, autonomic dysfunction has been shown to precede the onset of motor symptoms in PD by up to 20 years [124]. For example, about 30–40% of PD patients have orthostatic hypotension, likely due to cardiac postganglionic sympathetic denervation, extra-cardiac noradrenergic denervation (blunting sympathetic vasoconstriction of the peripheral vasculature), and baroreflex failure [69]. Recently, cutaneous autonomic sympathetic nerves were found to have alpha-synuclein deposits that correlated to upright hypotension during tilt table testing [131–133].

Sensory features of PDD

Hyposmia/anosmia is strongly associated with PD, with approximately 90% of PD patients found to have severe hyposmia or anosmia [134]. The underlying substrate for this symptom is thought to reflect the very early involvement of olfactory structures by LBD, and has been associated with Lewy body accumulation in areas of the peripheral nervous system [130]. For example, olfactory function is correlated with cardiac noradrenergic innervation in patients with alpha-synucleinopathies [135]. Impaired taste perception occurs in about a quarter of those with PD, may be secondary to the severe hyposmia seen in this disease, and can significantly impair quality of life [136, 137].

Early sensory features of PD: Severely impaired olfaction has been found to be present in otherwise asymptomatic individuals with Lewy body disease on autopsy, and is likely a prodromal symptom of PD, and therefore PDD [72]. This is supported by the fact that hyposmia helped to predict conversion to PD in asymptomatic individuals with RBD in one study [75]. Pain is a common and often under-diagnosed and undertreated sensory feature of PD that can happen early in the disease course; and the detrimental effect of this on quality of life in PD patients cannot be overstated [138]. The risk of B12 deficiency is significantly higher in PD than healthy controls and likely contributes to neuropathic pain in this disease [139].

Ocular features of PDD

Visual abnormalities, such as impaired color discrimination and contrast sensitivity, hypometric voluntary saccades characterized by increased latency, dry eyes due to reduced blink rate, and diplopia due to convergence insufficiency have all been described in PD, and can significantly impair vision-related quality of life [140–143]. Smooth pursuits may become hypometric and may exhibit saccadic intrusions, although this abnormality is certainly much less severe than that seen in PSP [76, 144]. Eyelid opening apraxia and/or blepharospasm has also been observed, although it occurs less frequently than in PSP [145].

Early ocular features of PD: Convergence insufficiency is a common early finding in PD, but actual diplopia is usually seen in patients later in their disease course [141]. Alterations in smell and color vision have also been shown in subjects with idiopathic RBD as risk factors for the development of parkinsonism and cognitive decline [75, 124].

Other clinical features of PDD

Several authors have suggested subtle deficits in social cognition and theory of mind in people with PD [146–148]. There is increasing evidence that patients with PD and perhaps especially PDD have deficits in recognizing emotions both in themselves and others [149, 150]. For example, patients with PD do not rate their emotional arousal as strongly as healthy controls do when shown emotion-provoking stimuli, and are less likely to correctly identify the emotion implied by either facial expressions or the voice [151]. This may result from altered autonomic and behavioral feedback, as well as changes within the basal ganglia and cortex in those with PD. However, the extent to which these deficits are actually manifestations of apathy or diminished executive function is still being actively researched. In addition to these features, fluctuations in cognition and arousal also clearly occur in PDD, although to a lesser extent than in DLB [14].

Cognitive features of PSP

Cognitive and behavioral changes are common in PSP [1]. Executive dysfunction is the most prominent cognitive deficit in PSP. Language dysfunction occurs with some frequency as well, particularly apraxia of speech and non-fluent aphasia [165, 166]. The concept of “subcortical dementia” has been applied to those with PSP, in which there is slowing of cognitive processing but “cortical” signs such as amnesia and agnosia are infrequent. Letter fluency (i.e., word generation starting with a letter of the alphabet over a specific time period), information processing, execution of sequential actions, set-shifting, and cognitive flexibility tend to be particularly impaired [158, 167–170]. This severe dysexecutive syndrome can be clinically identified with abnormal performances on the Luria test [171], applause sign [172], and antisaccade task [173]. Impairment of social cognition that includes deficits in voice emotion recognition and theory-of-mind are recognized in PSP [174].

