Randi Hagerman, MD

Aging With Developmental Disabilities, Part 2

Older adults with neurodevelopmental disorders constitute a growing segment of the population as overall life expectancy increases. With aging, a multitude of medical conditions can occur and/or existing conditions can be exacerbated, contributing causally to or amplifying neuropsychiatric comorbidities. 

 covered fragile X–related disorders, including X syndrome and fragile X–associated tremor/ataxia syndrome.

 Here we discuss autism spectrum disorders, Down syndrome, and 22q11.2 deletion syndrome (22qDS).

The prevalence of autism spectrum disorders in the general population has been estimated to be 2.24%, with a male to female gender ratio of 4 to 1.

 Compared with controls, adults who have an autism spectrum disorder are at significantly increased risk for all major psychiatric disorders, including anxiety, depression, bipolar disorder, obsessive-compulsive disorder, schizophrenia, and suicide attempts.

In addition, the prevalence of medical conditions (eg, diabetes, hypertension, hyperlipidemia, obesity, sleep disorders, vitamin deficiencies, stroke, and Parkinson disease) is higher among such patients.

Most individuals who have an autism spectrum disorder need various degrees of support throughout their adult life, and their quality of life decreases over time. As they age, two-thirds of adults with severe symptoms have a poor outcome.

 Moderately disabled individuals often live in residential facilities and require family support; high-functioning adults may live independently, are employed, and strive toward meaningful relationships.

On psychiatric evaluation, it is difficult to find all the signs and symptoms of autism spectrum disorders in adults who have received intensive social skills training and vocational therapy services. Broader recognition of this group of disorders has been attained only in the past 2 decades; thus, autism spectrum disorders may be underdiagnosed in geriatric patients.

A study of older adults, aged 60 to 90 years, revealed that 31% of individuals with depressive disorders had elevated autism spectrum disorder characteristics, compared with 6% of non-depressed participants, highlighting the importance of a thorough evaluation for autism spectrum disorder in this age group.

 Individuals with an autism spectrum disorder and intellectual disability may mistakenly receive a diagnosis of a major neurocognitive disorder, such as Alzheimer disease, if no collateral information or medical records are available to establish the premorbid cognitive baseline.

Down syndrome, most often caused by trisomy of chromosome 21, is the most common genetic disorder, affecting about 1 of 750 to 1000 live births.

 Persons with Down syndrome present with complex congenital cardiac malformations, intellectual disability, and anomalies in other organ systems, including digestive, musculoskeletal, urinary, and respiratory systems. Psychiatric comorbidities include anxiety, behavioral disturbances, and depressive symptoms.

 Moreover, Down syndrome is a known risk factor for Alzheimer disease.

The overexpression of genes located on chromosome 21, such as the 

 gene, leads to accumulation of Î²-amyloid with formation of amyloid plaques. In addition, middle-aged adults with Down syndrome develop neurofibrillary tangles, white matter disease, and cerebrovascular pathology-all of which can contribute to neurocognitive disorders. By age 40, most adults with Down syndrome have amyloid plaques and neurofibrillary tangles in numbers sufficient to support a neuropathological diagnosis of Alzheimer disease.

 About 15% of 45-year-olds with Down syndrome have Alzheimer disease, and the prevalence doubles every 5 years.

 Although the age of onset of Alzheimer disease in individuals with Down syndrome is earlier than in the general population (typically, 65 years or older) and the cognitive baseline and overall level of functioning differ between these 2 groups, their cognitive profiles are quite similar.

22qDS (ie, velocardiofacial or DiGeorge syndrome) is caused by hemizygous microdeletions on the long arm of chromosome 22. Its prevalence is estimated at approximately 1 of every 4000 live births.

 Individuals with 22qDS may have abnormal facies, cleft palate, congenital heart disease, neuromuscular problems, thymic aplasia leading to T-cell immune dysfunction, hypoparathyroidism, and hypocalcemia. Most persons with 22qDS have cognitive deficits, specifically in the domains of sustained attention, executive function, memory, and visuospatial skills.

