Prodromal MCI is a stage of pre-dementia with signs or symptoms that indicate that MCI will subsequently develop and encompasses cognitive deficits, motor symptoms and signs, sleep disorders, autonomic dysfunction, and neuropsychiatric impairment.
Because these early manifestations can occur ≥15 years before the onset of dementia, early diagnosis of MCI presents particular challenges.
| How does prodromal DLB usually present? |
Basic clinical features characteristic of a DLB developed before dementia may appear, which are generally accompanied by mild cognitive alterations. Spontaneous parkinsonism is not present in all patients.
TCR is a parasomnia that occurs years or decades before the onset of dementia or parkinsonism and may presage α-synucleinopathy. In patients with mild cognitive deficits, both parkinsonism and TCR strongly predict a subsequent transition to MCI rather than to Alzheimer’s disease (AD) or other types of dementia.
Delirium and fluctuations in cognition and arousal may appear during the pre-dementia stage. Visual hallucinations (VA) are likely to occur spontaneously or caused by illness or medication.
3 prototypical prodromal MCI syndromes were proposed:
(1) mild cognitive impairment (MCI),
(2) delirious onset, or
(3) psychiatric onset.
| ACL with Lewy bodies |
ACL with Lewy bodies (ACL-CL) requires cognitive impairment expressed by the patient or by an informant or doctor who knows them. Also required are deficits in one or more cognitive domains that are greater than expected for age, that do not represent long-standing low cognitive function, and that are not associated with acute medical or neurological illnesses.
These cognitive deficits do not interfere with typical daily functioning; there should be a general preservation of the previous level of independence with minimal interference in daily functional skills.
Cognitive impairment can further be categorized as single or multiple domain, and as amnestic or non-amnestic, which helps to classify subgroups according to their relationship with (1) pathological correlates and biomarkers, and (2) differences in the rate of decline and progression to dementia.
| Cognitive presentation of ACL-CL |
The cognitive pattern of ACL-CL is similar to that of MCI and includes marked deficits in attention/executive and visual processing, with memory and object mention relatively preserved. Impairments in attention tasks, processing speed, and verbal fluency constitute attentional/executive deficits, and visual discrimination, assembly, and figurative drawing tasks constitute visual and spatial perception deficits.
The performance pattern of ACL-CL is best characterized as single-domain or multidomain non-amnestic ACL, or as multidomain amnestic ACL, whereas single-domain amnestic ACL is more likely to represent AD-ACL. Non-amnestic ACL rarely progresses to AD, but is associated with increased risk of transition to MCI with a tenfold increased risk compared to amnestic ACL.
Given that a substantial subset of MCI patients have coexisting AD-related pathology that may influence their cognitive profile, ACL-CL should be considered an important part of the differential diagnosis in amnesic subjects.
| Operationalization of the ACL-CL |
Identification of ACL allows for a diagnosis of possible or probable ACL-CL based on the number of qualifying clinical features or biomarkers. The terms possible and probable refer to the probability of CL disease and not to MCI syndrome.
Structured diagnostic tools can help identify basic clinical features of MCI that precede, coincide with, or follow the onset of cognitive difficulties.
Cognitive fluctuations may be of lower amplitude or frequency than in more severe diseases. The clinical characteristics that support MCI may be secondary to other causes, which reduces diagnostic specificity.
| ACL-CL and ACL-EP |
There may be uncertainty in deciding how to best categorize patients who present with both MCI and parkinsonism. ACL-PD is the most appropriate diagnosis when Parkinson’s disease (PD) is diagnosed before significant cognitive impairment occurs.
Adopting the 1-year rule similar to that used to separate MCI and PD dementia may be useful in distinguishing some cases of ACL-CL and ACL-PD if the onset and order of mild parkinsonism symptoms and cognitive impairment can be clearly established.
Otherwise, an initial diagnosis of prodromal CL disease may be preferable. The cognitive deficits of ACL-PD may be heterogeneous, with attention/executive function, visuospatial skills, and memory disproportionately affected. Similar to what occurs in ACL-CL, non-amnestic ACL and multidomain amnestic ACL are more common.
| Biomarkers of prodromal MCI |
Direct measurements of α-synuclein would offer a definitive diagnosis at an early stage, but are not yet validated. Therefore, surrogate biomarkers of CL disease should be used, as is the case for the diagnosis of MCI.
| Proposed biomarkers: |
Reduction of dopamine transporter (TDA) uptake in ganglia demonstrated by SPECT or PET: useful for discriminating MCI from AD and sensitivity for distinguishing ACL-CL from ACL-AD.
Polysomnographic (PSG) confirmation of REM sleep without atonia: The association between a probable TCR plus clear documentation of REM sleep without atonia (SRSA) on PSG marks a high probability of an underlying prodromal synucleinopathy.
Reduced meta-iodobenzylguanidine (MIBG) uptake on myocardial scintigraphy: There appears to be sufficient evidence that this abnormal uptake in a patient with MCI supports the diagnosis of prodromal MCI, but further studies are required.
| Possible biomarkers: |
These are biomarkers compatible with CL disease that help in the evaluation, but for which there is not yet sufficient evidence of sensitivity and specificity.
• Quantitative EEG with slowing and dominant frequency variability: EEG slowing predicts dementia in PD and TCR; subsequent slow wave activity with periodic fluctuations in the pre-alpha range supports MCI.
Quantitative EEG (EEGC) methods show that a dominant frequency <8 Hz and a dominant frequency variability >1.5 Hz are typical of MCI, being predictors of the progression from ACL to MCI.
• Relative preservation of medial temporal lobe structures on structural imaging: Hippocampal preservation in patients with ACL supports progression to MCI rather than AD dementia with a sensitivity of 85% and specificity of 61%.