Early cognitive features of PSP: Since executive functioning and, less frequently, language functioning are most likely impaired in PSP, one would predict that MCI-single domain (executive or language) or MCI-multiple domain without amnesia (executive plus language) would be the presenting cognitive syndromes. At the Mayo Clinic in Rochester, USA we have encountered patients, who were later proven by autopsy to have PSP, presenting with each of these MCI syndromes, and also one with amnestic MCI. We have also found that among those who present with progressive apraxia of speech and the progressive non-fluent aphasia syndrome almost all those subsequently studied for pathology have had either PSP or CBD pathology [165, 166].

Behavioral/psychiatric features of PSP

Behavioral/psychiatric changes are common in PSP, and can include emotional lability, irritability, apathy (typically without other features of depression), disinhibition, compulsions/obsessions, and utilization/imitation behavior. In fact, some individuals with PSP present as an FTD subtype [158, 175]. Pseudobulbar affect can occur, with patients exhibiting sudden, involuntary outbursts of laughing or crying, without any clear trigger. Hallucinations are rare in PSP, and their presence should prompt re-evaluation of the diagnosis [160].

Early behavioral/psychiatric features of PSP: One can often elicit a history from caregivers that apathy was a prominent early feature of the illness. Obsessions, compulsions or both can be early features as well [176].

Motor/extrapyramidal features of PSP:

Some of the qualitative features of parkinsonism are diagnostically relevant, particularly axial greater than appendicular rigidity, tendency to walk, turn, and sit en bloc, and marked postural instability with frequent falls. Tremor is uncommon and is typically symmetric and postural; some patients may have a fine resting tremor [1]. The classic pill-rolling asymmetric tremor seen in PD is typically absent, although it has been described in PSP-P [164]. Retrocollis occurs with some frequency. While a minority of patients may experience a transient modest benefit with levodopa therapy, particularly those with PSP-P, dyskinesias do not typically develop [159].

Early motor/extrapyramidal features of PSP: Early falls due to postural instability characterized by unexplained falls backwards are the most frequent initial symptom of PSP-Richardson syndrome [164]. PSP-P typically lacks early gaze palsy and falls, and includes asymmetric rigidity, bradykinesia, and a jerky postural tremor, as well as a transient responsiveness to levodopa [160]. This subtype of PSP is often initially misdiagnosed as PD, but begins to overlap with PSP-Richardson syndrome after a few years, and is clinically similar after 6 years.

Sleep features of PSP

Both insomnia and hypersomnia, as well as reduced sleep efficiency, can occur in PSP [177–179]. RBD can occur, but is far less frequent than in PD, PDD, and DLB [32]. When RBD does occur in PSP, it tends to begin concurrently with or after the onset of the other neurologic features [177].

Autonomic features of PSP

While orthostatic hypotension is not a feature of PSP, other autonomic abnormalities, such as urinary urgency/frequency and constipation, can be present [76]. Prominent autonomic symptoms, however, have a higher positive predictive value for PD over PSP-P [160].

Sensory features of PSP

No sensory features have been found to be consistently abnormal in PSP.

Ocular features of PSP

Ophthalmologic complaints are very common in PSP. Supranuclear gaze palsy is characteristic of the disorder, with vertical gaze affected before horizontal gaze. Upgaze is affected first, but this can be a normal finding in older individuals. Therefore, the diagnostic specificity of ocular symptoms significantly increases when downgaze becomes impaired [1, 76]. Saccades are slow and hypometric, initially in the vertical plane, followed by the horizontal plane. Smooth pursuits eventually become hypometric with saccadic intrusions, first in the vertical and then in the horizontal direction of gaze. Global supranuclear ophthalmoplegia can develop in advanced PSP, but these impairments in gaze can be overcome with testing of the vestibulo-ocular reflex, which should be intact. Eyelid opening apraxia and/or blepharospasm is also observed and can cause functional blindness.

Early ocular features of PSP: Supranuclear gaze palsy usually presents later in the disease course of PSP, therefore identification of earlier manifestations of oculomotor abnormalities (such as loss of the fast component of optokinetic nystagmus, impaired volitional saccades, and gaze impersistence) may enable earlier diagnosis. Vertical saccades (upgaze and then downgaze) are impaired prior to horizontal saccades, and the velocity of saccades declines before the magnitude of saccades. Fixation instability with square-wave jerks can also be seen early in the disease course [163, 164]. Patients are likely unaware of these findings, but may complain of non-specific ocular symptoms, such as blurred vision, photophobia, diplopia or dry eyes due to markedly decreased blink rate.