With regard to intellectual functioning, most individuals score in the borderline IQ range: some reach low average IQ, while others have mild intellectual disability. A large study examined psychiatric comorbidities in 1402 participants with 22qDS, aged 6 to 68 years.

 The most common psychiatric diagnosis was ADHD (37%), noted to be more frequent in males; females had more anxiety and depressive disorders.

Confirming previous results, which consistently show a strong association of 22qDS with schizophrenia, Schneider and colleagues

 found that 41% of adults over age 25 had psychotic disorders. The prevalence of autism spectrum disorders in patients with 22qDS is 11%, which is higher than in the general population.

 An association of 22qDS with early-onset Parkinson disease has been reported; therefore, it is recommended that patients with this neurodevelopmental condition be monitored for the emergence of parkinsonism.

 summarizes the cognitive and psychiatric manifestations in older adults with neurodevelopmental disorders.

Treatment strategies for late-life manifestations of neurodevelopmental disorders include psychosocial approaches and symptomatic management for neuropsychiatric symptoms, such as agitation, anxiety, apathy, depression, insomnia, irritability, and psychosis. Psychosocial strategies include behavior modification based on the antecedent-behavior-consequence model, cognitive-behavioral therapy, social skills training, supportive psychotherapy, and family caregiver support and education interventions.

Cholinesterase inhibitors (donepezil, galantamine, and rivastigmine) and the NMDA antagonist memantine have been used off-label for persons with Down syndrome who have Alzheimer disease, although there is insufficient evidence to support this approach.

 More research is needed to identify effective treatments for neurodevelopmental disorders in late life.

The majority of adults with neurodevelopmental disorders are physically, emotionally, and financially dependent on their families throughout their lives; many are cared for at home by unpaid family caregivers. Clinicians should be vigilant and assess for caregiver burden at every visit and be familiar with local and national resources that can provide support and respite to families.

 was supported by the National Center for Advancing Translational Sciences, National Institutes of Health through grant number UL1TR000003 and linked award TL1 TR000133. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

The authors acknowledge the American Association for Geriatric Psychiatry (AAGP) for helping to bring this article to fruition. The AAGP is a national association representing and serving its members and the field of geriatric psychiatry. The AAGP promotes the mental health and well-being of older people through professional education, public advocacy, and support of career development for clinicians, educators, and researchers in geriatric psychiatry and mental health.

Dr Seritan is a Health Sciences Clinical Professor in the Department of Psychiatry, University of California, San Francisco, San Francisco, CA. Mr Ligsay is a medical student at the University of California, Davis School of Medicine, Sacramento, CA. Dr Hagerman is Distinguished Professor and Endowed Chair in Fragile X Research in the Department of Pediatrics, University of California, Davis Medical Center, Sacramento, CA, and Medical Director of the Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, Sacramento, CA. Dr Seritan and Mr Ligsay report no conflicts of interest concerning the subject matter of this article; Dr Hagerman reports that he has received support from the NIH for genotype-phenotype study in fragile X premutation disorders.

 Seritan A, Ligsay A, Hagerman R. Aging with developmental disabilities, part 1: fragile X–associated disorders. 

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 Croen LA, Zerbo O, Qian Y, et al. The health status of adults on the autism spectrum. 

 Chamak B, Bonniau B. Trajectories, long-term outcomes, and family experiences of 76 adults with autism spectrum disorders. 

 Seritan AL, Hopp K, Bacalman S, Ozonoff S. Anxiously looking for love. 

 Geurts HM, Stek M, Comijs H. Autism characteristics in older adults with depressive disorders. 

 Stoll C, Dott B, Alembik Y, Roth MK. Associated congenital anomalies among cases with Down syndrome. 

 Glenn S, Cunningham C, Nananidou A, et al. Routinised and compulsive-like behaviours in individuals with Down syndrome. 

