How Early Does Anosognosia Begin in Huntington's Disease?

Abstract

Background

Individuals with Huntington's disease (HD) commonly experience anosognosia, a lack of awareness of disease‐specific deficits. However, how early anosognosia begins in the course of HD remains unclear.

Objective

To characterize the onset of anosognosia in HD by exploring its presence/absence at various stages of disease.

Methods

The Anosognosia Scale was given to 60 gene carriers (stratified by the HD Integrated Staging System (HD‐ISS), Total Functional Capacity (TFC), CAG‐Age‐Product (CAP), and composite UHDRS (cUHDRS) score) as well as their study partners. Differences between informant and patient scores of ≥6 points were considered evidence of anosognosia.

Results

18% of participants in HD‐ISS stage 0/1, 22% with TFC = 13, 37% who would be eligible for clinical trials (CAP score 400–500), and 23% with a cUHDRS ≥14 displayed anosognosia.

Conclusions

We conclude that anosognosia appears early in HD. This lack of awareness should dissuade against over‐reliance on self‐report instruments in HD clinical research.

Huntington's disease (HD) is a genetic neurodegenerative disorder characterized by an expanded CAG trinucleotide repeat in the gene encoding the Huntingtin protein. ¹ People with the HD gene mutation typically begin to show cognitive, motor, and psychiatric symptoms in the 4th or 5th decades. ² Anosognosia, the lack of awareness of one's disease‐specific deficits, is common among patients with HD. Individuals with anosognosia often underestimate their degree of impairment. ³ , ⁴ , ⁵ , ⁶ This discrepancy has been captured in a publication from our laboratory ⁷ that compared a patient's self‐evaluation to that of their caregiver, using the Anosognosia Scale (AS). ³ This scale assesses a patient's ability, compared to peers of the same age and education, on eight items, comprising cognition, motor function, and emotional regulation. ³ Large differences between the patient and informant (a companion in our case, but a clinician in the original study by Deckel and Morrison ³ ) are considered evidence of anosognosia. While anosognosia has been well defined in HD, ³ , ⁴ , ⁵ , ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ , ¹² how early it begins in the course of disease is less clear.

Furthermore, disease progression and/or burden can be captured in multiple ways, including the HD Integrated Staging System (HD‐ISS), the Total Functional Capacity (TFC) of the Unified Huntington Disease Rating Scale (UHDRS), the CAG‐Age‐Product (CAP), and the composite UHDRS (cUHDRS). The HD‐ISS is used in cross‐sectional clinical research to objectively categorize participants into stages 0–3. Individuals in HD‐ISS Stage 0 have just the gene expansion, while Stage 1 is characterized by globus pallidus atrophy. Stage 2 is defined by cognitive and/or motoric decline, and Stage 3 denotes functional impairment. ¹³ HD progression can also be stratified using the TFC—a functional assessment from the UHDRS. TFC scores range from 0 to 13, with a score of 13 indicating full functional ability and lower scores reflecting increasing impairment. ¹⁴ The CAP score, an estimate of cumulative disease exposure or burden, is the product of an individual's CAG repeat number and age. ¹⁵ Clinical trials sometimes employ CAP scores as inclusion criteria. A recent HD trial only enrolled participants with CAP scores of 400–500, suggesting that a CAP score < 400 was too early in the course of disease for participation. ¹⁶ Finally, the cUHDRS is a composite score calculated from a patients’ TFC, UHDRS Total Motor Score (TMS), Symbol Digit Modalities Test (SDMT) score, and Stroop Word Reading (SWR) score, in which lower scores indicate greater disease burden. ¹⁷ The cUHDRS has been shown to be a good measure of clinical progression ¹⁷ and is a commonly used outcome measure in HD clinical trials. ¹⁸ , ¹⁹ , ²⁰ Trundell et al demonstrated that individuals with a cUHDRS ≥14 were generally high functioning and likely early in the course of their disease. ²¹

Many clinicians wrongly assume that anosognosia doesn’t occur until patients are fairly progressed, and that early self‐report assessments are therefore valid. Consequently, determining how early anosognosia appears is essential to appreciating the need for collateral information to ensure data accuracy. In the current study, we sought to identify the presence of anosognosia in HD, utilizing the most common measures of disease progression/burden—the HD‐ISS, TFC, CAP score, and cUHDRS.