Other clinical features of PSP

There is a characteristic facial appearance in PSP characterized by a wide-eyed anxious or surprised stare with eyelid retraction and reduced eyeblink frequency. This facial feature is often called the “procerus sign” and is attributed to dystonic activation of the frontalis, orbicularis oculi, corrugators, and procerus muscles, while reduced eyeblink frequency is due to axial rigidity and bradykinesia [180–182]. Other common features of PSP include dysphagia and dysarthria (with a typically strained, spastic and/or hypokinetic quality) [160]. A diverse set of frontal release signs can be elicited in PSP, and can be used as a distinguishing feature compared with PD [181].

Other early clinical features of PSP: Bulbar symptoms, including dysarthria and dysphagia, as well as the procerus sign, all detailed above, can present early in the disease course of PSP.

Cognitive features of MSA-P

Significant cognitive deficits are frequently observed in MSA. Dementia, though, is still listed as a non-supportive feature in the current diagnostic criteria for MSA. This has recently been challenged given data indicating that dementia is likely present more often than previously thought in MSA [188, 189]. Furthermore, dementia would likely occur in more patients if survival in this disease were longer, since significant cognitive impairment in MSA typically occurs at 7 years. Frontal-executive dysfunction is the most frequent presentation, and can include problem-solving difficulties, impaired attentional set-shifting, mental inflexibility, impaired abstract reasoning, and perseverative tendencies. Mild single-domain to more severe multiple-domain deficits can be seen, and often include deficits in attention and working memory, spontaneous immediate recall, verbal fluency, and visuospatial function [190].

Early cognitive features of MSA-P: Since frontal-dysexecutive impairment is most commonly observed in MSA, non-amnestic single- or multiple-domain MCI (executive dysfunction +/- language) would be predicted to be the most frequent early cognitive impairment seen in this disorder. Further study is warranted to better characterize this.

Behavioral/psychiatric features of MSA-P

Depression occurs in the majority of MSA patients [191], and anxiety has been reported in about one-third of patients [192], with mood disorders being more prevalent in MSA-P compared with MSA-C [193]. There are several major differences between the psychiatric symptoms associated with PD and those associated with MSA. In particular, hallucinations and delusions are rare outside of medication-related adverse effects in MSA [189], and pseudobulbar affect characterized by pathological laughter or crying is a supportive feature of MSA [187]. Furthermore, apathy is more common in MSA than in PD, and does not tend to improve with levodopa [194].

Motor/extrapyramidal features of MSA-P

Motor symptoms are often mixed, with cerebellar features (e.g., limb ataxia) appearing in MSA-P and parkinsonian features (rigidity, bradykinesia, rigidity) appearing in MSA-C [76, 183]. MSA-P can be initially misdiagnosed as Parkinson’s disease, given that about one-third of patients have a transient initial response to levodopa (that can last up to 3–4 years) [183], while a small number of these patients even have a sustained levodopa response [184]. Also, while rigidity and bradykinesia can be symmetric in this disease, the majority have an asymmetric presentation. Very small amplitude myoclonic movements (polyminimyoclonus) involving individual fingers can be misinterpreted as tremor [195]. An irregular postural tremor is more common than a resting tremor [183], although about 30% of patients do have a resting tremor, with one-third of these patients exhibiting a classic asymmetric parkinsonian pill-rolling rest tremor. The remaining patients have a jerky and irregular quality to their rest tremor [184]. In addition, patients can develop levodopa-induced motor complications (e.g., motor fluctuations). Dyskinesias can occur and are usually isolated to the orofacial and neck muscles, and can occur in the absence of motor benefit [196]. These PD-like features could result in aggressive administration of levodopa or invasive therapies (e.g., deep brain stimulation), which can be harmful or have little to no benefit in these patients [197–199].

Imbalance and falls due to postural instability are often present very early in the disease course (within 3 years of motor onset). As a result, most patients are wheelchair bound by 5 years [187, 200]. Postural deformities in MSA can be severe, and can include anterocollis, camptocormia (anterior flexion of the spine), and Pisa syndrome (lateral flexion of the spine). In fact, severe anterocollis raises the suspicion for MSA [76]. Pyramidal signs such as asymmetric hyper-reflexia and extensor plantar responses can also be observed and help differentiate patients with MSA-P from those with PD [201].

