When Mood Symptoms Signal Neurodegeneration

Depression, anxiety, agitation, hallucinations, and delusions are behavioral and psychological symptoms that frequently manifest during the course of neurodegenerative diseases. They can profoundly affect the quality of life of patients, their families, and their caregivers: They are difficult to manage, often necessitate admission to care facilities, and are usually associated with a poorer prognosis. However, they also serve as useful indicators of what is happening in the brain. Careful observation of these symptoms and research into the mechanisms that trigger them can provide insights for making an accurate diagnosis, predicting the course of the disease, and developing more appropriate and personalized treatment plans.Specialists who gathered in Florence from October 24 to 27 for the 2026 Congress of the Italian Society of Neurology discussed these issues.Anxiety and Depression: Early Symptoms“Depression and anxiety are fairly common symptoms, especially in the early stages of neurodegenerative diseases,” noted Stefania Basilico, PhD, a psychologist at the Cognitive Neuropsychology Center at the Niguarda Metropolitan Hospital in Milan, Italy. These symptoms may emerge before cognitive decline is detectable on clinical evaluation and may represent an intensification of preexisting personality traits. For example, a person with anxious tendencies may develop an anxiety disorder in response to perceived early cognitive changes and reduced independence. Depression may also arise as a person struggles to adapt to cognitive losses.But it is important to recognize them: “Since these disorders have a low etiological specificity and since, in the diagnosis of neurodegenerative diseases, the evaluation usually focuses primarily on cognitive symptoms, giving less attention to neuropsychiatric ones, there is a risk of misclassification — that is, that the distress may be attributed exclusively to a primary psychiatric disorder, delaying the recognition of the underlying neurodegenerative disease. Diagnosis may also be challenging because cognitive decline can fluctuate early in the disease. Symptoms may be more noticeable at some times and less apparent at others,” explained Basilico.Misclassification can delay recognition of an underlying neurodegenerative disease — and access to appropriate care — for several years. During that time, patients may receive treatments that do not address their overall clinical needs. When symptoms are evaluated by multiple specialists without being brought together into a coherent diagnosis, patients and families may face prolonged uncertainty and distress.“A well-structured medical history is needed to identify any elements warranting further investigation,” the psychologist concluded. This is also recommended by the Italian national guideline on the diagnosis and treatment of dementia and mild cognitive impairment: The initial assessment must consider both the cognitive and psychological dimensions, as well as the impact of these manifestations on the patient’s daily life. And both components must, when necessary, be treated appropriately.Delusions and Hallucinations as Diagnostic CluesWhile anxiety and depression are relatively nonspecific neuropsychiatric manifestations in neurodegenerative diseases, psychotic symptoms may have greater diagnostic value in certain contexts. “Delusions are thought disorders: unfounded beliefs that a person holds even in the face of clear evidence to the contrary. Hallucinations are perceptions that occur in the absence of a corresponding external stimulus,” explained Fabrizia D’Antonio, a neurologist and researcher at the Department of Human Neuroscience at Sapienza University of Rome, Rome, Italy, in her presentation at the conference.According to certain interpretive models, delusions and other psychotic manifestations may arise from the patient’s difficulty in correctly interpreting environmental stimuli. “For example, a person cannot find an object because of memory problems and concludes that someone has stolen it or fails to recognize their own home and thinks they are in someone else’s house,” explained D’Antonio.Other models point to the structural changes that the disease causes in the brain, impairing the functioning of specific areas. “Research into the neurobiological correlates of psychotic experiences can help better classify patients, understand the mechanisms that generate symptoms, and, in the long run, identify more targeted treatments,” added D’Antonio.In 2020, the International Psychogeriatric Association updated the criteria for defining and classifying psychotic disorders associated with neurodegenerative diseases through a process involving international specialists, researchers, representatives from the pharmaceutical industry, drug regulatory experts, and other stakeholders, with the goal of establishing criteria applicable to a broad range of conditions and usable in both clinical practice and research, including the testing of new treatments.In Alzheimer’s disease, psychotic symptoms become more frequent as cognitive decline progresses and are particularly common in the intermediate and advanced stages. “Delusions are more common than hallucinations: These often involve persecutory beliefs, such as the belief that someone has stolen or hidden objects, or that other people want to harm them. Erroneous beliefs about people’s identities may also arise: The patient may fail to recognize a family member. Hallucinations, when present, are primarily visual but may also involve hearing,” explained D’Antonio.A different picture is observed in Lewy body dementia, in which psychotic manifestations are particularly frequent and may appear as early as the initial stages. The most characteristic feature is recurrent visual hallucinations, which are often vivid, detailed, and well-structured. Delusions of misidentification are also common, such as the belief that a family member has been replaced by a look-alike, as occurs in the so-called Capgras syndrome.In Parkinson’s disease, hallucinations are predominantly visual. “Before actual hallucinations occur, milder perceptual phenomena may appear, such as the sensation that someone has quickly passed by the edge of one’s field of vision or the perception of a presence behind one’s back,” D’Antonio continued. Auditory hallucinations are also described but are less frequent. Symptoms may be triggered or exacerbated by dopaminergic medications used to treat Parkinson’s disease.“The management of psychotic symptoms does not necessarily rely on medication. Before resorting to antipsychotics — which require particular caution in people with neurodegenerative diseases — it is important to identify and address any clinical or environmental factors that may contribute to them and to adopt personalized support strategies,” concluded D’Antonio. When a person can still distinguish their perceptions from reality, it may help to gently identify delusions or hallucinations as symptoms, while offering reassurance and addressing the distress they cause. In more advanced stages, when this insight is lost, avoid arguing or insisting that the person’s beliefs are false. Instead, listen actively, provide reassurance, and use approaches that help ease fear and agitation.This story was translated from Univadis Italy, part of the Medscape Professional Network.