Methods

This study was approved by the University of California, San Diego (UCSD) Institutional Review Board (IRB) Committee (IRB Protocol #170038), in accordance with the requirements of the Code of Federal Regulations on the Protection of Human Subjects.

Sixty HD gene carriers were recruited from the UCSD Huntington's Disease Society of America Center of Excellence. Inclusion criteria comprised age ≥ 18, a confirmed CAG repeat length ≥ 40, and willingness of an informant to participate. Subjects were administered a clinical battery including the SDMT, SWR task, Mini Mental State Exam (MMSE), Montreal Cognitive Assessment (MoCA), UHDRS TMS, UHDRS TFC, Problem Behaviors Assessment‐short form (PBA‐s), and the AS: Subject Form. TFC and PBA‐s ratings were confirmed with informants. Companions for each patient rated the patient using the AS: Companion Form. This measure is scored on a 5‐point Likert scale, ranging from impaired (−2) to excellent (2). Difference scores (DS) were calculated by subtracting the total score (TS) rating by the companion from the patient's self‐rating (patient TS—companion TS). As defined by Deckel and Morrison, ³ a DS ≥6 indicates that a patient underestimated their deficits.

Patients were stratified by HD‐ISS stage (imputed from their Prognostic Index (PIN) Score ²² , ²³ ), TFC, CAP, and cUHDRS score. As suggested by Long et al, ²³ HD‐ISS stages 0 and 1 were combined to account for the absence of volumetric imaging information.

Lastly, the percentage of subjects who underestimated their deficits (DS ≥6) implying anosognosia, were appropriately aware of their insufficiencies (−6 < DS <6), and overestimated their difficulties (DS ≤6) were calculated for each cohort. These calculations were used to demonstrate the proportion of patients exhibiting anosognosia at various stages of disease progression.

Results

Participant Characteristics

Table 1 shows the demographics and clinical characteristics, as stratified by HD‐ISS stage, TFC, CAP score, and cUHDRS.

TABLE 1.

Demographics and clinical characteristics (mean, SD) stratified by disease progression/ burden scores

Demographics and Clinical Characteristics (Mean, SD)
	Age, years	Edu, years	CAG	TMS	MMSE	MoCA	PBA
HD‐ISS Stage 0/1 (N = 11)	47.09, 14.35	17.27, 2.28	41.55, 1.29	2.00, 2.53	27.55, 2.34	25.55, 3.96	7.45, 11.17
HD‐ISS Stage 2 (N = 18)	50.72, 11.25	15.55, 2.36	43.00, 2.89	17.94, 8.96	27.28, 2.16	25.94, 2.71	9.11, 8.12
HD‐ISS Stage 3 (N = 31)	54.32, 11.89	14.84, 2.83	44.38, 2.94	39.16, 14.07	23.42, 3.74	20.00, 4.73	7.74, 7.85
TFC = 13 (N = 18)	49.00, 14.28	16.83, 1.92	42.83, 3.15	7.61, 8.94	27.83, 2.20	26.17, 3.57	4.78, 5.91
TFC = 10–12 (N = 19)	54.50, 12.97	15.44, 2.79	42.39, 2.06	23.83, 10.99	25.89, 2.35	24.11, 2.35	10.67, 9.9
TFC ≤9 (N = 23)	52.17, 10.28	14.54, 2.84	44.71, 2.82	41.38, 14.72	23.04, 4.01	19.26, 5.19	8.67, 8.41
CAP ≤ 400 (N = 12)	43.17, 11.89	16.25, 2.90	41.92, 1.38	13.00, 15.96	27.42, 1.62	26.00, 2.37	11.83, 10.41
CAP 400 ≤ x ≤ 500 (N = 19)	55.47, 8.67	15.79, 2.62	41.89, 1.29	16.94, 11.36	26.21, 3.60	24.74, 3.60	4.84, 5.67
CAP ≥ 500 (N = 29)	53.21, 13.25	15.00, 2.70	45.10, 3.19	37.28, 16.74	23.90, 3.78	20.21, 5.27	8.69, 8.65
cUDHRS ≥ 14 (N = 22)	49.14, 13.48	16.95, 1.79	42.41, 2.68	9.55, 10.81	27.91, 1.90	26.41, 3.22	7.68, 9.32
cUHDRS 8 ≤ x ≤ 14 (N = 25)	54.12, 12.02	14.92, 2.84	43.48, 2.87	27.36, 9.37	24.92, 2.50	22.20, 2.84	7.92, 7.38
cUHDRS ≤8 (N = 13)	52.38, 11.00	14.15, 2.82	45.15, 2.54	51.15, 11.01	21.77, 4.55	17.67, 6.05	9.15, 9.56