Early motor/extrapyramidal features of MSA-P: Parkinsonism is one of the most common initial symptoms of MSA-P [184]. Although patients with MSA-P can present with asymmetric parkinsonism that is responsive to levodopa, there are several early clinical features that should make a clinician immediately suspicious of this diagnosis over PD. These include early and severe autonomic impairment, bulbar symptoms, and postural instability leading to early falls (within the first 3 years of diagnosis) [76].

Sleep features of MSA-P

Sleep disorders in MSA are common. RBD occurs in nearly all patients; other frequent sleep abnormalities include hypersomnia, insomnia, early morning awakening, and sleep fragmentation. Sleep-related breathing disorders include stridor, central hypoventilation, and obstructive sleep apnea, and likely contribute to the sudden death during sleep seen in this condition [196, 202]. Some patients choose treatment with continuous positive airway pressure (CPAP) or a tracheostomy to prevent such events, depending on their goals of care [203].

Early sleep features of MSA-P: RBD and nocturnal stridor are both considered red flags for MSA, and may be the earliest symptoms [203].

Autonomic features of MSA-P

Autonomic dysfunction is a diagnostic feature of MSA, and is typically severe. Orthostatic hypotension can lead to frequent fainting episodes upon standing, and can therefore prevent ambulation. The current diagnostic criteria define orthostatic hypotension as a drop of at least 30 mmHg systolic or 15 mmHg diastolic within 3 minutes of standing to reduce the risk of false positives [187]. Sexual dysfunction characterized by erectile dysfunction and anorgasmia is also common. Urinary urgency/frequency is often accompanied by incontinence due to its severity, and can be quite embarrassing to patients. Levodopa can improve motor symptoms, but its use can be limited by worsening of orthostatic hypotension [196]. Constipation typically accompanies these other autonomic symptoms.

Early autonomic features of MSA-P: Autonomic symptoms in MSA can be severe and often precede motor symptoms by several years. Erectile dysfunction in particular is often one of the earliest symptoms in MSA [196]. Early autonomic failure is a predictor of shorter survival [159].

Sensory features of MSA-P

Pain is a common complaint in MSA-P, with one series finding that 47% of MSA patients reported pain [204]. This included musculoskeletal pain, neuropathic type pain (described as paresthesias/cold or burning pain), dystonia pain, and pain associated with being in the off-medication state or associated with dyskinesias.

Early sensory features of MSA-P: Pain can be an early feature of MSA, appearing in the first 3 years of motor symptom onset, and can even precede motoric symptoms in almost one-third of patients [204].

Ocular features of MSA-P

Hypometric smooth pursuit with saccadic intrusions, as well as mild to moderate saccadic hypometria, is described in MSA. Given that many patients have symptoms associated with MSA-P and MSA-C concurrently, the presence of oculomotor abnormalities associated with cerebellar degeneration is not surprising. These can include downbeat nystagmus, gaze-evoked nystagmus, and abnormal vestibulo-ocular reflex suppression [144].

Other clinical features of MSA-P

Dysphagia can be severe, and can lead to aspiration events. Spastic dysarthria is also commonly seen as a result of a reduction in palatal movements [76].

Early clinical features of MSA-P: Bulbar symptoms, including dysarthria and dysphagia, can present early in the disease course, and raise the suspicion for an atypical parkinsonian syndrome. Additional early symptoms detailed above would then indicate a diagnosis of MSA-P.

Cognitive features of CBD

Cognitive impairment affects almost all patients with CBD [212]. The cognitive and neuropsychological profiles largely depend on the maximally affected cerebral hemisphere and the degree to which the frontal, temporal, parietal, and, in some cases, occipital lobes are involved. The frontosubcortical and parietal neural networks are most consistently affected and, therefore, the domains of executive functioning, language, praxis, and visuospatial functioning are most frequently impaired [169, 206, 213]. As in PSP, apraxia of speech and non-fluent aphasia can be the presenting features of CBD [165, 166, 214].

Early cognitive features of CBD: Cognitive impairment is common at the onset of the CBS subtype of CBD, but can be quite mild [205] with executive dysfunction, language impairment, and visuospatial deficits being the most commonly affected domains [206, 212]. Asymmetric ideomotor apraxia affecting function is also a presenting feature [207, 215]. Compared with CBS patients with underlying AD pathology, CBS patients with underlying CBD pathology were older and had less functional impairment on initial exam [209].