 Dick MB, Doran E, Phelan M, Lott IT. Cognitive profiles on the Severe Impairment Battery are similar in Alzheimer disease and Down syndrome with dementia. 

 Demily C, Rossi M, Schneider M, et al. Neurocognitive and psychiatric management of the 22q11.2 deletion syndrome. 

 Schneider M, DebannÃ© M, Basset AS, et al. Psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome: results from the International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome. 

 Richards C, Jones C, Groves L, et al. Prevalence of autism spectrum disorder phenomenology in genetic disorders: a systematic review and meta-analysis. 

 Butcher NJ, Kiehl TR, Hazrati LN, et al. Association between early-onset Parkinson disease and 22q11.2 deletion syndrome: identification of a novel genetic form of Parkinson disease and its clinical implications. 

 Mohan L, Carpenter PK, Bennett C. Donepezil for dementia in people with Down syndrome. 

 Hanney M, Prasher V, Williams N, et al. Memantine for dementia in adults older than 40 years with Down’s syndrome (MEADOWS): a randomized, double-blind, placebo-controlled trial. 

 Seritan AL, Ortigas M, Seritan S, et al. Psychiatric disorders associated with FXTAS. 

 Wadell PM, Hagerman RJ, Hessl DR. Fragile X syndrome: psychiatric manifestations, assessment and emerging therapies. 

Articles

With aging, a multitude of medical conditions can occur and/or existing conditions can be exacerbated, contributing causally to or amplifying neuropsychiatric comorbidities.

Autism Spectrum Disorders, Down Syndrome, and 22q Deletion Syndrome

Individuals with developmental disabilities encounter multiple difficulties as they age. Underlying molecular mechanisms may result in cascading changes at the neuronal level that, combined with the effects of aging, contribute to additional challenges, resulting in new psychiatric manifestations or exacerbations of preexisting conditions. At the same time, medical diseases, often comorbid with intellectual disabilities, may contribute to the development of cognitive deficits or psychiatric disorders in late life. For example, cerebrovascular risk factors, such as diabetes mellitus, hyperlipidemia, and hypertension, may cause microvascular ischemic changes, which are associated with vascular depression or cognitive disorders.

Several examples of neurodevelopmental disorders in older adults are discussed in this article. This is not intended to be an exhaustive review, but rather a quick guide to common neurodevelopmental conditions and their associated late-life neuropsychiatric manifestations. Here, we discuss the fragile X–associated disorders: fragile X–associated tremor/ataxia syndrome and fragile X syndrome (FXS). In part 2 of the article (in an upcoming issue of 

), the discussion will center on autism spectrum disorders, Down syndrome, and 22q deletion syndrome.

The project described in this article was supported by the National Center for Advancing Translational Sciences, National Institutes of Health through grant number UL1TR000003 and linked award TL1 TR000133. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Before beginning our discussion, we emphasize that a common point for the conditions associated with intellectual disability is the need to establish a cognitive baseline (and to understand whether a decline from baseline occurred) in order to make an accurate diagnosis of major neurocognitive disorder later in life.

Fragile X–associated disorders are a fascinating group of neurodevelopmental disorders. Awareness of the complex molecular and clinical phenomena associated with these conditions is still an area of growth for many psychiatrists. The fragile X mental retardation 1 (

) gene consists of successive CGG repeats in the promoter region of the gene. The number of CGG repeats determines the phenotype, as follows: neurotypical individuals have fewer than 45 repeats; those in the “gray zone” have 45 to 54 repeats (and may develop clinical problems similar to those with the premutation); 55 to 200 CGG repeats indicate the presence of a premutation; and the full mutation is found in those with over 200 repeats.

Approximately 1 in 150 to 200 females and 1 in 400 to 450 males in the general population have the premutation.

 premutation carriers have anxiety and depressive disorders, along with other, less frequent, psychiatric comorbidities.