Abbreviations: CAP, CAG‐Age‐Product; cUHDRS, composite Unified Huntington's Disease Rating Scale; Edu, Education; HD‐ISS, Huntington's Disease‐Integrated Staging System; MMSE, Mini Mental State Exam; MoCA, Montreal Cognitive Assessment; PBA‐s, Problem Behaviors Assessmen—short form; TFC, Total Functional Capacity; TMS, Total Motor Score; Years, years.

Proportion of Participants Exhibiting Anosognosia

Table 2 shows the percentage of individuals within each disease progression/burden cohort that exhibited anosognosia (DS ≥6), were appropriately aware of their insufficiencies (−6 < DS <6), and overestimated their difficulties (DS ≤6).

TABLE 2.

Distribution of Difference Scores (DS) stratified by disease progression/burden scores

Distribution of DS Across the HD Spectrum
	Difference Score (DS)
	Patient overestimates Abilities:Anosognosia	No considerable difference	Patient underestimates abilities
	≥ 6	5 ‐ (−5)	≤−6
HD‐ISS Stage 0/1 (N = 11)	18%	45%	36%
HD‐ISS Stage 2 (N = 18)	28%	61%	11%
HD‐ISS Stage 3 (N = 31)	32%	61%	7%
TFC = 13 (N = 18)	22%	56%	22%
TFC = 10–12 (N = 19)	28%	56%	16%
TFC ≤9 (N = 23)	31%	65%	4%
CAP ≤ 400 (N = 12)	8%	58%	33%
CAP 400 ≤ x ≤ 500 (N = 19)	37%	58%	5%
CAP ≥ 500 (N = 29)	31%	59%	10%
cUDHRS ≥ 14 (N = 22)	23%	50%	27%
cUHDRS 8 ≤ x ≤ 14 (N = 25)	24%	72%	4%
cUHDRS ≤8 (N = 13)	46%	46%	8%

Abbreviations: CAP, CAG‐Age‐Product; cUHDRS, composite Unified Huntington's Disease Rating Scale; HD‐ISS, Huntington's Disease‐Integrated Staging System; TFC, Total Functional Capacity.

Anosognosia was seen in 18% of HD‐ISS stage 0/1 (with no observable symptoms), 28% of Stage 2, and 32% of Stage 3 participants. Additionally, 36% of individuals in Stage 0/1 overestimated their difficulties, perhaps related to hypervigilance or anxiety.

When stratified by TFC, 22% of participants with no functional loss (TFC = 13); 28% with a TFC 10–12; and 31% with a TFC ≤9 exhibited anosognosia. Conversely, 22% of individuals with a TFC of 13 overestimated their symptoms.

When examining DS by CAP cohort, 8% of participants with a CAP score ≤ 400, 37% with a CAP score 400–500, and 31% with a CAP score ≥ 500 exhibited anosognosia. In addition, 33% of individuals with a CAP score of less than 400 overestimated their symptoms.

Finally, 23% of participants with a cUHDRS score of ≥14; 24% with a cUHDRS score 8–14; and 46% with a cUHDRS score ≤8 exhibited anosognosia. 27% of subjects with a cUHDRS score ≥ 14 overestimated their difficulties.

Discussion

In this cross‐sectional study, we found that anosognosia is present throughout the course of HD; even in the earliest stages of disease. This is apparent by the sizable percentage of individuals with an HD‐ISS Stage of 0/1 (18%), TFC = 13 (22%), CAP≤400 (8%), and cUHDRS≥14 (23%) who exhibited anosognosia. In fact, whether stage of disease is captured by HD‐ISS, TFC, CAP, or cUHDRS, it appears that anosognosia begins early and is present to a substantial degree throughout the course of HD.