• Insular thinning and gray matter volume loss: In prodromal DLB, insular cortical thinning occurs with gray matter atrophy that predominantly affects the anterior cingulate and medial frontal structures. This contrasts with the more extensive loss of gray matter in the temporal, frontal, and parietal regions of subjects with prodromal AD.
• Low occipital uptake on metabolism/perfusion scan: Occipital hypometabolism on PET together with relative preservation of posterior cingulate metabolism (cingulate island sign) constitutes a biomarker of MCI.
> Other biomarkers: There is currently no α-synuclein radioligand with sufficient evidence to support its usefulness in imaging DLB or other α-synucleinopathy. Measurement of α-synuclein aggregates in CSF provides encouraging preliminary results.
Other candidates for early direct or indirect biomarkers include the identification of deposits of phosphorylated α-synuclein in peripheral nervous tissue from skin biopsy, gait analysis, and abnormalities in color vision discrimination.
| MCI onset with delirium |
The occurrence of delirium (or acute confusion) as an early presenting feature of DLB has been described in numerous reports.
It is important to recognize that MCI may first present as delirium because most guidelines for behavioral disturbances with delirium recommend antipsychotics as first-line treatment. Prolonged delirium may also increase the index of suspicion for MCI.
In patients diagnosed with delirium, a careful search for other features of MCI should be performed with a low threshold for biomarker testing, especially in those with recurrent, unexplained, or prolonged delirium. The extent to which presentations with delirium show biomarker abnormalities associated with MCI or other prodromal presentations of MCI is unclear.
| Psychiatric onset MCI |
Previous studies suggested that MCI may present as a primary psychiatric disorder. Major depressive disorder and late-onset psychosis are the most common presentations. Symptoms include visual and other hallucinations and systemic delusions such as Capgras syndrome, apathy, anxiety, and depression.
Psychiatric-onset MCI cases are not easily differentiated from non-CL late-onset psychosis cases based only on primary psychiatric phenomena or neuropsychological profile. Although primary psychiatric manifestations are often accompanied by mild cognitive deficits, cognitive assessment and interpretation of performance can be difficult when psychiatric symptoms are prominent.
Initial reports suggest that 123I-MIBG scintigraphy may be useful in psychiatric-onset MCI, although further studies are needed to confirm these findings and to determine the value of other MCI biomarkers in these cases. In summary, it is still unclear how to identify patients with prominent late-onset psychiatric symptoms who may have underlying CL disease and subsequently progress to MCI.
| Idiopathic REM sleep behavior disorder |
TCR is characterized by abnormal sleep enactment behavior during REM sleep, accompanied by loss of muscle atonia (REM sleep without atonia or SRSA) in the PSG.
For the diagnosis of prodromal MCI, a history of TCR is obtained from a clear complaint of a dream reenactment by a bed partner or other witness, without evidence of disorders that could mimic TCR.
Known conditions that mimic a TCR include non-REM parasomnias (sleepwalking, sleep talking, or other behaviors arising from non-REM stages of sleep), obstructive sleep apnea, confusional awakenings, or nocturnal seizures.
In the absence of PSG, the risk of a false-positive TCR diagnosis is reduced by the use of optimized sleep questionnaires.
TCR is considered idiopathic until it is associated with another ongoing neurological condition, the most common being α-synucleinopathy (PD, ECL, or MSA). Although it may be one of the first manifestations, it is not possible to clearly distinguish whether a person presenting with TCR will develop dementia first, that is, whether it will progress to a primary diagnosis of MCI, or parkinsonism first, that is, to a diagnosis of PD. /primaryASM. Any subtype of MCI associated with TCR confirmed by PSG is most likely to represent underlying CL disease.
| Autonomic dysfunction/anosmia and other nonspecific prodromal symptoms of CL disease |
Patients with MCI frequently report a history of autonomic dysfunction, with 25%-50% complaining of one or more of constipation, orthostatic dizziness, urinary incontinence, erectile dysfunction, increased sweating or salivation. However, as there are many other causes of autonomic dysfunction in older people, these symptoms have a low predictive value.
| Conclusions and future direction |
The diagnosis of MCI in the dementia stage depends on the identification of fully expressed core clinical features that may be mild or absent in the prodromal stage, when biomarker evidence may also be weaker and even differ from that found in the prodromal stage. of dementia. Several new candidate biomarkers, direct and indirect, are in development.
It is recognized that the clinical phenotype of neurodegenerative disorders reflects the interaction between several brain pathologies, and therefore, multiple biomarkers of individual pathologies (e.g., α-synuclein, β-amyloid, and tau) or of disease surrogates (e.g., metabolic imaging/EEG).
Although the 3 prodromal syndromes of MCI have been described separately, they are unlikely to be mutually exclusive, and there may be substantial overlap.
Despite the potential benefits of early diagnosis, one should also be aware of the importance of avoiding a false diagnosis of prodromal MCI with the potential negative consequences this could have for an individual. The predictive validity of the different categories and combinations of criteria proposed here must be clarified by prospective studies before they are adopted for widespread clinical use.
The DSM5 recommends a diagnosis of mild neurocognitive disorder (NCD) with CL “for individuals who present with core or suggestive features at a stage where the cognitive or functional impairments are not severe enough to meet the criteria for major NCD.” ICD-11 takes a similar approach to diagnosing mild TNC at the syndromic level and lists both CL disease and PD as possible causes.
The diagnostic position for other prodromal manifestations of MCI, i.e., delirious onset and psychiatric onset, is less clear than for ACL. Operationalization of specific criteria for these syndromes is not yet justified, and reliable differentiation of the minority of delusional and psychiatric patients who have underlying CL pathology, from the majority who do not, will likely only be achieved when applicable biomarkers are developed. routine.
