Clinical scenario

Doctor's perspective: You are a core trainee working in the older adults’ community mental health clinic. A 69-year-old West African woman is referred by her general practitioner (GP) for ‘responding to unseen stimuli’ and ‘increasingly religious thinking’. She has a history of hypertension and severe depression in her 40s. Her GP reported her bloods as unremarkable.

Patient's account: She felt well other than some problems with her memory. She was able to recall more recent day-to-day events, but she relied on her son to recount autobiographical memories of her early life. She emphasised repeatedly that she is a devout follower of God, that the Lord is powerful and that she was being ‘attacked’ by demons and spirits. She spoke about having ‘the gift’ of being able to raise the dead and that her GP had poisoned her blood test.

Collateral: Her son reported that despite being religious (Pentecostal) lifelong, the intense expression of her religious belief was new. This change occurred insidiously over several years and 2 years ago he had asked the GP to alert mental health services. The patient had moved in with her son as she was no longer coping at home. She had incorrectly cut a wire while changing a plug, struggled with using kitchen appliances, limited her dietary repertoire and had started talking to strangers about God. She had also begun ‘speaking in tongues’ and was fixated on trying to print money to donate to those in need.

Diagnosis

Primary progressive aphasias (PPAs) refer to neurodegenerative syndromes where there are early and prominent effects on the domain of language. There are three main presentations, including semantic dementia (Fig. 1).^{Reference Gorno-Tempini, Hillis, Weintraub, Kertesz, Mendez and Cappa2} For semantic dementia the presentation reflects a progressive loss of semantic knowledge or ‘learned knowledge about the world’.

Fig. 1 The subtypes of frontotemporal dementia.

Arnold Pick had described a progressive disorder of language with associated frontotemporal atrophy in the late 19th century; however, it was not until 1975 that Elizabeth Warrington wrote about a selective impairment of semantic memory in three individuals with anomia.^{Reference Landin-Romero, Tan, Hodges and Kumfor3} In the same decade, Tulving had conceptualised memory into semantic and episodic systems^{Reference Tulving4} and then the first cases were described by Snowden et al (1989)^{Reference Snowden, Gouldi and Neary5} and Hodges et al (1992),^{Reference Hodges, Patterson, Oxbury and Funnell6} coining the term ‘semantic dementia’.

Semantic memory encompasses not just our knowledge of words and their meanings, but also learned properties of objects and more abstract conceptual knowledge, including moral and societal rules.^{Reference Kumar7} This understanding underlies our fundamental ability to navigate and interpret the world around us.^{Reference Hodges8}

People with neurodegeneration of the anterior temporal lobe (ATL) demonstrate not only verbal but also non-verbal semantic impairments, which leads to the conclusion that this region represents supramodal semantic knowledge. Building on this, Zahn et al showed, using functional magnetic resonance imaging (fMRI), how the ATL represents abstract social semantic knowledge.^{Reference Zahn, Moll, Krueger, Huey, Garrido and Grafman9}

The differential diagnoses

The clinical assessment of semantic dementia requires differentiation from other neurodegenerative conditions, such as bvFTD and Alzheimer's disease.

• • bvFTD: The Rascovsky criteria outline the six features that carry consensus for the diagnosis.^{Reference Rascovsky and Grossman23} In this case the patient's son described personality and behaviour changes, as well as dietary changes. However, over time, many patients with a language variant of FTD go on to develop behavioural symptoms that typify bvFTD.^{Reference Snowden, Bathgate, Varma, Blackshaw, Gibbons and Neary24} Key point: the focus in history taking should therefore be on the earliest or first presenting features for diagnostic categorisation.^{Reference Rascovsky and Grossman23}

• • Amnestic Alzheimer's disease: Features suggestive of amnestic Alzheimer's disease include episodic memory impairment and anomia. Semantic paraphasia can also feature in moderate Alzheimer's disease. An atypical form of Alzheimer's disease, frontal variant Alzheimer's disease, should also be considered. It involves executive dysfunction with progressive behavioural change, predominating and pre-dating an episodic amnesia.^{Reference Lehingue, Gueniat, Jourdaa, Hardouin, Pallardy and Courtemanche25} The severe semantic memory deficit in this patient made frontal variant Alzheimer's disease unlikely. In true cases of diagnostic uncertainty additional investigations such as cerebrospinal fluid biomarkers or fluorodeoxyglucose positron emission tomography (FDG-PET) may be used to help differentiate, particularly in younger patients.

Neurodegeneration versus a primary psychiatric disorder

Psychosis in older age can be part of a dementia, delirium or schizophrenia-like condition (psychotic depression with pseudodementia requires strong consideration). Although the onset of schizophrenia most commonly occurs in late adolescence or early adult life, there is a variant of non-affective functional psychosis that can occur after age 60 called very late-onset schizophrenia-like psychosis (VLOSLP).^{Reference Howard, Cort, Bradley, Harper, Kelly and Bentham26}

The common characteristics of VLOSLP (which help differentiate from early-onset psychosis) are:

1. (a) persecutory delusions relating to spying or home invasion by neighbours

2. (b) partition delusions (a belief centred on the permeability of a barrier such as wall)

3. (c) visual and tactile hallucinations are more common, whereas formal thought disorder is less common^{Reference Mueller27}

4. (d) importantly, the degree of cognitive impairment is not significantly higher than in those with early-onset psychosis.^{Reference Suen, Wong, Hui, Chan, Lee and Chang28}