Anosognosia has been well documented in HD for motoric, cognitive, and psychiatric symptoms. ⁸ , ⁹ , ¹⁰ To our knowledge, no previous study has examined anosognosia in HD using HD‐ISS, TFC, CAP, or cUHDRS stratification to quantify disease burden/progression. When looking across the HD‐ISS spectrum, anosognosia begins in the earliest stage (18% in HD‐ISS Stage 0/1) and increases with each subsequent stage (28% in Stage 2 and 32% in Stage 3). A previous study from Hinkle et al ¹¹ found significant correlations between anosognosia and reduced globus pallidus volumes. Given that globus pallidus atrophy is a defining criterion for HD‐ISS Stage 1, ¹³ these findings are consistent with our observation of anosognosia in Stage 0/1 subjects. Interestingly, these authors also found that structural changes such as globus pallidus atrophy explained more of the variance in anosognosia than TFC or CAP scores, and may constitute the substrate of unawareness in HD.

The UHDRS TFC appraises a patient's functional ability regarding occupation, finances, domestic chores, activities of daily living, and care level. ¹⁴ Like HD‐ISS staging, anosognosia is present in participants with intact functioning (22% of TFC = 13) and increases as function declines. Therefore, even participants with a perfect TFC score may not be aware of their symptoms and would not report them accurately.

Similarly, we evaluated a common clinical trial inclusion criteria, the CAP score. A recent clinical trial targeted prodromal or early manifest HD by requiring all participants to have a CAP score between 400 and 500. ¹⁶ We found that almost 10% of individuals who were too early (CAP score < 400) in the course of their HD to qualify for such a clinical trial, and over 1/3 of those who were eligible, demonstrated anosognosia.

Finally, the cUHDRS is a composite score that represents a patient's cognitive, motoric, and functional abilities, ¹⁷ and is a prominent outcome measure in HD clinical trials. ¹⁸ , ¹⁹ , ²⁰ Slightly under a quarter of individuals with the highest cUHDRS score (≥ 14), 23% of individuals with a moderate cUHDRS (8 ≤ x < 14), and almost half of patients with a low cUHDRS score (≤8) underestimated their deficits.

Taken together, our findings indicate that patient reports may not be a reliable reflection of an individual's symptoms and presentation, regardless of disease stage. Previous studies have shown that companion, as opposed to patient, ratings are better correlated with objective performance measures. ⁷ , ¹² This lack of awareness of cognitive, motoric, and functional abilities within all stages of disease is important to acknowledge, as many clinical trials use Patient Reported Outcomes (PROs) as endpoints. ²⁴ , ²⁵ Participants in such studies with anosognosia may not be reliable reporters, thereby compromising the accuracy of various study‐related outcomes. Investigators should strongly consider involving a collateral source informant to provide a more accurate reflection of a participant's abilities regardless of where the participant is in the course of their disease.

Limitations of this study include the modest sample sizes for milder participants as defined by the various staging systems. In large part, this was due to their lack of study partners. In addition, we were unable to examine the symptom domains (cognitive, functional, psychiatric) in which anosognosia was present or whether these domains evolved over time. Future studies should explore this.

To our knowledge, this is the first study to examine how early anosognosia begins in HD, and its presence across the disease spectrum. Taken together, our findings suggest that anosognosia is seen in all phases of disease, even early in its course, prior to manifest disease onset. Researchers should ensure the availability of collateral information and exercise caution in relying solely on self‐report instruments in HD clinical research.

Author Roles

(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.

K.B.: 1A, 1B, 1C, 2A, 2B, 2C, 3A

A.X.: 1B, 1C, 2B, 2C, 3B

A.H.: 1B, 1C, 3B

J.K.:1C, 2C, 3B

P.G.: 1A, 2C, 3B

J.C.B.: 1A, 1B, 2A, 2C, 3A, 3B

Disclosures

Ethical Compliance Statement: Institutional review board approval was obtained from the Institutional review board of the University of California, San Diego (Protocol no. #170038). Written informed consent was obtained from all participants before participation. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflicts of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.

Financial Disclosures for the Previous 12 Months: The authors declare that there are no financial disclosures related to this manuscript for the previous 12 months.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.