Behavioral/psychiatric features of CBD

Patients with CBD can exhibit prominent behavioral/neuropsychiatric features during the course of their illness [216, 217]. Thus, FTD-like features (executive dysfunction, disinhibition, impulsiveness, behavioral changes), depression, and obsessive–compulsive features occur with some frequency in CBD. Visual hallucinations, though, have not been described, and likely point to an alternative diagnosis [205, 217].

Early behavioral/psychiatric features of CBD: Depression, apathy, and/or agitation can be presenting symptoms in CBD patients [212, 218]. Early presentation with frontal lobe syndrome has been associated with a worse prognosis [207].

Motor/extrapyramidal features of CBD

The motor and extrapyramidal features in the CBS subtype of CBD tend to dominate the clinical symptomatology, often causing considerable disability. The features are either unilateral or markedly asymmetric, with limb bradykinesia, apraxia, and rigidity being most common. Within an average of 3.5 years, there is spread of parkinsonism, dystonia, and apraxia to the contralateral side [215]. Variable degrees of myoclonus, alien limb phenomenon, and dystonia can occur. Limb dystonia can be severe, leading to a fixed painful posture that can result in ulceration of the palm due to forced finger flexion [76, 215]. The features tend to be minimally responsive or entirely unresponsive to levodopa. Tremor has been described in nearly half of CBD cases, but differs from the typical rest tremor seen in PD. In addition, low-amplitude action myoclonus can resemble tremor in CBD [205]. Pyramidal signs such as asymmetric hyper-reflexia and extensor plantar responses can also be observed [76, 205, 208]. Gait abnormalities and falls are common, and include postural instability, apraxia of gait, shuffling, and en bloc turns [215].

Early motor/extrapyramidal features of CBD: Levodopa-resistant monomelic apraxia or rigidity is the most common presenting feature in the CBS subtype of CBD [212]. Postural instability leading to falls, axial rigidity, tremor, limb dystonia, and myoclonus (primarily action- and stimulus-sensitive) have also been described at onset [215]. Patients may describe these initial symptoms as “clumsiness,” “incoordination,” and “stiffness” in the involved limb(s) [205]. Early motor symptoms (tremor, rigidity and/or bradykinesia) have been associated with a shorter survival in CBD [207].

Sleep features of CBD

Sleep has received very little attention in CBD. One small study with five CBD patients showed that all had insomnia [219].

Early sleep features of CBD: RBD is typically absent in CBD, differentiating this atypical parkinsonian syndrome from those related to alpha-synuclein deposition (e.g., PD, MSA or DLB).

Autonomic features of CBD

No autonomic features have been found to be consistently abnormal in CBD.

Sensory features of CBD

Cortical sensory loss is relatively common in the CBS subtype of CBD and can include reports of numbness or tingling in the affected limb. Simultagnosia, in addition to impaired joint position sense, two-point discrimination, stereognosis, and graphesthesia are typically found on exam, and provide support for cortical sensory loss [205]. The resulting pseudoathetosis can add to the alien limb-like features [205, 220]. Limb dystonia can be associated with severe pain in the affected extremity [76].

Early sensory features of CBD: Monomelic cortical sensory loss can be a presenting feature in the CBS subtype of CBD [206]. This symptom can unfortunately lead to a misdiagnosis and surgical treatment for carpal tunnel syndrome, which of course has no beneficial effect [205].

Ocular features of CBD

Ocular motor apraxia is often present, and can include difficulty initiating saccades and voluntary gaze, although pursuit and optokinetic nystagmus is typically preserved [205, 220]. Eyelid-opening apraxia and a supranuclear gaze palsy (vertical and horizontal) can occur in CBD, especially later in the disease course [205, 207, 215].

Early ocular features of CBD: Limited voluntary vertical gaze can be an early symptom of CBD [207].

Other clinical features of CBD

Dysarthria in CBD is typically spastic and hypokinetic. Dysphagia is also common in CBD [76, 207], with resulting aspiration pneumonia being a frequent cause of death. Frontal release signs indicating frontal lobe neuronal degeneration can be seen [206].

Early other clinical features of CBD: Dysarthria can be a presenting symptom, characterized by slow, slurred, and hypophonic speech that is difficult to understand. Balint’s syndrome has been rarely described as a presenting symptom complex [221].