 Some carriers also have neurodevelopmental disorders, such as autism spectrum disorders and/or intellectual disability, although most do not.

 illustrates common psychiatric diagnoses encountered in premutation carriers. Male carriers may also present with multiple medical problems, including type 2 diabetes mellitus, dyslipidemia, hypertension, obesity, and sleep apnea. Female carriers have been known to have primary ovarian insufficiency leading to premature menopause (20%); they may also have hypertension (50%), migraines (40%), thyroid problems (40%), fibromyalgia (40%), and autoimmune diseases (10%).

Fragile X–associated tremor/ataxia syndrome (FXTAS)

 gene premutation carriers may develop FXTAS, a neurodegenerative disease that was discovered relatively recently.

 Initially thought to affect men exclusively, FXTAS is now known to occur in approximately 40% of males in their 60s and up to 16% of females with the premutation.

 FXTAS manifests with intention tremor, cerebellar ataxia, parkinsonism, neuropathy, psychiatric comorbidities, and progressive cognitive impairment, which can lead to a major neurocognitive disorder in some patients. Neuroimaging studies have shown generalized cerebral and cerebellar atrophy and white matter hyperintensities on T2 MRI in the middle cerebellar peduncles or in the splenium of the corpus callosum.

Cognitive deficits in premutation carriers include executive dysfunction (prominent and present early, even before the manifestation of FXTAS) and short-term memory deficits. FXTAS may occur in up to 30% of patients in advanced stages of disease, particularly men. This newly discovered major neurocognitive disorder has been described as a mixed cortical-subcortical picture, with psychomotor slowing, executive dysfunction, deficits in memory (recall and retrieval) and attention, and personality changes.

 The FXTAS major cognitive disorder is clinically and neuropathologically different from Alzheimer disease and all other known major neurocognitive disorders.

On pathological examination, eosinophilic ubiquitin-positive intranuclear inclusions are present in neurons and astrocytes throughout the brain, as well as in the peripheral nervous system and other organs. In a case series of 8 women with the premutation, all had these pathognomonic intranuclear inclusions. Three of the carriers also had amyloid plaques and neurofibrillary tangles sufficient to support a neuropathological diagnosis of Alzheimer disease.

 More research is needed to fully understand the major neurocognitive disorder of FXTAS. What is known indicates that the 

 premutation sometimes causes a neurodevelopmental disorder and more commonly causes late-life neurodegenerative changes, including FXTAS.

 full mutations lead to gene methylation and silencing and thus the absence of the FMR1 protein, which is an RNA-binding protein that plays an important role in synaptic plasticity and is thus critical in brain development and aging processes. The absence of the FMR1 protein leads to FXS, the most common cause of inherited intellectual disability, with an estimated prevalence of 1 per 3600 to 1 per 6000 in the general population.

Psychiatric manifestations of FXS include anxiety, ADHD, autism spectrum disorders, mood instability, and aggression. In fact, FXS is the most common single gene cause of autism spectrum disorders, which are present in 30% of males with the 

 FMR1 protein represses amyloid precursor protein translation, which leads to excess amyloid precursor protein and in turn results in formation of Î²-amyloid plaques. Few studies have focused on aging adults with FXS. In a review of 62 individuals with FXS (44 males, 18 females) aged 40 years or older, 6 (10%) reported cognitive decline or had received a diagnosis of a major neurocognitive disorder.

 Approximately 40% of participants also had neurological problems, including tremor, ataxia, parkinsonism, seizures, tardive dyskinesia, and tics. Other medical conditions included gastrointestinal symptoms, obesity, hypertension, and cardiac problems.

Treatment strategies for late-life manifestations of neurodevelopmental disorders include psychosocial approaches and management of symptoms such as agitation, anxiety, apathy, depression, insomnia, irritability, and psychosis. Psychosocial strategies include behavior modification based on the antecedent-behavior-consequence model, cognitive-behavioral therapy, social skills training, supportive psychotherapy, and family caregiver support and education interventions.