Delusions are common in neurodegenerative disorders too; in the largest series of 97 neuropathologically confirmed cases of FTD, 32% had psychotic symptoms, 20.6% had paranoid ideas, 17.5% hallucinated and 17.5% had delusions, with psychotic symptoms present in all pathological subtypes (tau, TDP, FUS).^{Reference Landqvist Waldö, Gustafson, Passant and Englund29} Delusions were most commonly paranoid or persecutory, followed by erotomania.^{Reference Landqvist Waldö, Gustafson, Passant and Englund29,Reference Hall and Finger30}

In Alzheimer's disease approximately 50% of patients experience delusions and around 30% experience hallucinations.^{Reference Hall and Finger30} Studies using the informant-based Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD) have reported that delusions of theft, abandonment and one's house not being one's home are often seen in Alzheimer's disease.^{Reference Reisberg, Monteiro, Torossian, Auer, Shulman and Ghimire31}

In Lewy body dementia (LBD) a spectrum of psychosis exists, where delusions, illusions and hallucinations become more elaborate and pronounced as cognitive impairment and insight worsen.^{Reference Ffytche, Creese, Politis, Chaudhuri, Weintraub and Ballard32} Delusions in LBD are more common than in Alzheimer's disease and tend to exist alongside visual misperceptions. Common delusions include Capgras phenomenon (believing a familiar person is an imposter), Othello delusion (believing that a spouse or partner is unfaithful), reduplicative phenomena (recognising a familiar environment as looking the same, but being an imitation/copy) or reference from the television.^{Reference Onofrj, Bonanni, Manzoli and Thomas33}

Further tests and investigations

Neuroimaging displaying marked anterior temporal lobe (ATL) atrophy can be a diagnostic keystone and pathognomic,^{Reference Hodges and Patterson34} as the molecular pathology is highly conserved in the presence of this imaging finding. Within the ATL there is a predilection for superior temporal gyrus atrophy and in 30% of cases right lateralised ATL atrophy occurs.^{Reference Gorno-Tempini, Hillis, Weintraub, Kertesz, Mendez and Cappa2,Reference Kumfor, Landin-Romero, Devenney, Hutchings, Grasso and Hodges18} Right hemispheric cortical involvement becomes more pronounced with disease progression if it is not apparent from the onset.

This patient's MRI (Fig. 2) showed a focal right ATL atrophy without disproportional hippocampal atrophy. Where there is diagnostic uncertainty, NICE also recommend the use of FDG-PET and perfusion SPECT.³⁵

Fig. 2 T₂-weighted axial image displaying the left-side anterior temporal atrophy.

In semantic dementia there is a strong clinicopathological concordance and genetic testing is not as relevant as in other FTD syndromes. Unlike other forms of FTD, semantic dementia is often sporadic and non-familial, and potentially due to post-zygotic (after fertilisation) or late-somatic variants during brain development.^{Reference Coyle-Gilchrist, Dick, Patterson, Rodríquez, Wehmann and Wilcox36}

Management

Currently there are no disease-modifying treatments for any of the FTD disorders, although there are trials underway investigating treatments for genetic forms of FTD. The Genetic Frontotemporal Dementia Initiative (GENFI) is a group of research centres across Europe and Canada investigating genetic forms of FTD, focusing on mutations in the GRN, microtubule-associated protein tau (MAPT) and C9orf72 genes. They are currently in their third phase, aiming to prepare GENFI participants for therapeutic trials with pharmaceutical companies.³⁷

At present, management revolves around caregiver education, environmental modification and working with speech and language therapy to optimise communication through aids. Two commonly encountered issues are:

• • pharmacological management of neuropsychiatric symptoms

• • availability of non-pharmacological interventions and specialist therapeutic input.

Hyperreligiosity in dementia

Hyperreligious patients require a holistic approach, considering both cultural and neuropsychiatric factors. The literature differentiates between an intensification of religious beliefs and ecstatic experience. The former is more commonly seen in FTD (predominantly affecting the temporal lobes) than in Alzheimer's disease or DLB.^{Reference Block and Miller49,Reference Coles50} One's sense of self is also important, influenced by: semantic information (knowledge about one's personal attributes), autobiographical memories (often affect laden) and will (motivation to maintain one's prior beliefs).^{Reference Block and Miller51} Furthermore, alteration in the integrity of self versus other in the right cultural context is thought to manifest as hyperreligiosity or a transcendent meditative experience.^{Reference Previc52}

These attributes have strong frontotemporal correlates, particularly with the prefrontal regions.^{Reference Northoff, Heinzel, de Greck, Bermpohl, Dobrowolny and Panksepp53} There may be a role played by overactive ventromedial dopaminergic systems, resulting in the transfer of attention and goal-directed behaviour to extra-personal space.^{Reference Previc52} Given that some people with FTD show an obsessional interest in traditionally rewarding stimuli such as sweet food or even music (musicophilia), FTD can be thought of as a disease that alters reward sensitivity and therefore reward-seeking behaviours.^{Reference Perry, Sturm, Seeley, Miller, Kramer and Rosen54,Reference Fletcher, Clark and Warren55} In addition, the more common behaviours in FTD, namely impulsivity, delusions and mental rigidity, may serve to reinforce the hyperreligiosity and worship behaviour.

About the authors

Richard H. Cole is a Clinical Research Fellow and PhD student at the Institute of Psychiatry, Psychology & Neuroscience, King's College London, UK and has completed core training with Camden and Islington NHS Foundation Trust, London, UK. Camilla N. Clark is an NIHR clinical lecturer in the Institute of Molecular & Clinical Sciences, St George's University of London, London, UK. Norman A. Poole is a consultant neuropsychiatrist at in the Department of Neuropsychiatry at St George's Hospital, South West London and St George's Mental Health NHS Trust, London, UK.