Assistant Professor of Neuropsychiatry in Clinical Neurology, Weill Cornell Medical College, and Assistant Attending Neurologist, NewYork-Presbyterian Hospital
Dr. Pahlajani reports no financial relationships relevant to this field of study.
SYNOPSIS: Clinical identification of fluctuating cognition is challenging. A better understanding of potential etiological mechanisms can allow for optimization of clinical assessment tools and targeted therapeutic approaches.
SOURCE: O’Dowd S, Schumacher J, Burn DJ, et al. Fluctuating cognition in the Lewy body dementias. Brain 2019;142:3338-3350.
Dementia with Lewy bodies (DLB) is the second most common type of neurodegenerative dementia in older adults (after Alzheimer’s disease). Per the 2017 consensus diagnostic criteria, one of the core clinical features of DLB is fluctuating cognition (FC), typically accompanied by parkinsonism, visual hallucinations, and REM sleep behavior disorder.
O’Dowd et al reviewed data related to potential etiological mechanisms of FC in DLB in correlation with clinical features. Alterations in attention and alertness are the primary manifestations of FC. A key distinguishing feature is that it demonstrates a spectrum of severity (lasting seconds or minutes to days of altered attention or drowsiness) due to an internally mediated process resulting in a spontaneous, periodic, and transient quality. Comparatively, fluctuations in Alzheimer’s disease generally are a consequence of interactions or changes in the external environment, with memory failure as a prominent symptom. Data collated from various studies revealed that prevalence rates of FC are lower (29-39%) and less heterogeneous in patients with possible DLB and mild cognitive impairment (MCI) compared to those with probable DLB (45-90%). Cognitive fluctuations in DLB are not necessarily associated with poorer prognosis or greater overall cognitive decline based on results of two cross-sectional studies. Fluctuating cognition in patients with non-amnestic MCI was a predictor of conversion to DLB and a characteristic feature of prodromal DLB.
Of the four clinical scales used for assessment of fluctuating cognition, the Dementia Cognitive Fluctuation Scale1 was found to accurately distinguish between DLB, Alzheimer’s disease, and vascular dementia, especially in patients with mild or moderate dementia. It also demonstrated good test-retest and inter-rater reliability and had two versions, a full 17-item questionnaire for use in research studies and a shorter four-item version for use in clinical practice.
Although several theories have been postulated to explain the underlying mechanisms of FC, there is evidence for two broad mechanistic etiologies: cognitive fluctuations due to disturbance in attentional circuitry (as a consequence of hypocholinergic etiology or alterations in large-scale networks) or due to a disorder of sleep/arousal. Attentional circuitry perturbations can be caused by a loss of cholinergic neurons in nucleus basalis of Meynert (NBM), involved in transmitting “bottom-up” signals of attention, and shown to correlate with reduced cortical choline acetyltransferase levels in DLB. This theory is supported by improvement in FC after treatment with cholinesterase inhibitors. Complex functional disturbances in large-scale neuronal networks can occur via various mechanisms. These include: 1) atrophy of regions containing von Economo neurons involved in the integrity of attentional circuits; 2) dysfunction at various levels of the default mode network; and 3) abnormal perfusion in motor areas followed by decreased perfusion in partial areas correlating with cognitive fluctuations. There is strong evidence to support that subcortical thalamic cholinergic denervation is associated with FC because alpha-synuclein pathology has a prominent impact on the reticulo-thalamo-cortical activating system, which is critical for mediating consciousness. Fluctuating cognition might be a manifestation of disrupted sleep-wake homeostasis. This is based on the affinity of Lewy bodies for the hypothalamus in DLB and Parkinson’s disease, as well as very poor sleep efficiency and distortions in sleep-wake architecture in advanced DLB. Some studies have suggested a correlation between multiple sleep latency tests and polysomnography parameters, whereas others have not. These findings further support that fluctuations may have two distinct aspects, one associated with arousal/alertness and another with attention.
EEG techniques, in addition to functional neuroimaging, also have helped better understand functional disturbances associated with FC. Distinct EEG patterns that correlate with cognitive fluctuations in DLB include the presence of prominent posterior slow-wave activity and an increase in dominant frequency variability and slowed dominant EEG rhythm compared to pre-alpha/fast theta activity. Studies show that these EEG abnormalities correlate with severity of FC in DLB and are identifiable in the MCI stage, potentially preceding symptoms of FC.
For symptomatic treatment, studies demonstrate that cholinesterase inhibitors, specifically donepezil, can improve fluctuating cognition, as measured by clinical assessment scales and EEG abnormalities. Memantine is more efficacious for targeting attention in DLB. There is conflicting evidence regarding the therapeutic effect of deep brain stimulation and the use of modafinil and armodafinil.
There are limited treatment options available to patients with DLB. Identification and appropriate therapeutic management of fluctuating cognition in DLB can improve a patient’s quality of life and ability to perform activities of daily living and reduce caregiver burden. Better understanding of mechanistic theories can be useful in clinical practice, especially when considering medication trials for symptoms of cognitive fluctuations vs. attentional deficits in DLB. It also increases the neurologist’s awareness to screen for a constellation of symptoms, potentially leading to more accurate identification
of FC, therefore obtaining targeted and pertinent tests.
- Lee DR, McKeith I, Mosimann U, et al. The dementia cognitive fluctuation scale, a new psychometric test for clinicians to identify cognitive fluctuations in people with dementia. Am J Geriatr Psychiatry 2014;22:926-935.