Adults with neurodevelopmental disorders encounter multifaceted medical and psychiatric challenges as they get older. They may be more prone to major neurocognitive disorders than age-matched adults in the general population-either by virtue of underlying molecular pathology or because of a higher prevalence of cerebrovascular risk factors. In addition, the various psychiatric comorbidities associated with neurodevelopmental disorders may increase the risk of morbidity and mortality. It is therefore crucial to adequately recognize and treat neuropsychiatric symptoms and to provide support not only to older adults with neurodevelopmental disorders but to their families as well.

Targeted treatments are being explored for FXS (antagonists of the metabotropic glutamate receptor mGluR5, GABA A and B receptor antagonists, minocycline, and others), although these agents have not been studied specifically in older adults with FXS. The NMDA antagonist memantine has been used off-label for maladaptive behaviors in FXS.14 One randomized, double-blind, placebo-controlled trial that evaluated the effects of memantine on the cognitive and motor symptoms of FXTAS did not reveal any significant benefit.

 Clearly, more research is needed to identify effective treatments for neurodevelopmental disorders in late life.

The majority of adults with neurodevelopmental disorders are physically, emotionally, and financially dependent on their families throughout their lives; many are cared for at home by unpaid family caregivers. In fragile X families the same individual (who may also be a premutation carrier) may care for young children with FXS and aging parents with FXTAS. Clinicians should be vigilant and assess for caregiver burden at every visit and be familiar with local and national resources that can provide support and respite to families.

Dr Seritan is a Geriatric Psychiatrist in the Department of Psychiatry, University of California, San Francisco, San Francisco, CA. Mr Ligsay is a medical student at the University of California, Davis School of Medicine, Sacramento, CA. Dr Hagerman is Distinguished Professor and Endowed Chair in Fragile X Research in the Department of Pediatrics, University of California, Davis Medical Center, Sacramento, CA and Medical Director of the Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, Sacramento, CA. Dr Seritan and Mr Ligsay report no conflicts of interest concerning the subject matter of this article; Dr Hagerman reports that he has received support from the NIH for genotype-phenotype study in fragile X premutation disorders.

1. Hagerman PJ, Hagerman RJ. Fragile X-associated tremor/ataxia syndrome. 

 Roberts JE, Bailey D, Mankowski J, et al. Mood and anxiety disorders in females with the FMR1 premutation. 

 Bourgeois JA, Seritan AL, Casillas M, et al. Lifetime prevalence of mood and anxiety disorders in fragile X premutation carriers. 

 Coffey SM, Cook K, Tartaglia N, et al. Expanded clinical phenotype of women with the FMR1 premutation. 

 Hagerman RJ, Leehey M, Heinrichs W, et al. Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. 

 Jacquemont S, Hagerman RJ, Leehey MA, et al. Penetrance of the fragile X-associated tremor/ataxia syndrome in a premutation carrier population. 

 Apartis E, Blancher A, Meissner WG, et al. FXTAS: new insights and the need for revised diagnostic criteria. 

 Seritan AL, Nguyen DV, Farias ST, et al. Dementia in fragile X-associated tremor/ataxia syndrome (FXTAS): comparison with Alzheimer disease. 

 Tassone F, Greco CM, Hunsaker MR, et al. Neuropathological, clinical, and molecular pathology in female fragile X premutation carriers with and without FXTAS. 

 Schneider A, Ligsay A, Hagerman RJ. Fragile X syndrome: an aging perspective.

 Richards C, Jones C, Groves L, et al. Prevalence of autism spectrum disorder phenomenology in genetic disorders: a systematic review and meta-analysis.

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 Erickson CA, Mullett JE, McDougle CJ. Open-label memantine in fragile X syndrome. 

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A quick guide to common neurodevelopmental conditions and their associated late-life neuropsychiatric manifestations. 

Author | Randi Hagerman, MD

Articles

Autism Spectrum Disorders, Down Syndrome, and 22q Deletion Syndrome

Aging With Developmental Disabilities, Part 1: Fragile X–Associated Disorders